65 results on '"Wellman CL"'
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2. Maternal antibiotics disrupt microbiome, behavior, and temperature regulation in unexposed infant mice.
- Author
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Harshaw C, Kojima S, Wellman CL, Demas GE, Morrow AL, Taft DH, Kenkel WM, Leffel JK, and Alberts JR
- Subjects
- Animals, Animals, Newborn, Anti-Bacterial Agents pharmacology, Female, Humans, Maternal Behavior, Maternal Deprivation, Mice, Mice, Inbred C57BL, Temperature, Autism Spectrum Disorder chemically induced, Microbiota, Prenatal Exposure Delayed Effects
- Abstract
Maternal antibiotic (ABx) exposure can significantly perturb the transfer of microbiota from mother to offspring, resulting in dysbiosis of potential relevance to neurodevelopmental disorders such as autism spectrum disorder (ASD). Studies in rodent models have found long-term neurobehavioral effects in offspring of ABx-treated dams, but ASD-relevant behavior during the early preweaning period has thus far been neglected. Here, we exposed C57BL/6J mouse dams to ABx (5 mg/ml neomycin, 1.25 μg/ml pimaricin, .075% v/v acetic acid) dissolved in drinking water from gestational day 12 through offspring postnatal day 14. A number of ASD-relevant behaviors were assayed in offspring, including ultrasonic vocalization (USV) production during maternal separation, group huddling in response to cold challenge, and olfactory-guided home orientation. In addition, we obtained measures of thermoregulatory competence in pups during and following behavioral testing. We found a number of behavioral differences in offspring of ABx-treated dams (e.g., modulation of USVs by pup weight, activity while huddling) and provide evidence that some of these behavioral effects can be related to thermoregulatory deficiencies, particularly at younger ages. Our results suggest not only that ABx can disrupt microbiomes, thermoregulation, and behavior, but that metabolic effects may confound the interpretation of behavioral differences observed after early-life ABx exposure., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
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3. Maternal stress and the maternal microbiome have sex-specific effects on offspring development and aggressive behavior in Siberian hamsters (Phodopus sungorus).
- Author
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Cusick JA, Wellman CL, and Demas GE
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- Aggression physiology, Animals, Anti-Bacterial Agents, Cricetinae, Female, Male, Pregnancy, Social Behavior, Microbiota, Phodopus physiology
- Abstract
The gut microbiome, a community of commensal, symbiotic and pathogenic bacteria, fungi, and viruses, interacts with many physiological systems to affect behavior. Prenatal experiences, including exposure to maternal stress and different maternal microbiomes, are important sources of organismal variation that can affect offspring development. These physiological systems do not act in isolation and can have long-term effects on offspring development and behavior. Here we investigated the interactive effects of maternal stress and manipulations of the maternal microbiome on offspring development and social behavior using Siberian hamsters, Phodopus sungorus. We exposed pregnant females to either a social stressor, antibiotics, both the social stressor and antibiotics, or no treatment (i.e., control) over the duration of their pregnancy and quantified male and female offspring growth, gut microbiome composition and diversity, stress-induced cortisol concentrations, and social behavior. Maternal antibiotic exposure altered the gut microbial communities of male and female offspring. Maternal treatment also had sex-specific effects on aspects of offspring development and aggressive behavior. Female offspring produced by stressed mothers were more aggressive than other female offspring. Female, but not male, offspring produced by mothers exposed to the combined treatment displayed low levels of aggression, suggesting that alteration of the maternal microbiome attenuated the effects of prenatal stress in a sex-specific manner. Maternal treatment did not affect non-aggressive behavior in offspring. Collectively, our study offers insight into how maternal systems can interact to affect offspring in sex-specific ways and highlights the important role of the maternal microbiome in mediating offspring development and behavior., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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4. Impaired cognitive flexibility and heightened urgency are associated with increased alcohol consumption in rodent models of excessive drinking.
- Author
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De Falco E, White SM, Morningstar MD, Ma B, Nkurunziza LT, Ahmed-Dilibe A, Wellman CL, and Lapish CC
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- Animals, Attention, Ethanol pharmacology, Rats, Rats, Wistar, Rodentia, Alcohol Drinking psychology, Alcoholism psychology, Cognition
- Abstract
Alcohol use disorder (AUD) is characterized by impairments in decision-making that can exist as stable traits or transient states. Cognitive inflexibility reflects an inability to update information that guides decision-making and is thought to contribute to the inability to abstain from drinking. While several studies have reported evidence of impaired cognitive flexibility following chronic alcohol exposure, evidence that a pre-existing impairment in cognitive flexibility is a heritable risk factor for AUD is scarce. Here, we found that cognitive flexibility was impaired in rodents selectively bred for excessive alcohol consumption (alcohol preferring (P) rats), on the attentional set-shifting task (ASST). Further, the degree of impairment is predictive of future ethanol consumption, thus suggesting that cognitive inflexibility is a stable trait capable of predisposing one for drinking. In a second set of experiments, we observed an impairment in the ability of P rats to use a previously learned rule to guide foraging in a simple discrimination task. Convergence across several behavioral measures suggested that this impairment reflected a state of heightened urgency that interfered with decision-making. A similar impairment on a simple discrimination task was observed in Wistar rats with a history of alcohol consumption. These findings indicate how trait and state variables-in this case, impaired cognitive flexibility and heightened urgency, respectively-may influence the risk for excessive drinking. Furthermore, our results suggest that cognitive inflexibility and urgency can exist as both risk factors for and the result of alcohol exposure., (© 2021 Society for the Study of Addiction.)
- Published
- 2021
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5. The ontogeny of personality: Repeatability of social and escape behaviors across developmental stages in Siberian hamsters (Phodopus sungorus).
- Author
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Adaniya CH, Wellman CL, Demas GE, and Cusick JA
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- Animals, Female, Male, Reproducibility of Results, Aging physiology, Behavior, Animal physiology, Escape Reaction physiology, Phodopus growth & development, Social Behavior
- Abstract
Animal personality is defined as behavioral tendencies that are consistent across time and contexts within an individual, but differ across individuals. Studies investigating personality typically examine individuals across short time periods or within a single life stage. Growing evidence suggests that personality may be less stable across life stages, highlighting the need to consider the effects of ontogeny on the expression of consistent behavioral traits. We investigated individual consistency in social and escape behaviors across developmental stages using Siberian hamsters (Phodopus sungorus). To determine whether individuals were consistent in these behaviors as juveniles and across developmental stages, we measured male and female social and escape behaviors twice as juveniles and once as adults. Individuals' social scores were significantly repeatable within the juvenile stage, but not across developmental stages. In contrast, escape scores were highly repeatable across developmental stages, with males' scores being more repeatable than females' scores. Our results support previous findings that personality traits, especially those associated with social behavior, are less stable across development, whereas behaviors associated with stress or coping may represent a more permanent feature of an individual's phenotype. Our results also indicate potential sex differences in long-term repeatability of personality. Considering how ontogeny affects animal personality for males and females can provide insight into the evolution and mechanisms that maintain animal personality., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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6. The call of the wild: using non-model systems to investigate microbiome-behaviour relationships.
- Author
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Cusick JA, Wellman CL, and Demas GE
- Subjects
- Animals, Gastrointestinal Tract, Immune System, Social Behavior, Gastrointestinal Microbiome, Microbiota
- Abstract
On and within most sites across an animal's body live complex communities of microorganisms. These microorganisms perform a variety of important functions for their hosts, including communicating with the brain, immune system and endocrine axes to mediate physiological processes and affect individual behaviour. Microbiome research has primarily focused on the functions of the microbiome within the gastrointestinal tract (gut microbiome) using biomedically relevant laboratory species (i.e. model organisms). These studies have identified important connections between the gut microbiome and host immune, neuroendocrine and nervous systems, as well as how these connections, in turn, influence host behaviour and health. Recently, the field has expanded beyond traditional model systems as it has become apparent that the microbiome can drive differences in behaviour and diet, play a fundamental role in host fitness and influence community-scale dynamics in wild populations. In this Review, we highlight the value of conducting hypothesis-driven research in non-model organisms and the benefits of a comparative approach that assesses patterns across different species or taxa. Using social behaviour as an intellectual framework, we review the bidirectional relationship between the gut microbiome and host behaviour, and identify understudied mechanisms by which these effects may be mediated., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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7. Prior stress followed by a novel stress challenge results in sex-specific deficits in behavioral flexibility and changes in gene expression in rat medial prefrontal cortex.
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Moench KM, Breach MR, and Wellman CL
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- Adaptation, Physiological genetics, Animals, Attention drug effects, Female, Gene Expression physiology, Male, Rats, Rats, Sprague-Dawley, Restraint, Physical psychology, Sex Characteristics, Stress, Psychological metabolism, Synaptic Transmission physiology, Adaptation, Physiological physiology, Behavior, Animal physiology, Prefrontal Cortex metabolism, Repetition Priming physiology, Stress, Psychological genetics
- Abstract
Chronic stress leads to sex-specific changes in the structure and function of rat medial prefrontal cortex (mPFC). Little is known about whether these effects persist following the cessation of chronic stress, or how these initial effects may impact responses to future stressors. Here we examined attentional set-shifting in male and female rats following chronic restraint stress, a post-chronic stress rest period, and an acute novel stress challenge. Chronic stress resulted in a reversible impairment in extradimensional set-shifting in males, but had no effect on attentional set-shifting in females. Surprisingly, chronically stressed female, but not male, rats had impaired extradimensional set-shifting following a novel stress challenge. Alterations in the balance of excitation and inhibition of mPFC have been implicated in behavioral deficits following chronic stress. Thus, in a separate group of rats, we examined changes in the expression of genes related to glutamatergic (NR1, NR2A, NR2B, GluR1) and GABAergic (Gad67, parvalbumin, somatostatin) neurotransmission in mPFC after acute and chronic stress, rest, and their combination. Stress significantly altered the expression of NR1, GluR1, Gad67, and parvalbumin. Notably, the pattern of stress effects on NR1, Gad67, and parvalbumin expression differed between males and females. In males, these genes were upregulated following the post-chronic stress rest period, while minimal changes were found in females. In contrast, both males and females had greater GluR1 expression following a rest period. These findings suggest that chronic stress leads to sex-specific stress adaptation mechanisms that may contribute to sex differences in response to subsequent stress exposure., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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8. Effects of stress on the structure and function of the medial prefrontal cortex: Insights from animal models.
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Wellman CL, Bollinger JL, and Moench KM
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- Animals, Behavior, Animal physiology, Prefrontal Cortex pathology, Prefrontal Cortex physiopathology, Sex Characteristics, Stress, Psychological physiopathology
- Abstract
Stress alters both cognitive and emotional function, and increases risk for a variety of psychological disorders, such as depression and posttraumatic stress disorder. The prefrontal cortex is critical for executive function and emotion regulation, is a target for stress hormones, and is implicated in many stress-influenced psychological disorders. Therefore, understanding how stress-induced changes in the structure and function of the prefrontal cortex are related to stress-induced changes in behavior may elucidate some of the mechanisms contributing to stress-sensitive disorders. This review focuses on data from rodent models to describe the effects of chronic stress on behaviors mediated by the medial prefrontal cortex, the effects of chronic stress on the morphology and physiology of the medial prefrontal cortex, mechanisms that may mediate these effects, and evidence for sex differences in the effects of stress on the prefrontal cortex. Understanding how stress influences prefrontal cortex and behaviors mediated by it, as well as sex differences in this effect, will elucidate potential avenues for novel interventions for stress-sensitive disorders characterized by deficits in executive function and emotion regulation., Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interest., (© 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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9. Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT 2A receptor activation.
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Godar SC, Mosher LJ, Scheggi S, Devoto P, Moench KM, Strathman HJ, Jones CM, Frau R, Melis M, Gambarana C, Wilkinson B, DeMontis MG, Fowler SC, Coba MP, Wellman CL, Shih JC, and Bortolato M
- Subjects
- Age Factors, Animals, Animals, Newborn, Antisocial Personality Disorder psychology, Dose-Response Relationship, Drug, Female, Locomotion drug effects, Locomotion physiology, Male, Mice, Mice, Transgenic, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Rats, Serotonin 5-HT2 Receptor Antagonists pharmacology, Stress, Psychological psychology, Antisocial Personality Disorder metabolism, Gene-Environment Interaction, Maternal Deprivation, Receptor, Serotonin, 5-HT2A metabolism, Stress, Psychological metabolism
- Abstract
The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 - but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB - and a significant and selective up-regulation of serotonin 5-HT
2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT2 receptor antagonist ketanserin (1-3 mg kg-1 , IP), as well as the selective 5-HT2A receptor blocker MDL-100,907 (volinanserin, 0.1-0.3 mg kg-1 , IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT2A receptor activation as a key mechanism for the ontogeny of this condition. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'., (Copyright © 2019. Published by Elsevier Ltd.)- Published
- 2019
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10. Social instability in adolescence differentially alters dendritic morphology in the medial prefrontal cortex and its response to stress in adult male and female rats.
- Author
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Breach MR, Moench KM, and Wellman CL
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- Animals, Dendrites physiology, Female, Hypothalamo-Hypophyseal System physiology, Male, Pituitary-Adrenal System pathology, Pituitary-Adrenal System physiopathology, Prefrontal Cortex pathology, Pyramidal Cells pathology, Rats, Sprague-Dawley, Stress, Psychological physiopathology, Dendrites pathology, Hypothalamo-Hypophyseal System physiopathology, Prefrontal Cortex physiopathology, Stress, Physiological physiology
- Abstract
Adolescence is an important period for HPA axis development and synapse maturation and reorganization in the prefrontal cortex (PFC). Thus, stress during adolescence could alter stress-sensitive brain regions such as the PFC and may alter the impact of future stressors on these brain regions. Given that women are more susceptible to many stress-linked psychological disorders in which dysfunction of PFC is implicated, and that this increased vulnerability emerges in adolescence, stress during this time could have sex-dependent effects. Therefore, we investigated the effects of adolescent social instability stress (SIS) on dendritic morphology of Golgi-stained pyramidal cells in the medial PFC of adult male and female rats. We then examined dendritic reorganization following chronic restraint stress (CRS) with and without a rest period in adult rats that had been stressed in adolescence. Adolescent SIS conferred long-term alterations in prelimbic of males and females, whereby females show reduced apical length and basilar thin spine density and males show reduced basilar length. CRS in adulthood failed to produce immediate dendritic remodeling in SIS rats. However, CRS followed by a rest period reduced apical dendritic length and increases mushroom spine density in adolescently stressed adult males. Conversely, CRS followed by rest produced apical outgrowth and decreased mushroom spine density in adolescently stressed adult females. These results suggest that stress during adolescence alters development of the PFC and modulates stress-induced dendritic changes in adulthood., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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11. Gonadal hormones differentially regulate sex-specific stress effects on glia in the medial prefrontal cortex.
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Bollinger JL, Salinas I, Fender E, Sengelaub DR, and Wellman CL
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- Animals, Astrocytes drug effects, Astrocytes physiology, Female, Male, Neuroglia physiology, Neuronal Plasticity drug effects, Neurons drug effects, Neurons physiology, Prefrontal Cortex cytology, Rats, Rats, Sprague-Dawley, Sex Characteristics, Stress, Psychological pathology, Stress, Psychological physiopathology, Gonadal Hormones pharmacology, Neuroglia drug effects, Prefrontal Cortex drug effects, Stress, Psychological psychology
- Abstract
Women are more susceptible to various stress-linked psychopathologies, including depression. Dysfunction of the medial prefrontal cortex (mPFC) has been implicated in depression, and studies indicate sex differences in stress effects on mPFC structure and function. For example, chronic stress induces dendritic atrophy in the mPFC in male rats, yet dendritic growth in females. Recent findings suggest glial pathways toward depression. Glia are highly responsive to neuronal activity and function as critical regulators of synaptic plasticity. Preclinical models demonstrate stress-induced microglial activation in mPFC in males, yet deactivation in females. By contrast, stress reduces astrocyte complexity in mPFC in male rats, whereas the effects in females are unknown. Glia possess receptors for most gonadal hormones and gonadal hormones are known to modulate neuronal activity. Thus, gonadal hormones represent a potential mechanism underlying sex differences in glia, as well as divergent stress effects. Therefore, we examined the role of gonadal hormones in sex-specific stress effects on neuronal activity (ie FosB/ ΔFosB induction) and glia in the mPFC. The findings obtained indicate greater microglial activation in mPFC in females and a greater astrocyte area in males. Basal astrocyte morphology is modulated by androgens, whereas androgens or oestrogens dampen the microglial state in males. Astrocyte morphology is associated with neuronal activity in both sexes, regardless of hormonal condition. Chronic stress induced astrocytic atrophy in males, yet hypertrophy in females, with gonadal hormones partly regulating this difference. Stress effects on microglia are oestradiol-dependent in females. Taken together, these data suggest sex-specific, gonadal hormone-dependent stress effects on astrocytes and microglia in the mPFC., (© 2019 British Society for Neuroendocrinology.)
- Published
- 2019
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12. Chronic stress produces enduring sex- and region-specific alterations in novel stress-induced c-Fos expression.
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Moench KM, Breach MR, and Wellman CL
- Abstract
Prolonged or repeated exposure to stress increases risk for a variety of psychological disorders, many of which are marked by dysfunction of corticolimbic brain regions. Notably, women are more likely than men to be diagnosed with these disorders, especially when onset of symptoms follows stressful life events. Using rodent models, investigators have recently begun to elucidate sex-specific changes in the brain and behavior that occur immediately following chronic stress. However, little is known regarding the lasting sequelae of chronic stress, as well as how potential changes may impact responsivity to future stressors. We recently demonstrated that male and female rats show different patterns of dendritic reorganization in medial prefrontal cortex in the days following chronic stress. Here, we examined the immediate and lasting effects of chronic restraint stress (CRS; 3 h/day, 10 days) on neuronal activation, across several corticolimbic brain regions, induced by novel acute stress exposure. Chronically stressed male and female rats were exposed to acute elevated platform stress (EPS) either 1 (CRS-EPS) or 7 (CRS-Rest-EPS) days after CRS. Compared to rats exposed to EPS only, significant reductions in acute stress-induced c-Fos expression were observed in the medial prefrontal cortex, hippocampus, and paraventricular nucleus of the hypothalamus (PVN) in CRS-EPS male rats, some of which persisted to 7 days post-stress. In contrast, we found little modulation of novel stress-induced c-Fos expression in CRS-EPS female rats. However, CRS-Rest-EPS female rats exhibited a significant enhancement of acute stress-induced neuronal activity in the PVN. Together, these data show that prior chronic stress produces sex- and region-specific alterations in novel stress-induced neuronal activation, which are dependent on the presence or absence of a rest period following chronic stress. These findings suggest that the post-stress rest period may give rise to sex-specific neuroadaptations to stress, which may underlie sex differences in stress susceptibility versus resilience.
- Published
- 2019
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13. Preclinical studies of stress, extinction, and prefrontal cortex: intriguing leads and pressing questions.
- Author
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Wellman CL and Moench KM
- Subjects
- Animals, Humans, Nerve Net metabolism, Nerve Net pathology, Neuronal Plasticity physiology, Prefrontal Cortex pathology, Stress, Psychological pathology, Extinction, Psychological physiology, Fear physiology, Fear psychology, Prefrontal Cortex metabolism, Stress, Psychological metabolism, Stress, Psychological psychology
- Abstract
Background: Stress is associated with cognitive and emotional dysfunction, and increases risk for a variety of psychological disorders, including depression and posttraumatic stress disorder. Prefrontal cortex is critical for executive function and emotion regulation, is a target for stress hormones, and is implicated in many stress-influenced psychological disorders. Extinction of conditioned fear provides an excellent model system for examining how stress-induced changes in corticolimbic structure and function are related to stress-induced changes in neural function and behavior, as the neural circuitry underlying this behavior is well characterized., Objectives: This review examines how acute and chronic stress influences extinction and describes how stress alters the structure and function of the medial prefrontal cortex, a potential neural substrate for these effects. In addition, we identify important unanswered questions about how stress-induced change in prefrontal cortex may mediate extinction deficits and avenues for future research., Key Findings: A substantial body of work demonstrates deficits in extinction after either acute or chronic stress. A separate and substantial literature demonstrates stress-induced neuronal remodeling in medial prefrontal cortex, along with several key neurohormonal contributors to this remodeling, and there is substantial overlap in prefrontal mechanisms underlying extinction and the mechanisms implicated in stress-induced dysfunction of-and neuronal remodeling in-medial prefrontal cortex. However, data directly examining the contribution of changes in prefrontal structure and function to stress-induced extinction deficits is currently lacking., Conclusions: Understanding how stress influences extinction and its neural substrates as well as individual differences in this effect will elucidate potential avenues for novel interventions for stress-sensitive disorders characterized by deficits in extinction.
- Published
- 2019
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14. Sex Differences in Risk and Resilience: Stress Effects on the Neural Substrates of Emotion and Motivation.
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Wellman CL, Bangasser DA, Bollinger JL, Coutellier L, Logrip ML, Moench KM, and Urban KR
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- Animals, Brain metabolism, Brain pathology, Female, Humans, Male, Mental Disorders metabolism, Mental Disorders pathology, Mental Disorders psychology, Neuroglia metabolism, Neuroglia pathology, Neurons metabolism, Neurons pathology, Risk Factors, Stress, Psychological pathology, Stress, Psychological psychology, Corticotropin-Releasing Hormone metabolism, Emotions physiology, Motivation physiology, Resilience, Psychological, Sex Characteristics, Stress, Psychological metabolism
- Abstract
Risk for stress-sensitive psychopathologies differs in men and women, yet little is known about sex-dependent effects of stress on cellular structure and function in corticolimbic regions implicated in these disorders. Determining how stress influences these regions in males and females will deepen our understanding of the mechanisms underlying sex-biased psychopathology. Here, we discuss sex differences in CRF regulation of arousal and cognition, glucocorticoid modulation of amygdalar physiology and alcohol consumption, the age-dependent impact of social stress on prefrontal pyramidal cell excitability, stress effects on the prefrontal parvalbumin system in relation to emotional behaviors, contributions of stress and gonadal hormones to stress effects on prefrontal glia, and alterations in corticolimbic structure and function after cessation of chronic stress. These studies demonstrate that, while sex differences in stress effects may be nuanced, nonuniform, and nonlinear, investigations of these differences are nonetheless critical for developing effective, sex-specific treatments for psychological disorders., (Copyright © 2018 the authors 0270-6474/18/389423-10$15.00/0.)
- Published
- 2018
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15. Behavioral stress alters corticolimbic microglia in a sex- and brain region-specific manner.
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Bollinger JL, Collins KE, Patel R, and Wellman CL
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- Animals, Female, Limbic System metabolism, Male, Polymerase Chain Reaction, Rats, Rats, Sprague-Dawley, Brain metabolism, Microglia metabolism, Stress, Psychological
- Abstract
Women are more susceptible to numerous stress-linked psychological disorders (e.g., depression) characterized by dysfunction of corticolimbic brain regions critical for emotion regulation and cognitive function. Although sparsely investigated, a number of studies indicate sex differences in stress effects on neuronal structure, function, and behaviors associated with these regions. We recently demonstrated a basal sex difference in- and differential effects of stress on- microglial activation in medial prefrontal cortex (mPFC). The resident immune cells of the brain, microglia are implicated in synaptic and dendritic plasticity, and cognitive-behavioral function. Here, we examined the effects of acute (3h/day, 1 day) and chronic (3h/day, 10 days) restraint stress on microglial density and morphology, as well as immune factor expression in orbitofrontal cortex (OFC), basolateral amygdala (BLA), and dorsal hippocampus (DHC) in male and female rats. Microglia were visualized, classified based on their morphology, and stereologically counted. Microglia-associated transcripts (CD40, iNOS, Arg1, CX3CL1, CX3CR1, CD200, and CD200R) were assessed in brain punches from each region. Expression of genes linked with cellular stress, neuroimmune state, and neuron-microglia communication varied between unstressed male and female rats in a region-specific manner. In OFC, chronic stress upregulated a wider variety of immune factors in females than in males. Acute stress increased microglia-associated transcripts in BLA in males, whereas chronic stress altered immune factor expression in BLA more broadly in females. In DHC, chronic stress increased immune factor expression in males but not females. Moreover, acute and chronic stress differentially affected microglial morphological activation state in male and female rats across all brain regions investigated. In males, chronic stress altered microglial activation in a pattern consistent with microglial involvement in stress-induced dendritic remodeling across OFC, BLA, and DHC. Together, these data suggest the potential for microglia-mediated sex differences in stress effects on neural structure, function, and behavior.
- Published
- 2017
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16. Differential dendritic remodeling in prelimbic cortex of male and female rats during recovery from chronic stress.
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Moench KM and Wellman CL
- Subjects
- Adrenal Glands pathology, Animals, Body Weight physiology, Cell Size, Chronic Disease, Corticosterone blood, Dendrites pathology, Disease Models, Animal, Female, Male, Neuronal Outgrowth physiology, Organ Size, Prefrontal Cortex pathology, Pyramidal Cells pathology, Pyramidal Cells physiology, Rats, Sprague-Dawley, Recovery of Function physiology, Restraint, Physical, Stress, Psychological pathology, Dendrites physiology, Neuronal Plasticity physiology, Prefrontal Cortex physiopathology, Sex Characteristics, Stress, Psychological physiopathology
- Abstract
Chronic stress produces differential dendritic remodeling of pyramidal neurons in medial prefrontal cortex of male and female rats. In males, this dendritic remodeling is reversible. However, the timeline of recovery, as well as the potential for reversibility in females, is unknown. Here, we examined dendritic recovery of pyramidal neurons in layer II-II of prelimbic cortex in male and female rats following chronic restraint stress (3h/day for 10days). Dendritic morphology and spine density were analyzed immediately following the cessation of stress, or following a 7- or 10-day recovery period. Chronic stress produced apical dendritic retraction in males, which was coupled with a decrease in the density of stubby spine on apical dendrites. Further, following a 10-day recovery period, the morphology of neurons from stressed rats resembled that of unstressed rats. Male rats given a 7-day recovery period had apical dendritic outgrowth compared to unstressed rats. Immediately after cessation of stress, females showed only minimal dendritic remodeling. The morphology of neurons in stressed females resembled those of unstressed rats following only 7days of recovery, at which time there was also a significant increase in stubby spine density. Males and females also showed different changes in baseline corticosterone concentrations during recovery. These findings not only indicate that dendritic remodeling in prelimbic cortex following chronic stress is different between males and females, but also suggest chronic stress induces differential hypothalamic-pituitary-adrenal axis dysregulation in males and females. These differences may have important implications for responses to subsequent stressors., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2017
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17. Visualizing Changes in Neuronal Dendritic Morphology in Response to Stress and Pharmacological Challenge.
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Wellman CL
- Subjects
- Animals, Brain, Golgi Apparatus, Mice, Neuronal Plasticity physiology, Rats, Staining and Labeling, Stress, Physiological, Dendrites
- Abstract
This unit outlines a protocol for Golgi staining, which has been used extensively to reliably and quantitatively assess alterations in dendritic arborization and spine density as a result of a variety of factors, including chronic administration of glucocorticoids, chronic stress, and pharmacological manipulations. The method stains neurons in their entirety, allowing for sophisticated analyses of branch lengths and numbers as well as patterns of dendritic branching. Advantages of the technique include its usefulness in multisite collaborations and its utility in visualizing neurons in multiple regions within the same brain. Given that it typically labels approximately one in one hundred neurons, many neurons per region of interest can be sampled per animal, greatly increasing the ability to obtain a representative sample of neurons. Limitations include its time-consuming nature, the hazardous chemicals employed, and the inability to use the stain to identify discrete subpopulations of neurons based on their projections, activation, or protein expression. © 2017 by John Wiley & Sons, Inc., (Copyright © 2017 John Wiley & Sons, Inc.)
- Published
- 2017
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18. Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex.
- Author
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Bollinger JL, Bergeon Burns CM, and Wellman CL
- Subjects
- Animals, Body Weight, Dendrites metabolism, Female, Male, Microglia cytology, Microglia immunology, Prefrontal Cortex cytology, Prefrontal Cortex immunology, Rats, Rats, Sprague-Dawley, Sex Factors, Stress, Physiological immunology, Stress, Psychological immunology, Microglia metabolism, Prefrontal Cortex metabolism, Stress, Physiological physiology, Stress, Psychological metabolism
- Abstract
Susceptibility to stress-linked psychological disorders, including post-traumatic stress disorder and depression, differs between men and women. Dysfunction of medial prefrontal cortex (mPFC) has been implicated in many of these disorders. Chronic stress affects mPFC in a sex-dependent manner, differentially remodeling dendritic morphology and disrupting prefrontally mediated behaviors in males and females. Chronic restraint stress induces microglial activation, reflected in altered microglial morphology and immune factor expression, in mPFC in male rats. Unstressed females exhibit increased microglial ramification in several brain regions compared to males, suggesting both heightened basal activation and a potential for sex-dependent effects of stress on microglial activation. Therefore, we assessed microglial density and ramification in the prelimbic region of mPFC, and immune-associated genes in dorsal mPFC in male and female rats following acute or chronic restraint stress. Control rats were left unstressed. On the final day of restraint, brains were collected for either qPCR or visualization of microglia using Iba-1 immunohistochemistry. Microglia in mPFC were classified as ramified, primed, reactive, or amoeboid, and counted stereologically. Expression of microglia-associated genes (MHCII, CD40, IL6, CX3CL1, and CX3CR1) was also assessed using qPCR. Unstressed females showed a greater proportion of primed to ramified microglia relative to males, alongside heightened CX3CL1-CX3CR1 expression. Acute and chronic restraint stress reduced the proportion of primed to ramified microglia and microglial CD40 expression in females, but did not significantly alter microglial activation in males. This sex difference in microglial activation could contribute to the differential effects of stress on mPFC structure and function in males versus females., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2016
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19. Stress-induced alterations in prefrontal dendritic spines: Implications for post-traumatic stress disorder.
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Moench KM and Wellman CL
- Subjects
- Animals, Dendritic Spines metabolism, Female, Humans, Male, Prefrontal Cortex metabolism, Pyramidal Cells metabolism, Pyramidal Cells pathology, Sex Factors, Stress Disorders, Post-Traumatic etiology, Stress Disorders, Post-Traumatic metabolism, Stress, Psychological complications, Stress, Psychological metabolism, Dendritic Spines pathology, Prefrontal Cortex pathology, Stress Disorders, Post-Traumatic pathology, Stress, Psychological pathology
- Abstract
The medial prefrontal cortex (mPFC) is involved in a variety of important functions including emotional regulation, HPA axis regulation, and working memory. It also demonstrates remarkable plasticity in an experience-dependent manner. There is extensive evidence that stressful experiences can produce profound changes in the morphology of neurons within mPFC with a variety of behavioral consequences. The deleterious behavioral outcomes associated with mPFC dysfunction have been implicated in multiple psychopathologies, including post-traumatic stress disorder (PTSD). Given the prevalence of these disorders, a deeper understanding of the cellular mechanisms underlying stress-induced morphological changes in mPFC is critical, and could lead to improved therapeutic treatments. Here we give a brief review of recent studies examining the mechanisms underlying changes in mPFC pyramidal neuron dendritic spines - the primary sites of excitatory input in cortical pyramidal neurons. We begin with an overview of the effects of chronic stress on mPFC dendritic spine density and morphology followed by proposed mechanisms for these changes. We then discuss the time course of stress effects on mPFC as well as potential intercellular influences. Given that many psychopathologies, including PTSD, have different prevalence rates among men and women, we end with a discussion of the sex differences that have been observed in morphological changes in mPFC. Future directions and implications for PTSD are discussed throughout., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2015
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20. Monoamine Oxidase A is Required for Rapid Dendritic Remodeling in Response to Stress.
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Godar SC, Bortolato M, Richards SE, Li FG, Chen K, Wellman CL, and Shih JC
- Subjects
- Animals, Anxiety etiology, Disease Models, Animal, Male, Mice, Mice, 129 Strain, Monoamine Oxidase deficiency, Stress, Psychological complications, Anxiety enzymology, Basolateral Nuclear Complex pathology, Dendrites pathology, Monoamine Oxidase metabolism, Prefrontal Cortex pathology, Pyramidal Cells pathology, Stress, Psychological enzymology
- Abstract
Background: Acute stress triggers transient alterations in the synaptic release and metabolism of brain monoamine neurotransmitters. These rapid changes are essential to activate neuroplastic processes aimed at the appraisal of the stressor and enactment of commensurate defensive behaviors. Threat evaluation has been recently associated with the dendritic morphology of pyramidal cells in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA); thus, we examined the rapid effects of restraint stress on anxiety-like behavior and dendritic morphology in the BLA and OFC of mice. Furthermore, we tested whether these processes may be affected by deficiency of monoamine oxidase A (MAO-A), the primary enzyme catalyzing monoamine metabolism., Methods: Following a short-term (1-4h) restraint schedule, MAO-A knockout (KO) and wild-type (WT) mice were sacrificed, and histological analyses of dendrites in pyramidal neurons of the BLA and OFC of the animals were performed. Anxiety-like behaviors were examined in a separate cohort of animals subjected to the same experimental conditions., Results: In WT mice, short-term restraint stress significantly enhanced anxiety-like responses, as well as a time-dependent proliferation of apical (but not basilar) dendrites of the OFC neurons; conversely, a retraction in BLA dendrites was observed. None of these behavioral and morphological changes were observed in MAO-A KO mice., Conclusions: These findings suggest that acute stress induces anxiety-like responses by affecting rapid dendritic remodeling in the pyramidal cells of OFC and BLA; furthermore, our data show that MAO-A and monoamine metabolism are required for these phenomena., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)
- Published
- 2015
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21. D1 receptors regulate dendritic morphology in normal and stressed prelimbic cortex.
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Lin GL, Borders CB, Lundewall LJ, and Wellman CL
- Subjects
- Animals, Benzazepines pharmacology, Cell Shape drug effects, Dendrites drug effects, Dopamine Antagonists pharmacology, Male, Neurons drug effects, Prefrontal Cortex drug effects, Rats, Rats, Sprague-Dawley, Restraint, Physical, Stress, Physiological drug effects, Cell Shape physiology, Dendrites metabolism, Neurons metabolism, Prefrontal Cortex metabolism, Receptors, Dopamine D1 metabolism, Stress, Physiological physiology, Stress, Psychological metabolism
- Abstract
Both stress and dysfunction of prefrontal cortex are linked to psychological disorders, and structure and function of medial prefrontal cortex (mPFC) are altered by stress. Chronic restraint stress causes dendritic retraction in the prelimbic region (PL) of mPFC in rats. Dopamine release in mPFC increases during stress, and chronic administration of dopaminergic agonists results in dendritic remodeling. Thus, stress-induced alterations in dopaminergic transmission in PL may contribute to dendritic remodeling. We examined the effects of dopamine D1 receptor (D1R) blockade in PL during daily restraint stress on dendritic morphology in PL. Rats either underwent daily restraint stress (3h/day, 10 days) or remained unstressed. In each group, rats received daily infusions of either the D1R antagonist SCH23390 or vehicle into PL prior to restraint; unstressed and stressed rats that had not undergone surgery were also examined. On the final day of restraint, rats were euthanized and brains were processed for Golgi histology. Pyramidal neurons in PL were reconstructed and dendritic morphology was quantified. Vehicle-infused stressed rats demonstrated dendritic retraction compared to unstressed rats, and D1R blockade in PL prevented this effect. Moreover, in unstressed rats, D1R blockade produced dendritic retraction. These effects were not due to attenuation of the HPA axis response to acute stress: plasma corticosterone levels in a separate group of rats that underwent acute restraint stress with or without D1R blockade were not significantly different. These findings indicate that dopaminergic transmission in mPFC during stress contributes directly to the stress-induced retraction of apical dendrites, while dopamine transmission in the absence of stress is important in maintaining normal dendritic morphology., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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22. Convergent effects of mouse Pet-1 deletion and human PET-1 variation on amygdala fear and threat processing.
- Author
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Wellman CL, Camp M, Jones VM, MacPherson KP, Ihne J, Fitzgerald P, Maroun M, Drabant E, Bogdan R, Hariri AR, and Holmes A
- Subjects
- Animals, Anxiety Disorders genetics, Conditioning, Classical, Dendrites ultrastructure, Extinction, Psychological physiology, Female, Genotype, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Polymorphism, Single Nucleotide, Young Adult, Amygdala physiology, DNA-Binding Proteins genetics, Emotions physiology, Fear physiology, Genetic Predisposition to Disease genetics, Nuclear Proteins genetics, Transcription Factors genetics
- Abstract
Serotonin is critical for shaping the development of neural circuits regulating emotion. Pet-1 (FEV-1) is an ETS-domain transcription factor essential for differentiation and forebrain targeting of serotonin neurons. Constitutive Pet-1 knockout (KO) causes major loss of serotonin neurons and forebrain serotonin availability, and behavioral abnormalities. We phenotyped Pet-1 KO mice for fear conditioning and extinction, and on a battery of assays for anxiety- and depression-related behaviors. Morphology of Golgi-stained neurons in basolateral amygdala (BLA) and prelimbic cortex was examined. Using human imaging genetics, a common variant (rs860573) in the PET-1 (FEV) gene was tested for effects on threat-related amygdala reactivity and psychopathology in 88 Asian-ancestry subjects. Pet-1 KO mice exhibited increased acquisition and expression of fear, and elevated fear recovery following extinction, relative to wild-type (WT). BLA dendrites of Pet-1 KO mice were significantly longer than in WT. Human PET-1 variation associated with differences in amygdala threat processing and psychopathology. This novel evidence for the role of Pet-1 in fear processing and dendritic organization of amygdala neurons and in human amygdala threat processing extends a growing literature demonstrating the influence of genetic variation in the serotonin system on emotional regulation via effects on structure and function of underlying corticolimbic circuitry., (© 2013.)
- Published
- 2013
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23. Sex differences and chronic stress effects on the neural circuitry underlying fear conditioning and extinction.
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Farrell MR, Sengelaub DR, and Wellman CL
- Subjects
- Animals, Female, Humans, Male, Brain physiology, Conditioning, Psychological physiology, Extinction, Psychological physiology, Fear physiology, Nerve Net physiology, Sex Characteristics, Stress, Psychological physiopathology
- Abstract
There are sex differences in the rates of many stress-sensitive psychological disorders such as posttraumatic stress disorder (PTSD). As medial prefrontal cortex and amygdala are implicated in many of these disorders, understanding differential stress effects in these regions may shed light on the mechanisms underlying sex-dependent expression of disorders like depression and anxiety. Prefrontal cortex and amygdala are key regions in the neural circuitry underlying fear conditioning and extinction, which thus has emerged as a useful model of stress influences on the neural circuitry underlying regulation of emotional behavior. This review outlines the current literature on sex differences and stress effects on dendritic morphology within medial prefrontal cortex and basolateral amygdala. Such structural differences and/or alterations can have important effects on fear conditioning and extinction, behaviors that are mediated by the basolateral amygdala and prefrontal cortex, respectively. Given the importance of extinction-based exposure therapy as a treatment for anxiety disorders such as PTSD, understanding the neural mechanisms by which stress differentially influences fear learning and extinction in males and females is an important goal for developing sex-appropriate interventions for stress-related disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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24. Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons.
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Maroun M, Ioannides PJ, Bergman KL, Kavushansky A, Holmes A, and Wellman CL
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- Animals, Male, Rats, Rats, Sprague-Dawley, Amygdala ultrastructure, Dendritic Spines ultrastructure, Extinction, Psychological physiology, Fear physiology, Stress, Physiological
- Abstract
Stress-sensitive psychopathologies such as post-traumatic stress disorder are characterized by deficits in fear extinction and dysfunction of corticolimbic circuits mediating extinction. Chronic stress facilitates fear conditioning, impairs extinction, and produces dendritic proliferation in the basolateral amygdala (BLA), a critical site of plasticity for extinction. Acute stress impairs extinction, alters plasticity in the medial prefrontal cortex-to-BLA circuit, and causes dendritic retraction in the medial prefrontal cortex. Here, we examined extinction learning and basolateral amygdala pyramidal neuron morphology in adult male rats following a single elevated platform stress. Acute stress impaired extinction acquisition and memory, and produced dendritic retraction and increased mushroom spine density in basolateral amygdala neurons in the right hemisphere. Unexpectedly, irrespective of stress, rats that underwent fear and extinction testing showed basolateral amygdala dendritic retraction and altered spine density relative to non-conditioned rats, particularly in the left hemisphere. Thus, extinction deficits produced by acute stress are associated with increased spine density and dendritic retraction in basolateral amygdala pyramidal neurons. Furthermore, the finding that conditioning and extinction as such was sufficient to alter basolateral amygdala morphology and spine density illustrates the sensitivity of basolateral amygdala morphology to behavioral manipulation. These findings may have implications for elucidating the role of the amygdala in the pathophysiology of stress-related disorders., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)
- Published
- 2013
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25. Early adverse experience alters dendritic spine density and gene expression in prefrontal cortex and hippocampus in lambs.
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Coulon M, Wellman CL, Marjara IS, Janczak AM, and Zanella AJ
- Subjects
- Animals, Animals, Newborn, Female, Hippocampus metabolism, Male, Prefrontal Cortex metabolism, Pregnancy, Prenatal Exposure Delayed Effects genetics, Prenatal Exposure Delayed Effects metabolism, Sheep, Stress, Psychological genetics, Stress, Psychological metabolism, Dendritic Spines physiology, Gene Expression, Hippocampus physiopathology, Prefrontal Cortex physiopathology, Prenatal Exposure Delayed Effects physiopathology, Pyramidal Cells physiology, Stress, Psychological physiopathology
- Abstract
In the laboratory, prenatal stress produces alterations in the structure and function of corticolimbic neurons. Here we report changes in gene expression and corticolimbic dendritic spine morphology in the offspring of pregnant ewes subjected to aversive interactions with human handlers during the last five weeks of pregnancy (AVS) compared to control dams that received gentle handling (GEN). AVS lambs had higher spine density on pyramidal neurons in area CA1 of the hippocampus and in medial prefrontal cortex compared to GEN lambs, as well as a lower ratio of mushroom spines to stubby and thin spines in area CA1. Expression of genes involved in brain development and spine morphogenesis was decreased in hippocampus and prefrontal cortex in AVS compared to GEN lambs. This study is the first demonstration that an ecologically relevant aversive experience in a field setting alters neuronal structure similarly to previous reports from laboratory settings and that even for animals domesticated over 12,000 years ago, an apparently mild stressor, resulting from human-animal interactions, can have similarly profound impacts on corticolimbic morphology., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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26. Monoamine oxidase A and A/B knockout mice display autistic-like features.
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Bortolato M, Godar SC, Alzghoul L, Zhang J, Darling RD, Simpson KL, Bini V, Chen K, Wellman CL, Lin RC, and Shih JC
- Subjects
- Animals, Autistic Disorder genetics, Male, Mice, Mice, 129 Strain, Mice, Knockout, Monoamine Oxidase genetics, Motor Activity genetics, Vocalization, Animal physiology, Autistic Disorder enzymology, Interpersonal Relations, Maze Learning physiology, Monoamine Oxidase deficiency, Motor Activity physiology
- Abstract
Converging lines of evidence show that a sizable subset of autism-spectrum disorders (ASDs) is characterized by increased blood levels of serotonin (5-hydroxytryptamine, 5-HT), yet the mechanistic link between these two phenomena remains unclear. The enzymatic degradation of brain 5-HT is mainly mediated by monoamine oxidase (MAO)A and, in the absence of this enzyme, by its cognate isoenzyme MAOB. MAOA and A/B knockout (KO) mice display high 5-HT levels, particularly during early developmental stages. Here we show that both mutant lines exhibit numerous behavioural hallmarks of ASDs, such as social and communication impairments, perseverative and stereotypical responses, behavioural inflexibility, as well as subtle tactile and motor deficits. Furthermore, both MAOA and A/B KO mice displayed neuropathological alterations reminiscent of typical ASD features, including reduced thickness of the corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of the cerebellum. The severity of repetitive responses and neuropathological aberrances was generally greater in MAOA/B KO animals. These findings suggest that the neurochemical imbalances induced by MAOA deficiency (either by itself or in conjunction with lack of MAOB) may result in an array of abnormalities similar to those observed in ASDs. Thus, MAOA and A/B KO mice may afford valuable models to help elucidate the neurobiological bases of these disorders and related neurodevelopmental problems.
- Published
- 2013
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27. Genetic strain differences in learned fear inhibition associated with variation in neuroendocrine, autonomic, and amygdala dendritic phenotypes.
- Author
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Camp MC, Macpherson KP, Lederle L, Graybeal C, Gaburro S, Debrouse LM, Ihne JL, Bravo JA, O'Connor RM, Ciocchi S, Wellman CL, Lüthi A, Cryan JF, Singewald N, and Holmes A
- Subjects
- Analysis of Variance, Animals, Antidepressive Agents, Second-Generation therapeutic use, Anxiety Disorders drug therapy, Avoidance Learning drug effects, Corticosterone blood, Discrimination, Psychological, Disease Models, Animal, Electrocardiography, Extinction, Psychological drug effects, Fear drug effects, Fluoxetine therapeutic use, Humans, Male, Mice, Mice, Inbred Strains, RNA, Messenger metabolism, Receptors, Glucocorticoid, Telemetry, Amygdala pathology, Anxiety Disorders complications, Anxiety Disorders pathology, Autonomic Nervous System Diseases etiology, Dendrites pathology, Endocrine System Diseases etiology, Extinction, Psychological physiology, Fear physiology, Inhibition, Psychological
- Abstract
Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.
- Published
- 2012
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28. Social deficits and perseverative behaviors, but not overt aggression, in MAO-A hypomorphic mice.
- Author
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Bortolato M, Chen K, Godar SC, Chen G, Wu W, Rebrin I, Farrell MR, Scott AL, Wellman CL, and Shih JC
- Subjects
- Animals, Dendrites enzymology, Dendrites pathology, Disease Models, Animal, Frontal Lobe abnormalities, Frontal Lobe enzymology, Frontal Lobe pathology, Humans, Male, Mental Disorders genetics, Mental Disorders physiopathology, Mice, Mice, 129 Strain, Mice, Knockout, Mice, Neurologic Mutants, Monoamine Oxidase genetics, Pyramidal Cells enzymology, Pyramidal Cells pathology, Stereotyped Behavior physiology, Aggression, Behavior, Animal physiology, Mental Disorders enzymology, Monoamine Oxidase deficiency, Social Behavior
- Abstract
Monoamine oxidase (MAO)-A is a key enzyme for the degradation of brain serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE). In humans and mice, total MAO-A deficiency results in high 5-HT and NE levels, as well as elevated reactive aggression. Here we report the generation of MAO-A(Neo) mice, a novel line of hypomorphic MAO-A mutants featuring the insertion of a floxed neomycin-resistance cassette in intron-12 of the Maoa gene. This construct resulted in a chimeric, non-functional variant of the Maoa-Neo transcript, with a truncated C-terminus, likely due to aberrant splicing; these deficits notwithstanding, small amounts of functional Maoa transcript were found in the brain of MAO-A(Neo) mice. In the prefrontal cortex and amygdala, MAO-A(Neo) mice showed low, yet detectable, MAO-A catalytic activity, as well as 5-HT levels equivalent to WT littermates; conversely, the hippocampus and midbrain of MAO-A(Neo) mice featured a neurochemical profile akin to MAO-A-knockout (KO) mice, with undetectable MAO-A activity and high 5-HT concentrations. MAO-A(Neo) mice showed significant increases in dendritic length in the pyramidal neurons of orbitofrontal cortex, but not basolateral amygdala, in comparison with WT littermates; by contrast, the orbitofrontal cortex of MAO-A KO mice showed significant reductions in basilar dendritic length, as well as a profound increase in apical dendritic length. MAO-A(Neo) mice showed a unique set of behavioral abnormalities, encompassing reduced open-field locomotion, perseverative responses, such as marble burying and water mist-induced grooming, and a lack of anxiety-like behaviors in the elevated plus-maze and light-dark box paradigms. Notably, whereas MAO-A(Neo) and KO mice showed significant reductions in social interaction, only the latter genotype showed increases in resident-intruder aggression. Taken together, our findings indicate that MAO A hypomorphism results in behavioral and morphological alterations distinct from those featured by MAO-A KO mice.
- Published
- 2011
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29. NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex.
- Author
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Martin KP and Wellman CL
- Subjects
- Animals, Dendrites metabolism, Male, Piperazines therapeutic use, Prefrontal Cortex drug effects, Pyramidal Cells drug effects, Pyramidal Cells metabolism, Pyramidal Cells pathology, Rats, Rats, Sprague-Dawley, Stress, Psychological pathology, Dendrites pathology, Excitatory Amino Acid Antagonists therapeutic use, Prefrontal Cortex metabolism, Prefrontal Cortex pathology, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Receptors, N-Methyl-D-Aspartate physiology, Stress, Psychological metabolism, Stress, Psychological therapy
- Abstract
The development and relapse of many psychopathologies can be linked to both stress and prefrontal cortex dysfunction. Glucocorticoid stress hormones target medial prefrontal cortex (mPFC) and either chronic stress or chronic administration of glucocorticoids produces dendritic remodeling in prefrontal pyramidal neurons. Exposure to stress also causes an increase in the release of the excitatory amino acid glutamate, which binds to N-methyl-D-aspartate (NMDA) receptors, which are plentiful in mPFC. NMDA receptor activation is crucial for producing hippocampal dendritic remodeling due to stress and for dendritic reorganization in frontal cortex after cholinergic deafferentation. Thus, NMDA receptors could mediate stress-induced dendritic retraction in mPFC. To test this hypothesis, dendritic morphology of pyramidal cells in mPFC was assessed after blocking NMDA receptors with the competitive NMDA antagonist ±3-(2-carboxypiperazin-4yl)propyl-1-phosphonic acid (CPP) during restraint stress. Administration of CPP prevented stress-induced dendritic atrophy. Instead, CPP-injected stressed rats showed hypertrophy of apical dendrites compared with controls. These results suggest that NMDA activation is crucial for stress-induced dendritic atrophy in mPFC. Furthermore, NMDA receptor blockade uncovers a new pattern of stress-induced dendritic changes, suggesting that other neurohormonal changes in concert with NMDA receptor activation underlie the net dendritic retraction seen after chronic stress.
- Published
- 2011
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30. Neonatal corticosterone administration impairs adult eyeblink conditioning and decreases glucocorticoid receptor expression in the cerebellar interpositus nucleus.
- Author
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Wilber AA, Lin GL, and Wellman CL
- Subjects
- Aging drug effects, Aging physiology, Animals, Animals, Newborn, Cerebellar Nuclei drug effects, Conditioning, Eyelid drug effects, Corticosterone administration & dosage, Disease Models, Animal, Female, Male, Rats, Rats, Long-Evans, Receptors, Glucocorticoid biosynthesis, Receptors, Glucocorticoid deficiency, Stress, Psychological metabolism, Cerebellar Nuclei metabolism, Conditioning, Eyelid physiology, Corticosterone blood, Maternal Deprivation, Receptors, Glucocorticoid antagonists & inhibitors, Stress, Psychological physiopathology
- Abstract
Neonatal maternal separation alters adult learning and memory. Previously, we showed that neonatal separation impaired eyeblink conditioning in adult rats and increased glucocorticoid receptor (GR) expression in the cerebellar interpositus nucleus, a critical site of learning-related plasticity. Daily neonatal separation (1 h/day on postnatal days 2-14) increases neonatal plasma corticosterone levels. Therefore, effects of separation on GR expression in the interpositus and consequently adult eyeblink conditioning may be mediated by neonatal increases in corticosterone. As a first step in exploring a potential role for corticosterone in the neonatal separation effects we observed, we assessed whether systemic daily (postnatal days 2-14) corticosterone injections mimic neonatal separation effects on adult eyeblink conditioning and GR expression in the interpositus. Control uninjected animals were compared to animals receiving either daily corticosterone injections or daily injections of an equal volume of vehicle. Plasma corticosterone values were measured in a separate group of control, neonatally separated, vehicle injected, or corticosterone injected pups. In adulthood, rats underwent surgery for implantation of recording and stimulating electrodes. After recovery from surgery, rats underwent 10 daily sessions of eyeblink conditioning. Then, brains were processed for GR immunohistochemistry and GR expression in the interpositus nucleus was assessed. Vehicle and corticosterone injections both produced much larger increases in neonatal plasma corticosterone than did daily maternal separation, with the largest increases occurring in the corticosterone-injected group. Neonatal corticosterone injections impaired adult eyeblink conditioning and decreased GR expression in the interpositus nucleus, while the effects of vehicle injections were intermediate. Thus, while neonatal injections and maternal separation both produce adult impairments in learning and memory, these manipulations produce opposite changes in GR expression. This suggests an inverted U-shaped relationship may exist between both neonatal corticosterone levels and adult GR expression in the interpositus nucleus, and adult GR expression in the interpositus and eyeblink conditioning., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2011
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31. Chronic stress-induced hippocampal dendritic retraction requires CA3 NMDA receptors.
- Author
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Christian KM, Miracle AD, Wellman CL, and Nakazawa K
- Subjects
- Adrenal Glands pathology, Animals, Body Weight, CA3 Region, Hippocampal metabolism, Corticosterone blood, Discrimination Learning, Exploratory Behavior, Fear, Immobilization, Male, Memory, Short-Term, Mice, Mice, Knockout, Motor Activity, Mutation, Receptors, N-Methyl-D-Aspartate genetics, Stress, Psychological metabolism, Stress, Psychological psychology, CA3 Region, Hippocampal ultrastructure, Dendrites ultrastructure, Receptors, N-Methyl-D-Aspartate physiology, Stress, Psychological pathology
- Abstract
Chronic stress induces dendritic retraction in the hippocampal CA3 subregion, but the mechanisms responsible for this retraction and its impact on neural circuitry are not well understood. To determine the role of NMDA (N-methyl-d-aspartic acid) receptor (NMDAR)-mediated signaling in this process, we compared the effects of chronic immobilization stress (CIS) on hippocampal dendritic morphology, hypothalamic-pituitary-adrenal (HPA) axis activation, and anxiety-related and hippocampus-dependent behaviors, in transgenic male mice in which the NMDAR had been selectively deleted in CA3 pyramidal cells and in non-mutant littermates. We found that CIS exposure for 10 consecutive days in non-mutant mice effectively induces HPA axis activation and dendritic retraction of CA3 short-shaft pyramidal neurons, but not CA3 long-shaft pyramidal neurons, suggesting a differential cellular stress response in this region. Dendritic reorganization of short-shaft neurons occurred throughout the longitudinal axis of the hippocampus and, in particular, in the ventral pole of this structure. We also observed a robust retraction of dendrites in dorsal CA1 pyramidal neurons in the non-mutant C57BL/6 mouse strain. Strikingly, chronic stress-induced dendritic retraction was not evident in any of the neurons in either CA3 or CA1 in the mutant mice that had a functional lack of NMDARs restricted to CA3 pyramidal neurons. Interestingly, the prevention of dendritic retraction in the mutant mice had a minimal effect on HPA axis activation and behavioral alterations that were induced by chronic stress. These data support a role for NMDAR-dependent glutamatergic signaling in CA3 in the cell-type specific induction of dendritic retraction in two hippocampal subregions following chronic stress., (Published by Elsevier Ltd.)
- Published
- 2011
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32. Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction.
- Author
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Wilber AA, Walker AG, Southwood CJ, Farrell MR, Lin GL, Rebec GV, and Wellman CL
- Subjects
- Action Potentials, Animals, Conditioning, Operant, Fear, Male, Neurons physiology, Rats, Rats, Sprague-Dawley, Restraint, Physical, Stress, Psychological psychology, Extinction, Psychological, Prefrontal Cortex physiopathology, Stress, Psychological physiopathology
- Abstract
Chronic restraint stress produces morphological changes in medial prefrontal cortex and disrupts a prefrontally mediated behavior, retrieval of extinction. To assess potential physiological correlates of these alterations, we compared neural activity in infralimbic and prelimbic cortex of unstressed versus stressed rats during fear conditioning and extinction. After implantation of microwire bundles into infralimbic or prelimbic cortex, rats were either unstressed or stressed via placement in a plastic restrainer (3 h/day for 1 week). Rats then underwent fear conditioning and extinction while activity of neurons in infralimbic or prelimbic cortex was recorded. Percent freezing and neural activity were assessed during all phases of training. Chronic stress enhanced freezing during acquisition of conditioned fear, and altered both prelimbic and infralimbic activity during this phase. Stress did not alter initial extinction or conditioned stimulus (CS)-related activity during this phase. However, stress impaired retrieval of extinction assessed 24 h later, and this was accompanied by alterations in neuronal activity in both prelimbic and infralimbic cortex. In prelimbic cortex, unstressed rats showed decreased activity in response to CS presentation, whereas stressed rats showed no change. In infralimbic cortex, neurons in unstressed rats exhibited increased firing in response to the CS, whereas stressed rats showed no increase in infralimbic firing during the tone. Finally, CS-related firing in infralimbic but not prelimbic cortex was correlated with extinction retrieval. Thus, the stress-induced alteration of neuronal activity in infralimbic cortex may be responsible for the stress-induced deficit in retrieval of extinction., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2011
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33. Electrophysiological and structural alterations in striatum associated with behavioral sensitization to (±)3,4-methylenedioxymethamphetamine (Ecstasy) in rats: role of drug context.
- Author
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Ball KT, Wellman CL, Miller BR, and Rebec GV
- Subjects
- Adrenergic Uptake Inhibitors toxicity, Animals, Behavior, Animal physiology, Cell Shape drug effects, Cell Shape physiology, Electrophysiology methods, Male, Neostriatum physiopathology, Neurons physiology, Rats, Rats, Sprague-Dawley, Silver Staining methods, Behavior, Animal drug effects, N-Methyl-3,4-methylenedioxyamphetamine toxicity, Neostriatum drug effects, Neostriatum pathology, Neurons drug effects, Neurons pathology
- Abstract
We examined whether repeated exposure to the increasingly abused amphetamine (AMPH) derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) results in long-lasting neurobehavioral changes, and further, the ability of contextual cues to modulate these changes. We focused on dorsal striatum, a brain region implicated in the formation of persistent drug-related habits. Rats were transported to a novel recording chamber and treated with once-daily injections (s.c.) of (±)-MDMA (5.0 mg/kg) or saline for 5 days, followed by a challenge injection 14 days later either in the same (Experiment 1) or different context (Experiment 2). Chronically implanted micro-wire bundles were used to record from populations of striatal neurons on days 1, 5, and challenge. Twenty-four hours after the last injection, brains were removed and processed using a modified Golgi method to assess changes in neuronal morphology. A sensitized locomotor response was observed following MDMA challenge in 11 of 12 rats in Experiment 1 (same context), whereas only 58% of rats (7 of 12) displayed sensitization in Experiment 2 (different context). Furthermore, several alterations in striatal electrophysiology were apparent on challenge day, but only in rats that displayed sensitization. Conversely, structural changes in striatal medium spiny neurons, such as increases in spine density, were observed in MDMA-treated rats regardless of whether they displayed behavioral sensitization. Thus, it appears that reorganization of synaptic connectivity in dorsal striatum may contribute to long-lasting drug-induced behavioral alterations, but that these behavioral alterations are subject to modification depending on individual differences and the context surrounding drug administration., (Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
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34. Glucocorticoid receptor blockade in the posterior interpositus nucleus reverses maternal separation-induced deficits in adult eyeblink conditioning.
- Author
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Wilber AA, Lin GL, and Wellman CL
- Subjects
- Age Factors, Animals, Animals, Newborn, Cerebellar Nuclei drug effects, Hormone Antagonists pharmacology, Male, Mifepristone pharmacology, Rats, Rats, Long-Evans, Receptors, Glucocorticoid antagonists & inhibitors, Cerebellar Nuclei metabolism, Conditioning, Eyelid physiology, Maternal Deprivation, Receptors, Glucocorticoid metabolism, Stress, Psychological metabolism
- Abstract
Previously, we showed that neonatal maternal separation impaired eyeblink conditioning in adult rats. This impairment is correlated with increased glucocorticoid receptor (GR) expression in the cerebellar posterior interpositus nucleus, a critical site of learning-related plasticity. To assess whether increased GR expression is responsible for the separation-induced learning impairment, we infused a GR antagonist (mifepristone) or vehicle into the posterior interpositus during eyeblink conditioning in adult male Long-Evans rats that had undergone control rearing or neonatal maternal separation (1h/day, postnatal days 2-14). Rats received standard rearing (control) or neonatal maternal separation (separated; 1h/day on postnatal days 2-14). In adulthood, rats underwent surgery for implantation of recording electrodes in the orbicularis oculi of the left eyelid, a bipolar stimulating electrode dorsocaudal to the left eye, and an infusion guide cannula positioned over the posterior interpositus. Then, rats underwent 10 daily sessions of eyeblink conditioning. Rats in each group received either 0.2microl of mifepristone (2ng in 2% EtOH) or vehicle infusion prior to each eyeblink conditioning session. Mifepristone infusions improved conditioning in separated rats, but impaired control rats' performance. Thus, separation-induced increases in GRs may mediate the learning deficit seen in adult neonatally separated rats., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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35. Lesion of infralimbic cortex occludes stress effects on retrieval of extinction but not fear conditioning.
- Author
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Farrell MR, Sayed JA, Underwood AR, and Wellman CL
- Subjects
- Analysis of Variance, Animals, Association Learning physiology, Extinction, Psychological drug effects, Ibotenic Acid pharmacology, Limbic System, Male, Mental Recall drug effects, Neurotoxins pharmacology, Prefrontal Cortex drug effects, Rats, Rats, Sprague-Dawley, Stress, Psychological pathology, Conditioning, Operant physiology, Extinction, Psychological physiology, Mental Recall physiology, Prefrontal Cortex physiology, Stress, Psychological physiopathology
- Abstract
Chronic stress produces dendritic retraction in medial prefrontal cortex and impairs retrieval of extinction of conditioned fear, a behavior mediated by the infralimbic region (IL) of medial prefrontal cortex. To test the hypothesis that stress-induced changes in IL contribute to the stress-induced impairment in extinction retrieval, we performed an occlusion experiment in which we assessed the effects of stress alone, lesion of IL alone, and the combined effects of stress and lesion on extinction retrieval. If IL is the substrate upon which stress acts to produce deficits in extinction retrieval, then prior removal of IL should prevent the effect of stress on extinction retrieval. Rats received either sham or ibotenic acid lesions of IL. Rats in each group then remained unstressed or underwent daily restraint stress for 1week. Following the final day of restraint, rats received five habituation trials to a 30-s tone, followed by seven pairings of the tone with a 500-ms coterminating footshock. One hour later, rats received tone-alone extinction trials. On the following day, rats were given two extinction trials to test for extinction retrieval. Percent freezing was assessed throughout. Stress increased freezing during conditioning, and IL lesion did not block this effect. Either IL lesion alone or stress alone increased freezing on initial extinction trials. IL lesion did not attenuate the effect of stress during initial extinction. Similarly, IL lesion alone and stress alone produced deficits in extinction retrieval. However, stressed rats with IL lesions showed extinction retrieval comparable to that seen in unstressed, sham-lesioned rats. Thus, lesion of IL occluded the stress-induced impairment of extinction retrieval but failed to prevent the stress-induced facilitation of fear conditioning. This dissociation suggests that the effects of stress on these two aspects of emotion regulation are mediated at least in part by independent mechanisms, and that stress-induced changes in IL contribute to stress-induced deficits in extinction retrieval., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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36. Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.
- Author
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Mozhui K, Karlsson RM, Kash TL, Ihne J, Norcross M, Patel S, Farrell MR, Hill EE, Graybeal C, Martin KP, Camp M, Fitzgerald PJ, Ciobanu DC, Sprengel R, Mishina M, Wellman CL, Winder DG, Williams RW, and Holmes A
- Subjects
- Animals, Dendritic Spines physiology, Excitatory Postsynaptic Potentials genetics, Excitatory Postsynaptic Potentials physiology, Gene Expression, Hippocampus physiopathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Neuronal Plasticity genetics, Neuronal Plasticity physiology, Prefrontal Cortex physiopathology, Receptors, AMPA deficiency, Receptors, AMPA genetics, Receptors, AMPA metabolism, Receptors, N-Methyl-D-Aspartate deficiency, Receptors, N-Methyl-D-Aspartate genetics, Receptors, N-Methyl-D-Aspartate metabolism, Restraint, Physical, Species Specificity, Synaptic Transmission genetics, Synaptic Transmission physiology, Amygdala physiopathology, Glutamic Acid metabolism, Neurons physiology, Stress, Psychological genetics, Stress, Psychological physiopathology
- Abstract
Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress and the qualitative nature of stress effects on behavior differ markedly among individuals. This is partly because of the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene-stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and after exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus maze). Gene expression analysis of amygdala, medial prefrontal cortex, and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after repeated restraint. Restraint produced strain-dependent expression alterations in various genes including glutamate receptors (e.g., Grin1, Grik1). To elucidate neuronal correlates of these strain differences, we performed ex vivo analysis of glutamate excitatory neurotransmission in amygdala principal neurons. Repeated restraint augmented amygdala excitatory postsynaptic signaling and altered metaplasticity (temporal summation of NMDA receptor currents) in DBA/2J but not C57BL/6J. Furthermore, we found that the C57BL/6J-like changes in anxiety-related behavior after restraint were absent in null mutants lacking the modulatory NMDA receptor subunit Grin2a, but not the AMPA receptor subunit Gria1. Grin2a null mutants exhibited significant ( approximately 30%) loss of dendritic spines on amygdala principal neurons under nonrestraint conditions. Collectively, our data support a model in which genetic variation in glutamatergic neuroplasticity in corticolimbic circuitry underlies phenotypic variation in responsivity to stress.
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- 2010
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37. Neonatal maternal separation alters the development of glucocorticoid receptor expression in the interpositus nucleus of the cerebellum.
- Author
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Wilber AA and Wellman CL
- Subjects
- Animals, Blinking physiology, Cerebellar Nuclei anatomy & histology, Conditioning, Classical physiology, Female, Glucocorticoids metabolism, Learning physiology, Male, Memory physiology, Random Allocation, Rats, Rats, Long-Evans, Receptors, Glucocorticoid genetics, Cerebellar Nuclei embryology, Cerebellar Nuclei metabolism, Maternal Deprivation, Receptors, Glucocorticoid physiology
- Abstract
Adverse early experience impairs adult learning and memory. Previously, we showed that neonatal maternal separation impaired eyeblink conditioning in adult male rats. This impairment was correlated with increases in glucocorticoid receptor expression in the posterior region of the cerebellar interpositus nucleus, a key structure in the neural circuitry controlling eyeblink conditioning. To begin to establish how separation results in altered glucocorticoid receptor expression in adulthood, we assessed the developmental pattern of glucocorticoid receptor expression in the interpositus nucleus in controls versus rats that had undergone maternal separation for 1h per day on postnatal days 2-14. Rat pups were exposed to either standard rearing (control) or maternal separation and glucocorticoid receptor expression was assessed at postnatal day 15, postnatal day 21, and adulthood. In control males, glucocorticoid receptor expression in the interpositus nucleus declined between postnatal days 15 and 21, then increased into adulthood. On postnatal day 15, there was less glucocorticoid receptor expression in the interpositus nucleus in males that were maternally separated than in controls. However, neonatal separation significantly attenuated the normal decline in the third postnatal week, resulting in significantly greater glucocorticoid receptor expression in the interpositus in separated males than in control rats at postnatal day 21. The developmental pattern of glucocorticoid receptor expression was not altered by maternal separation in female rats. Thus, maternal separation may impair learning and memory in adult males by altering normal developmental changes in glucocorticoid receptor expression.
- Published
- 2009
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38. Neonatal maternal separation-induced changes in glucocorticoid receptor expression in posterior interpositus interneurons but not projection neurons predict deficits in adult eyeblink conditioning.
- Author
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Wilber AA and Wellman CL
- Subjects
- Animals, Animals, Newborn, Cerebellar Nuclei cytology, Interneurons metabolism, Male, Rats, Rats, Long-Evans, Blinking, Cerebellar Nuclei metabolism, Conditioning, Classical, Maternal Deprivation, Neurons metabolism, Receptors, Glucocorticoid biosynthesis
- Abstract
Neonatal maternal separation impairs adult eyeblink conditioning. This impairment is correlated with increases in adult glucocorticoid receptor (GR) expression in the posterior interpositus nucleus [A.A. Wilber, C. Southwood, G. Sokoloff, J.E. Steinmetz, C.L. Wellman, Neonatal maternal separation alters adult eyeblink conditioning and glucocorticoid receptor expression in the interpositus nucleus of the cerebellum, Developmental Neurobiology 67 (2007) 1751-1764], a key structure in the neural circuitry controlling eyeblink conditioning. To further localize this effect, we assessed adult eyeblink conditioning and GR expression in projection versus interneurons in the interpositus of rats that had undergone standard rearing or maternal separation (1h/day) on postnatal days 2-14. At 3 months of age, interpositus neurons were labeled with the retrograde tracer biotinylated dextran amine (BDA). After delay eyeblink conditioning, brains were processed immunohistochemically for GR and BDA labeling of interpositus neurons. GR expression was quantified in BDA-labeled and unlabeled neurons. Neonatal maternal separation impaired adult eyeblink conditioning. Control rats had significantly less GR expression in posterior interpositus BDA-unlabeled versus BDA-labeled neurons, but this difference was absent in maternally separated rats. While neonatal separation significantly increased GR expression in BDA-labeled and unlabeled posterior interpositus neurons, only GR expression in non-BDA-labeled neurons was associated with eyeblink conditioning. Thus, neonatal maternal separation may alter interneuronal modulation of interpositus output neurons, producing deficits in adult eyeblink conditioning.
- Published
- 2009
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39. Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence.
- Author
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Garrett JE and Wellman CL
- Subjects
- Analysis of Variance, Animals, Body Weight drug effects, Body Weight physiology, Dendrites drug effects, Estradiol administration & dosage, Estrogens administration & dosage, Female, Male, Organ Size, Ovariectomy, Prefrontal Cortex drug effects, Pyramidal Cells cytology, Pyramidal Cells drug effects, Pyramidal Cells physiopathology, Rats, Rats, Sprague-Dawley, Restraint, Physical, Uterus drug effects, Uterus pathology, Dendrites physiology, Estrogens metabolism, Prefrontal Cortex cytology, Prefrontal Cortex physiopathology, Sex Characteristics, Stress, Psychological physiopathology
- Abstract
A growing body of work has documented sex differences in many behavioral, neurochemical, and morphological responses to stress. Chronic stress alters morphology of dendrites in medial prefrontal cortex in male rats. However, potential sex differences in stress-induced morphological changes in medial prefrontal cortex have not been examined. Thus, in Experiment 1 we assessed dendritic morphology in medial prefrontal cortex in male and female rats after chronic stress. Male and female rats underwent either 3 hours of restraint daily for 1 week or were left unhandled except for weighing. On the final day of restraint, all rats were euthanized and brains were stained using a Golgi-Cox procedure. Pyramidal neurons in layer II-III of medial prefrontal cortex were drawn in three dimensions, and morphology of apical and basilar arbors was quantified. In males, stress decreased apical dendritic branch number and length, whereas in females, stress increased apical dendritic length. In Experiment 2, we assessed whether estradiol mediates this stress-induced dendritic hypertrophy in females by assessing the effects of restraint stress on female rats that had received either ovariectomy with or without 17-beta-estradiol replacement or sham ovariectomy. Brains were processed and neurons reconstructed as described in Experiment 1. Both sham-operated and ovariectomized rats with estradiol implants showed stress-induced increases in apical dendritic material, whereas ovariectomy without estradiol replacement prevented the stress-induced increase. Thus, the stress-induced increase in apical dendritic material in females is estradiol-dependent.
- Published
- 2009
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40. Stress-induced prefrontal reorganization and executive dysfunction in rodents.
- Author
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Holmes A and Wellman CL
- Subjects
- Animals, Anxiety physiopathology, Attention physiology, Behavior, Animal physiology, Conditioning, Psychological physiology, Depression physiopathology, Fear, Learning physiology, Memory physiology, Neurons cytology, Neurons physiology, Prefrontal Cortex anatomy & histology, Prefrontal Cortex cytology, Cognition Disorders physiopathology, Neuronal Plasticity physiology, Prefrontal Cortex physiopathology, Stress, Psychological physiopathology
- Abstract
The prefrontal cortex (PFC) mediates a range of higher order 'executive functions' that subserve the selection and processing of information in such a way that behavior can be planned, controlled and directed according to shifting environmental demands. Impairment of executive functions typifies many forms of psychopathology, including schizophrenia, mood and anxiety disorders and addiction, that are often associated with a history of trauma and stress. Recent research in animal models demonstrates that exposure to even brief periods of intense stress is sufficient to cause significant structural remodeling of the principle projection neurons within the rodent PFC. In parallel, there is growing evidence that stress-induced alterations in PFC neuronal morphology are associated with deficits in rodent executive functions such as working memory, attentional set-shifting and cognitive flexibility, as well as emotional dysregulation in the form of impaired fear extinction. Although the molecular basis of stress-induced changes in PFC morphology and function are only now being elucidated, an understanding of these mechanisms could provide important insight into the pathophysiology of executive dysfunction in neuropsychiatric disease and foster improved strategies for treatment.
- Published
- 2009
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41. Sensitizing regimens of (+/-)3, 4-methylenedioxymethamphetamine (ecstasy) elicit enduring and differential structural alterations in the brain motive circuit of the rat.
- Author
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Ball KT, Wellman CL, Fortenberry E, and Rebec GV
- Subjects
- Adaptation, Physiological drug effects, Animals, Cerebrum cytology, Drug Administration Schedule, Gyrus Cinguli cytology, Gyrus Cinguli drug effects, Hallucinogens pharmacology, Male, Motor Activity drug effects, N-Methyl-3,4-methylenedioxyamphetamine pharmacology, Neural Pathways drug effects, Nucleus Accumbens cytology, Nucleus Accumbens drug effects, Prefrontal Cortex cytology, Prefrontal Cortex drug effects, Rats, Rats, Sprague-Dawley, Synaptic Transmission drug effects, Behavior, Animal drug effects, Cerebrum drug effects, Dendritic Spines drug effects, Hallucinogens administration & dosage, N-Methyl-3,4-methylenedioxyamphetamine administration & dosage, Neuronal Plasticity drug effects
- Abstract
Repeated, intermittent exposure to the psychomotor stimulants amphetamine and cocaine induces a progressive and enduring augmentation of their locomotor-activating effects, known as behavioral sensitization, which is accompanied by similarly stable adaptations in the dendritic structure of cortico-striatal neurons. We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also results in long-lasting behavioral and morphological changes in mesocortical (medial prefrontal cortex) and ventral striatal (nucleus accumbens) neurons. Rats received two daily injections of either 5.0 mg/kg (+/-)-MDMA or saline vehicle, approximately 6 h apart, for 3 consecutive days, followed by 4 drug-free days for a total of 3 weeks. Following a 4-week drug-free period, MDMA-pretreated rats displayed behavioral sensitization, as well as large increases in spine density and the number of multiple-headed spines on medium spiny neurons in core and shell subregions of nucleus accumbens. In medial prefrontal cortex, the prelimbic subregion showed increased spine density on distal dendrites of layer V pyramidal neurons, while the anterior cingulate subregion showed a change in the distribution of dendritic material instead. Collectively, our results show that long-lasting locomotor sensitization to MDMA is accompanied by reorganization of synaptic connectivity in limbic-cortico-striatal circuitry. The differential plasticity in cortical subregions, moreover, suggests that drug-induced structural changes are not homogeneous and may be specific to the circuitry underlying long-term changes in drug-seeking and drug-taking behavior.
- Published
- 2009
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42. Brief neonatal maternal separation alters extinction of conditioned fear and corticolimbic glucocorticoid and NMDA receptor expression in adult rats.
- Author
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Wilber AA, Southwood CJ, and Wellman CL
- Subjects
- Amygdala metabolism, Animals, Animals, Newborn, Behavior, Animal, Female, Freezing Reaction, Cataleptic physiology, Male, Pregnancy, Rats, Rats, Long-Evans, Conditioning, Classical physiology, Extinction, Psychological physiology, Fear, Frontal Lobe metabolism, Maternal Deprivation, Receptors, Glucocorticoid metabolism, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
Neonatal maternal separation alters adult HPA axis responsiveness to stress, adult emotionality, and glucocorticoid receptor (GR) concentrations in forebrain regions such as hippocampus. To investigate effects of neonatal maternal separation on emotion regulation and its neural substrates, we assessed acquisition and extinction of conditioned fear in adult rats that underwent neonatal maternal separation. Corticolimbic structures including basolateral amygdala and medial prefrontal cortex are critical for acquisition and extinction of conditioned fear, and such learning is N-methyl-D-aspartic acid (NMDA) receptor-dependent. Thus, we used immunohistochemistry to assess expression of the GR and the NR1 subunit of the NMDA receptor in basolateral amygdala and medial prefrontal cortex. On postnatal days 2-14, pups underwent control rearing or maternal separation for 15 min per day. Fear conditioning and extinction in adulthood were then assessed in male rats. Rats received five tone-alone habituation trials, then seven tone/footshock pairings. After 1 h, rats received tone-alone extinction trials to criterion, and 15 recall of extinction trials the next day. Brains were processed for immunohistochemical labeling of GR and NR1, and staining was quantified. Brief maternal separation did not alter acquisition or initial extinction, but impaired extinction recall. Brief maternal separation did not alter GR or NR1 expression in basolateral amygdala. However, brief maternal separation increased GR and decreased NR1 expression specifically in the infralimbic region of medial prefrontal cortex, consistent with work implicating this area in extinction recall. Thus, brief maternal separation impaired extinction recall and altered GR and NR1 expression in its neural substrate in adults.
- Published
- 2009
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43. Neonatal maternal separation alters adult eyeblink conditioning and glucocorticoid receptor expression in the interpositus nucleus of the cerebellum.
- Author
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Wilber AA, Southwood CJ, Sokoloff G, Steinmetz JE, and Wellman CL
- Subjects
- Animals, Animals, Newborn, Association Learning physiology, Conditioning, Classical, Female, Immunohistochemistry, Male, Rats, Rats, Long-Evans, Sex Characteristics, Blinking physiology, Cerebellum metabolism, Maternal Deprivation, Receptors, Glucocorticoid biosynthesis
- Abstract
Neonatal maternal separation alters learning and memory. Glucocorticoids also modulate adult learning and memory, and neonatal maternal separation alters forebrain glucocorticoid receptor (GR) concentrations. We used eyeblink classical conditioning to assess the effect of neonatal maternal separation on associative learning. We assessed delay eyeblink conditioning, GR expression, and total neuron number in the interpositus nucleus, a critical site of plasticity in eyeblink conditioning, in adult rats that had undergone either standard animal facilities rearing, handling for 15 min, or maternal separation for either 15 or 60 min per day on postnatal days 2-14. At 2-3 months of age, delay eyeblink classical conditioning was assessed. Brains were processed for GR immunohistochemistry, and GR expression in the interpositus nucleus was assessed using a computer-based densitometry system. Neuron counts and nuclear volumes were obtained from an alternate series of thionin-stained sections. Maternal separation significantly impaired eyeblink conditioning in male but not female rats. Handling and maternal separation did not significantly affect interpositus neuron number and volume. However, prolonged maternal separation significantly increased GR expression in the posterior interpositus in males, and increases were correlated with eyeblink conditioning. In female rats, maternal separation and handling did not significantly alter interpositus neuron number, volume, or GR protein expression, and GR expression did not correlate with eyeblink conditioning. Thus, neonatal maternal separation produces adult deficits in eyeblink conditioning and alterations in GR expression in its neural substrate in a sex-dependent manner., (2007 Wiley Periodicals, Inc)
- Published
- 2007
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44. Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice.
- Author
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Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein R, Lesch KP, Murphy DL, and Holmes A
- Subjects
- Amygdala cytology, Amygdala metabolism, Animals, Conditioning, Psychological physiology, Dendrites metabolism, Dendrites ultrastructure, Limbic System cytology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Serotonin Plasma Membrane Transport Proteins physiology, Stress, Psychological genetics, Adaptation, Psychological physiology, Extinction, Psychological physiology, Fear physiology, Limbic System metabolism, Serotonin Plasma Membrane Transport Proteins deficiency, Serotonin Plasma Membrane Transport Proteins genetics, Stress, Psychological metabolism
- Abstract
A lesser-expressing form of the human 5-HT transporter (5-HTT) gene has been associated with increased fear and anxiety and vulnerability to the effects of stress. These phenotypic abnormalities are linked to functional and anatomical disturbances in a neural pathway connecting the prefrontal cortex (PFC) and amygdala. Likewise, rodent and nonhuman primate studies indicate a major role for PFC and amygdala in the mediation of fear- and stress-related behaviors. We used a 5-HTT knock-out (KO) mouse to examine the effects of genetically driven loss of 5-HTT function for the following: (1) depression-related behavior in response to repeated stress, and pavlovian fear conditioning, extinction, and extinction recall; and (2) dendritic morphology and spine density of Golgi-stained pyramidal neurons in the infralimbic cortex (IL) and the basolateral amygdala (BLA). 5-HTT KO mice exhibited increased depressive-like immobility after repeated exposure to forced swim stress, compared with wild-type (WT) controls. Whereas fear conditioning and fear extinction was normal, 5-HTT KO mice exhibited a significant deficit in extinction recall. The apical dendritic branches of IL pyramidal neurons in 5-HTT KO mice were significantly increased in length relative to WT mice. Pyramidal neurons in BLA had normal dendritic morphology but significantly greater spine density in 5-HT KO mice compared with WT mice. Together, the present findings demonstrate a specific phenotypic profile of fear- and stress-related deficits in 5-HTT KO mice, accompanied by morphological abnormalities in two key neural loci. These data provide insight into the behavioral sequelae of loss of 5-HTT gene function and identify potential neural substrates underlying these phenotypes.
- Published
- 2007
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45. Receptor autoradiographic correlates of deafferentation-induced reorganization in adult primate somatosensory cortex.
- Author
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Garraghty PE, Arnold LL, Wellman CL, and Mowery TM
- Subjects
- Afferent Pathways anatomy & histology, Afferent Pathways injuries, Animals, Autoradiography, Binding, Competitive physiology, Denervation, Neural Inhibition physiology, Peripheral Nerve Injuries, Peripheral Nerves physiology, Peripheral Nerves surgery, Radioligand Assay, Receptors, AMPA metabolism, Receptors, GABA-A metabolism, Receptors, GABA-B metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Saimiri anatomy & histology, Somatosensory Cortex anatomy & histology, Time Factors, gamma-Aminobutyric Acid metabolism, Afferent Pathways metabolism, Neuronal Plasticity physiology, Receptors, Neurotransmitter metabolism, Saimiri physiology, Somatosensory Cortex metabolism
- Abstract
The primate somatosensory system provides an excellent model system with which to investigate adult neural plasticity. We have previously shown that transection of the median and ulnar nerves is followed by an expansion in the representation of radial nerve skin, and that this plasticity proceeds in stages. Immediately following nerve injury, new receptive fields are "unmasked" in a fraction of the affected cortex. The remaining deprived cortex regains responsiveness to tactile stimulation over the following days to weeks. Given these progressive changes, it has been suggested that different mechanisms might account for the earlier and later phases of reorganization. In the present experiments, we quantified receptor autoradiographic binding data for GABAA and GABAB, AMPA, and NMDA receptors in the primary somatosensory cortices of adult squirrel monkeys at four postnerve injury survival durations: immediately (1-3 hours), 3 days, 1 month, and 2 months. We found dramatic reductions in GABAA binding in layer IV within hours following nerve injury, and this reduction was maintained across all survival durations. This finding is consistent with the idea that the earliest reorganizational changes are due to a relaxation in tonic inhibitory mechanisms permitting the expression of formerly subthreshold receptive fields. GABAB receptor binding is decreased in layer IV by 1 month after nerve injury, while binding for AMPA receptors is increased in layer IV by this time. These findings are consistent with our previous suggestion that the second stage of reorganization proceeds via mechanisms comparable to those revealed to account for NMDA-dependent long-term potentiation in the hippocampus., (Copyright 2006 Wiley-Liss, Inc.)
- Published
- 2006
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46. Effect of N-methyl-d-aspartate receptor blockade on plasticity of frontal cortex after cholinergic deafferentation in rat.
- Author
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Garrett JE, Kim I, Wilson RE, and Wellman CL
- Subjects
- Animals, Antibodies, Monoclonal toxicity, Cell Count methods, Choline O-Acetyltransferase metabolism, Cholinergic Agents toxicity, Cholinergic Fibers drug effects, Denervation methods, Dizocilpine Maleate pharmacology, Excitatory Amino Acid Antagonists pharmacology, Functional Laterality, Immunohistochemistry methods, Immunotoxins toxicity, N-Glycosyl Hydrolases, Neuronal Plasticity drug effects, Neurons drug effects, Neurons ultrastructure, Rats, Receptors, AMPA antagonists & inhibitors, Ribosome Inactivating Proteins, Type 1, Saporins, Silver Staining methods, Spine metabolism, Spine ultrastructure, Cholinergic Fibers metabolism, Frontal Lobe cytology, Neuronal Plasticity physiology, Neurons metabolism, Receptors, AMPA physiology
- Abstract
Cholinergic projections from the nucleus basalis play a critical role in cortical plasticity. For instance, cholinergic deafferentation increases dendritic spine density and expression of the GluR1 subunit of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor in frontal cortex. Acetylcholine modulates glutamatergic activity in cortex, and the N-methyl-d-aspartate subtype of glutamate receptor plays a role in many forms of synaptic plasticity. To assess whether N-methyl-d-aspartate receptors mediate the increase in GluR1 and spine density resulting from cholinergic deafferentation, we examined the effect of N-methyl-d-aspartate receptor blockade on nucleus basalis lesion-induced upregulation of GluR1 and dendritic spines. Rats received unilateral sham or 192 IgG saporin lesions of the nucleus basalis. Half of the rats in each group were treated with the N-methyl-d-aspartate antagonist MK-801 or phosphate-buffered saline. Two weeks later, brains were processed for either immunohistochemical staining of the GluR1 subunit or Golgi histology. In layer II-III of frontal cortex, neuronal GluR1 expression was assessed using an unbiased stereological technique, and spine density was assessed on basilar branches of pyramidal neurons. GluR1 expression was increased after nucleus basalis lesion, but this increase was prevented with MK-801. Similarly, nucleus basalis-lesioned animals had significantly higher spine densities, and this effect was also prevented by treatment with MK-801. Thus, N-methyl-d-aspartate receptor blockade prevented both GluR1 and spine density upregulation following cholinergic deafferentation, suggesting that these effects are N-methyl-d-aspartate receptor-mediated.
- Published
- 2006
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47. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice.
- Author
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Izquierdo A, Wellman CL, and Holmes A
- Subjects
- Animals, Cerebral Cortex physiopathology, Conditioning, Classical, Limbic System physiopathology, Male, Mice, Mice, Inbred C57BL, Stress, Physiological physiopathology, Cerebral Cortex pathology, Dendrites pathology, Extinction, Psychological, Fear, Limbic System pathology, Stress, Physiological pathology
- Abstract
Extinction of conditioned fear responses is an active learning process resulting from the repeated presentation of a conditioned stimulus in the absence of the unconditioned aversive stimulus. Recent research implicates the medial prefrontal cortex (mPFC) in the mediation of fear extinction in rodents and the pathophysiology of posttraumatic stress disorder. However, there is currently little understanding of precisely how stress can impact fear extinction and the neural circuitry subserving this behavior. The present study examined the effects of brief exposure to an uncontrollable stressor on (1) fear conditioning and fear extinction, and (2) dendritic morphology of pyramidal neurons in the infralimbic (IL) and prelimbic (PL) regions of the mPFC in mice. Exposure to three episodes of stress ending 24 h before fear conditioning significantly attenuated the rate of cued fear extinction relative to nonstressed controls, but did not affect fear conditioning or cue or context recall. Analysis of Golgi-stained neurons showed that one or three exposures to daily swim stress caused significant retraction of terminal branches of apical, but not basilar, dendrites of IL neurons. In contrast, PL neuronal morphology was unaltered by stress. These data demonstrate that IL, but not PL, neurons are highly sensitive to even brief exposure to stress, and that this same form of stress impairs fear extinction. Present findings suggest that trauma may compromise the functional integrity of the mPFC with implications for the pathophysiology of certain neuropsychiatric disorders.
- Published
- 2006
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48. Chronic stress impairs recall of extinction of conditioned fear.
- Author
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Miracle AD, Brace MF, Huyck KD, Singler SA, and Wellman CL
- Subjects
- Animals, Chronic Disease, Dendrites physiology, Habituation, Psychophysiologic, Male, Mental Recall, Prefrontal Cortex physiology, Rats, Rats, Sprague-Dawley, Conditioning, Psychological, Extinction, Psychological, Fear, Stress, Psychological psychology
- Abstract
Chronic restraint stress produces retraction of apical dendrites of pyramidal neurons in medial prefrontal cortex. To begin to examine the functional significance of this dendritic reorganization, we assessed the effects of chronic restraint stress on a prefrontally mediated behavior, extinction of conditioned fear. After bar press training to obtain a baseline of activity against which to measure freezing, rats were either unstressed or stressed via placement in a plastic restrainer (3 h/day for 1 week). After an additional day of bar press training, rats underwent fear conditioning and extinction. Rats received five habituation trials to a 30-s tone (4.5 kHz, 80 db) followed by seven pairings of tone and footshock (500 ms, 0.5 mA). One hour later, rats received tone-alone extinction trials to criterion. The next day, rats received 15 additional extinction trials. Percent freezing was assessed during all phases of training. Stress did not significantly affect unconditioned responding to tone, acquisition of conditioned fear, or initial extinction, but significantly increased freezing on extinction day 2. Thus, consistent with the regressive dendritic changes seen in medial prefrontal cortex, one week of restraint stress specifically impaired recall of extinction, a pattern of deficits typical of animals with impaired medial prefrontal function.
- Published
- 2006
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49. Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex.
- Author
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Brown SM, Henning S, and Wellman CL
- Subjects
- Adaptation, Physiological, Animals, Corticosterone blood, Male, Rats, Rats, Sprague-Dawley, Stress, Physiological blood, Dendrites pathology, Neuronal Plasticity, Prefrontal Cortex pathology, Restraint, Physical methods, Stress, Physiological pathology
- Abstract
Prefrontal cortex is a target for glucocorticoids, shows neurochemical changes in response to stress and mediates many of the behaviors that are altered by chronic corticosterone administration. Three weeks of either daily corticosterone injections or 3 h daily restraint stress result in dendritic changes in pyramidal neurons in medial prefrontal cortex. Interestingly, vehicle injection results in similar but less pronounced changes. Thus, the mild stress of daily injections alone may alter morphology of medial prefrontal cortex, suggesting an exquisite sensitivity to chronic stress. To further examine this morphological sensitivity, we assessed the effect of 1 week of daily brief restraint stress on dendritic morphology in medial prefrontal cortex. Male rats were restrained 10 min per day for one week, handled daily or left unhandled. Rats were then overdosed and brains were stained using a Golgi-Cox procedure. Layer II-III pyramidal neurons in medial prefrontal cortex were drawn and dendritic morphology was quantified. One week of daily brief restraint resulted in selective remodeling of apical dendrites, with atrophy of up to 22-35% in distal branches and sparing of proximal branches. This pattern of reorganization is similar to that seen after either corticosterone injections or 3 weeks of daily 3 h restraint stress. Thus, the stress-induced dendritic changes in medial prefrontal cortex occur rapidly, and in response to a mild stressor.
- Published
- 2005
- Full Text
- View/download PDF
50. NMDA receptor binding declines differentially in three spinal motor nuclei during postnatal development.
- Author
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Verhovshek T, Wellman CL, and Sengelaub DR
- Subjects
- Age Factors, Animals, Animals, Newborn, Dizocilpine Maleate pharmacokinetics, Male, Protein Binding drug effects, Rats, Rats, Sprague-Dawley, Tritium pharmacokinetics, Receptors, N-Methyl-D-Aspartate metabolism, Spinal Cord anatomy & histology, Spinal Cord drug effects, Spinal Cord growth & development, Spinal Cord metabolism
- Abstract
The NMDA subtype of glutamate receptors mediates a variety of neuronal processes involved in the development of dendritic morphology. For example, NMDA receptor antagonism during the early postnatal period attenuates dendritic growth in spinal motoneurons. NMDA receptors are present in high levels in the spinal cord early in the postnatal period and decline during development, a period of extensive dendritic plasticity in the spinal cord. Previous studies have suggested that an adult pattern of distribution of NMDA receptors is established as early as postnatal day (P)21 (day of birth = P1). However, given that dendritic growth in spinal motoneurons is not complete by this age and that NMDA receptor activation is necessary for dendritic growth, we assessed NMDA receptor binding in specific spinal motor nuclei during normal development. NMDA receptors were labeled with [3H]MK-801 at P7, P14, P28, P49, and in adult male rats. Receptor binding in the spinal nucleus of the bulbocavernosus (SNB), dorsolateral nucleus (DLN) and retrodorsolateral nucleus (RDLN) was measured using in vitro quantitative autoradiography. NMDA receptor binding over the SNB, DLN and RDLN in intact males was initially high, and declined to adult levels. However, the time course of the decline differed across nuclei. The local decline in NMDA receptor binding observed in the SNB and DLN is coincident with the periods of dendritic growth in these nuclei, further supporting a role for NMDA receptors in the development of motoneuron dendritic morphology.
- Published
- 2005
- Full Text
- View/download PDF
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