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Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised., We would like to thank Loren Frank, UCSF, USA; Sheena Josselyn, Hospital for Sick Children, University of Toronto, Canada; Shantanu Jadhav, Brandeis University, USA; the European Animal Research Association (EARA); the Federation of European Neuroscience Societies Committee on Animals in Research (CARE); the Swiss Society for Neuroscience; the Society for Neuroscience Committee on Animals in Research (CAR); and Stichting Informatie Dierproeven (the Dutch foundation for public information on animal testing: SID) for input on and support for this article.

Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function. Studies employing rats lacking the serotonin transporter have shown that elevations in serotonin levels particularly affect the development of the whisker related part of the primary somatosensory (barrel) cortex. Therefore, we hypothesized that serotonin level disturbances during development alter brain activity related to whisker stimulation. We treated female dams with fluoxetine or vehicle from gestational day 11 onwards for 21 days. We investigated offspring’s brain activity during whisker stimulation using functional magnetic resonance imaging (fMRI) at adolescence and adulthood. Our results indicate that adolescent offspring displayed increased activity in hippocampal subareas and the mammillary body in the thalamus. Adult offspring exhibited increased functional activation of areas associated with (higher) sensory processing and memory such as the hippocampus, perirhinal and entorhinal cortex, retrospinal granular cortex, piriform cortex and secondary visual cortex. Our data imply that perinatal SSRI exposure leads to complex alterations in brain networks involved in sensory perception and processing.

Serotonin is synthetized through the action of tryptophan hydroxylase (TPH) enzymes. While the TPH2 isoform is responsible for the production of serotonin in the brain, TPH1 is expressed in peripheral organs. Interestingly, despite its peripheral localization, alterations of the gene coding for TPH1 have been related to stress sensitivity and an increased susceptibility for psychiatric pathologies. On these bases, we took advantage of newly generated TPH1−/− rats, and we evaluated the impact of the lack of peripheral serotonin on the behavior and expression of brain plasticity-related genes under basal conditions and in response to stress. At a behavioral level, TPH1−/− rats displayed reduced anxiety-like behavior. Moreover, we found that neuronal activation, quantified by the expression of Bdnf and the immediate early gene Arc and transcription of glucocorticoid responsive genes after 1 h of acute restraint stress, was blunted in TPH1−/− rats in comparison to TPH1+/+ animals. Overall, we provided evidence for the influence of peripheral serotonin levels in modulating brain functions under basal and dynamic situations.

Schizophrenia (SZ) is a psychiatric disorder with a convoluted etiology that includes cognitive symptoms, which arise from among others a dysfunctional dorsolateral prefrontal cortex (dlPFC). In our search for the molecular underpinnings of the cognitive deficits in SZ, we here performed RNA sequencing of gray matter from the dlPFC of SZ patients and controls. We found that the differentially expressed RNAs were enriched for mRNAs involved in the Liver X Receptor/Retinoid X Receptor (LXR/RXR) lipid metabolism pathway. Components of the LXR/RXR pathway were upregulated in gray matter but not in white matter of SZ dlPFC. Intriguingly, an analysis for shared genetic etiology, using two SZ genome-wide association studies (GWASs) and GWAS data for 514 metabolites, revealed genetic overlap between SZ and acylcarnitines, VLDL lipids, and fatty acid metabolites, which are all linked to the LXR/RXR signaling pathway. Furthermore, analysis of structural T1-weighted magnetic resonance imaging in combination with cognitive behavioral data showed that the lipid content of dlPFC gray matter is lower in SZ patients than in controls and correlates with a tendency towards reduced accuracy in the dlPFC-dependent task-switching test. We conclude that aberrations in LXR/RXR-regulated lipid metabolism lead to a decreased lipid content in SZ dlPFC that correlates with reduced cognitive performance.

Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits., Dysfunction of GABAergic neurons in the prefrontal cortex has been reported in schizophrenia. Here, the authors use the apomorphine-susceptible rat, which displays some schizophrenia-like behaviors, and show that interneurons in the medial prefrontal cortex are hypomyelinated, which may contribute to this behavioral phenotype.

Rats display a rich social behavioral repertoire. An important component of this repertoire is the emission of whistle-like calls in the ultrasonic range, so-called ultrasonic vocalizations (USV). Long low-frequency 22-kHz USV occur in aversive situations, including aggressive interactions, predator exposure, and electric shocks during fear conditioning. They are believed to reflect a negative affective state akin to anxiety and fear. A prominent theory suggests that 22-kHz USV function as alarm calls to warn conspecifics. Serotonin (5-hydroxytryptamine, 5-HT) is strongly implicated in the regulation of affective states, particularly anxiety and fear. A key component of the system is the 5-HT transporter (5-HTT, also known as SERT), regulating 5-HT availability in the synaptic cleft. In the present experiment, we studied the effects of SERT deficiency on overt fear-related behavior and alarm 22-kHz USV during fear conditioning in male and female rats. While overt fear-related behavior was not affected by SERT deficiency and sex, the emission of alarm 22-kHz USV was clearly reduced in homozygous SERT-/- but not heterozygous SERT+/- mutants, as compared to their wildtype SERT+/+ littermate controls. Genotype effects were particularly prominent in females. Females in general emitted fewer alarm 22-kHz USV than males. This supports the view that 22-kHz USV are, at least partly, independently regulated from anxiety or fear and as socially mediated alarm calls do not simply express a negative affective state. Reduced 22-kHz USV emission in rats lacking SERT might be due to social deficits in the use of 22-kHz USV as a socio-affective signal to warn conspecifics about threats. ispartof: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY vol:108 ispartof: location:England status: published

Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5–90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.

Contains fulltext : 229212.pdf (Publisher’s version ) (Open Access) Over the last few years, research indicated that Human Milk Oligosaccharides (HMOs) may serve to enhance cognition during development. HMOs hereby provide an exciting avenue in the understanding of the molecular mechanisms that contribute to cognitive development. Therefore, this review aims to summarize the reported observations regarding the effects of HMOs on memory and cognition in rats, mice and piglets. Our main findings illustrate that the administration of fucosylated (single or combined with Lacto-N-neoTetraose (LNnT) and other oligosaccharides) and sialylated HMOs results in marked improvements in spatial memory and an accelerated learning rate in operant tasks. Such beneficial effects of HMOs on cognition already become apparent during infancy, especially when the behavioural tasks are cognitively more demanding. When animals age, its effects become increasingly more apparent in simpler tasks as well. Furthermore, the combination of HMOs with other oligosaccharides yields different effects on memory performance as opposed to single HMO administration. In addition, an enhanced hippocampal long-term potentiation (LTP) response both at a young and at a mature age are reported as well. These results point towards the possibility that HMOs administered either in singular or combination forms have long-lasting, beneficial effects on memory and cognition in mammals.

Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other’s impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.

Vulnerability to drug addiction relies on substantial individual differences. We previously demonstrated that serotonin transporter knockout (SERT−/−) rats show increased cocaine intake and develop signs of compulsivity. However, the underlying neural mechanisms are not fully understood. Given the pivotal role of glutamate and prefrontal cortex in cocaine‐seeking behavior, we sought to investigate the expression of proteins implicated in glutamate neurotransmission in the prefrontal cortex of naïve and cocaine‐exposed rats lacking SERT. We focused on the infralimbic (ILc) and prelimbic (PLc) cortices, which are theorized to exert opposing effects on the control over subcortical brain areas. SERT−/− rats, which compared to wild‐type (SERT+/+) rats show increased ShA and LgA intake short‐access (ShA) and long‐access (LgA) cocaine intake, were sacrificed 24 h into withdrawal for ex vivo molecular analyses. In the ILc homogenate of SERT−/− rats, we observed a sharp increase in glial glutamate transporter 1 (GLT‐1) after ShA, but not LgA, cocaine intake. This was paralleled by ShA‐induced increases in GluN1, GluN2A, and GluN2B NMDA receptor subunits and their scaffolding protein SAP102 in the ILc homogenate, but not postsynaptic density, of these knockout animals. In the PLc, we found no major changes in the homogenate; conversely, the expression of GluN1 and GluN2A NMDA receptor subunits was increased in the postsynaptic density under ShA conditions and reduced under LgA conditions. These results point to SERT as a critical regulator of glutamate homeostasis in a way that differs between the subregions investigated, the duration of cocaine exposure as well as the cellular compartment analyzed., Serotonin transporter deletion is associated with increase cocaine intake. We sought to investigate the underlying mechanisms at the level of the glutamate synapse in the prelimbic and infralimbic cortices. We observed that serotonin transporter deletion is associated with dysregulation of the serotonergic synapse in a region specific manner.

Early life overfeeding is associated with cognitive decline and anxiety-like behaviors in later life. It is not clear whether there are individual differences in the effects of early life overfeeding and what the underlying mechanistic pathways are. We investigated the long-lasting effects of small litter size, an experimental manipulation to induce neonatal overfeeding, in two strains of mice, C57BL/6 and NMRI. We measured body weight, learning and memory, anxiety-related behaviors, interleukin-(IL)-1β and brain-derived-neurotrophic-factor (BDNF) levels in the hippocampus, and both basal and stress corticosterone levels in adult mice which have been nursed in small litters compared with those from control litters. Our findings showed that small litter size led to increased body weight in both strains of mice. Small litter size significantly decreased spatial memory and hippocampal BDNF levels, and increased hippocampal IL-1β, in NMRI mice, but not C57BL/6 mice. Interestingly, we found that small litter size resulted in a significant increase in anxiety-like behaviors and stress-induced corticosterone in NMRI mice, whereas small litter size reduced anxiety-like symptoms and stress-induced corticosterone levels in C57BL/6 mice. These data show that small litter size, which is life-long associated with increased body weight, affects memory and anxiety-related behaviors in a strain-dependent manner in male mice. This suggests that there are individual differences in the developmental consequences of early life overfeeding.

Contains fulltext : 169819.pdf (Publisher’s version ) (Closed access) The interaction of early life stress (ELS) and the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) has been associated with increased risk to develop depression in later life. We have used the maternal separation paradigm as a model for ELS exposure in homozygous and heterozygous 5-HTT knockout rats and measured urocortin 1 (Ucn1) mRNA and/or protein levels, Ucn1 DNA methylation, as well as 5-HT innervation in the centrally projecting Edinger-Westphal (EWcp) and dorsal raphe (DR) nuclei, both implicated in the regulation of stress response. We found that ELS and 5-HTT genotype increased the number of 5-HT neurons in specific DR subdivisions, and that 5-HTT knockout rats showed decreased 5-HT innervation of EWcp-Ucn1 neurons. Furthermore, ELS was associated with increased DNA methylation of the promoter region of the Ucn1 gene and increased expression of 5-HT receptor 1A in the EWcp. In contrast, 5-HTT deficiency was associated with site-specific alterations in DNA methylation of the Ucn1 promoter, and heterozygous 5-HTT knockout rats showed decreased expression of CRF receptor 1 in the EWcp. Together, our findings extend the existing literature on the relationship between EWcp-Ucn1 and DR-5-HT neurons. These observations will further our understanding on their potential contribution to mediate affect as a function of ELS interacting with 5-HTTLPR.

Active sensing requires adaptive motor (positional) control of sensory organs based on contextual, sensory and task requirements, and develops postnatally after the maturation of intracortical circuits. Alterations in sensorimotor network connectivity during this period are likely to impact sensorimotor computation also in adulthood. Serotonin is among the cardinal developmental regulators of network formation, thus changing the serotonergic drive might have consequences for the emergence and maturation of sensorimotor control. Here we tested this hypothesis on an object localization task by quantifying the motor control dynamics of whiskers during tactile navigation. The results showed that sustained alterations in serotonergic signaling in serotonin transporter knockout rats, or the transient pharmacological inactivation of the transporter during early postnatal development, impairs the emergence of adaptive motor control of whisker position based on recent sensory information. A direct outcome of this altered motor control is that the mechanical force transmitted to whisker follicles upon contact is reduced, suggesting that increased excitability observed upon altered serotonergic signaling is not due to increased synaptic drive originating from the periphery upon whisker contact. These results argue that postnatal development of adaptive motor control requires intact serotonergic signaling and that even its transient dysregulation during early postnatal development causes lasting sensorimotor impairments in adulthood.

Adolescence is a developmental phase characterized by emotional turmoil and coincides with the emergence of affective disorders. Inherited serotonin transporter (5-HTT) downregulation in humans increases sensitivity to these disorders. To reveal whether and how 5-HTT gene variance affects fear-driven behavior in adolescence, we tested wildtype and serotonin transporter knockout (5-HTT&minus, /&minus, ) rats of preadolescent, adolescent, and adult age for cued fear extinction and extinction recall. To analyze neural circuit function, we quantified inhibitory synaptic contacts and, through RT-PCR, the expression of c-Fos, brain-derived neurotrophic factor (BDNF), and NDMA receptor subunits, in the medial prefrontal cortex (mPFC) and amygdala. Remarkably, the impaired recall of conditioned fear that characterizes preadolescent and adult 5-HTT&minus, rats was transiently normalized during adolescence. This did not relate to altered inhibitory neurotransmission, since mPFC inhibitory immunoreactivity was reduced in 5-HTT&minus, rats across all ages and unaffected in the amygdala. Rather, since mPFC (but not amygdala) c-Fos expression and NMDA receptor subunit 1 expression were reduced in 5-HTT&minus, rats during adolescence, and since PFC c-Fos correlated negatively with fear extinction recall, the temporary normalization of fear extinction during adolescence could relate to altered plasticity in the developing mPFC.

Sensory Processing Sensitivity (SPS) is a common, heritable and evolutionarily conserved trait describing inter-individual differences in sensitivity to both negative and positive environments. Despite societal interest in SPS, scientific knowledge is lagging behind. Here, we critically discuss how SPS relates to other theories, how to measure SPS, whether SPS is a continuous vs categorical trait, its relation to other temperament and personality traits, the underlying aetiology and neurobiological mechanisms, and relations to both typical and atypical development, including mental and sensory disorders. Drawing on the diverse expertise of the authors, we set an agenda for future research to stimulate the field. We conclude that SPS increases risk for stress-related problems in response to negative environments, but also provides greater benefit from positive and supportive experiences. The field requires more reliable and objective assessment of SPS, and deeper understanding of its mechanisms to differentiate it from other traits. Future research needs to target prevention of adverse effects associated with SPS, and exploitation of its positive potential to improve well-being and mental health. ispartof: NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS vol:98 pages:287-305 ispartof: location:United States status: published

Contains fulltext : 200575.pdf (Publisher’s version ) (Open Access) Background: Active sensing is crucial for navigation. It is characterized by self-generated motor action controlling the accessibility and processing of sensory information. In rodents, active sensing is commonly studied in the whisker system. As rats and mice modulate their whisking contextually, they employ frequency and amplitude modulation. Understanding the development, mechanisms, and plasticity of adaptive motor control will require precise behavioral measurements of whisker position. Findings: Advances in high-speed videography and analytical methods now permit collection and systematic analysis of large datasets. Here, we provide 6,642 videos as freely moving juvenile (third to fourth postnatal week) and adult rodents explore a stationary object on the gap-crossing task. The dataset includes sensory exploration with single- or multi-whiskers in wild-type animals, serotonin transporter knockout rats, rats received pharmacological intervention targeting serotonergic signaling. The dataset includes varying background illumination conditions and signal-to-noise ratios (SNRs), ranging from homogenous/high contrast to non-homogenous/low contrast. A subset of videos has been whisker and nose tracked and are provided as reference for image processing algorithms. Conclusions: The recorded behavioral data can be directly used to study development of sensorimotor computation, top-down mechanisms that control sensory navigation and whisker position, and cross-species comparison of active sensing. It could also help to address contextual modulation of active sensing during touch-induced whisking in head-fixed vs freely behaving animals. Finally, it provides the necessary data for machine learning approaches for automated analysis of sensory and motion parameters across a wide variety of signal-to-noise ratios with accompanying human observer-determined ground-truth. 6 p.

Summary Aims One potential risk factor for posttraumatic stress disorder (PTSD) involves the low activity (short; s) allelic variant of the serotonin transporter‐linked polymorphic region (5‐HTTLPR), possibly due to reduced prefrontal control over the amygdala. Evidence shows that DNA methylation/demethylation is crucial for fear extinction in these brain areas and is associated with neuronal activation marker c‐Fos expression. We hypothesized that impaired fear extinction in serotonin transporter knockout (5‐HTT −/−) rats is related to changes in DNA (de) methylation and c‐Fos expression in the prefrontal cortex (PFC) and/or amygdala. Methods 5‐HTT −/− and 5‐HTT +/+ rats were subjected to fear extinction. 2 hours after the extinction session, the overall levels of DNA methylation (5‐mC), demethylation (5‐hmC), and c‐Fos in fear extinction and nonfear extinction rats were measured by immunohistochemistry. Results 5‐HTT −/− rats displayed decreased fear extinction. This was associated with reduced c‐Fos activity in the infralimbic PFC. In the central nucleus of the amygdala, c‐Fos immunoreactivity was increased in the fear extinction group compared to the no‐fear extinction group, regardless of genotype. 5‐hmC levels were unaltered in the PFC, but reduced in the amygdala of nonextinction 5‐HTT −/− rats compared to nonextinction wild‐type rats, which caught up to wild‐type levels during fear extinction. 5‐mC levels were stable in central amygdala in both wild‐type and 5‐HTT −/− extinction rats. Finally, c‐Fos and 5‐mC levels were correlated with the prelimbic PFC, but not amygdala. Conclusions In the amygdala, DNA demethylation, independent from c‐Fos activation, may contribute to individual differences in risk for PTSD, as conferred by the 5‐HTTLPR s‐allele.

Contains fulltext : 174398.pdf (Publisher’s version ) (Closed access) Autism spectrum disorders (ASD) are a highly heterogeneous group of neurodevelopmental disorders caused by complex interplay between various genes and environmental factors during embryonic development. Changes at the molecular, cellular and neuroanatomical levels are especially evident in the medial prefrontal cortex (mPFC) of ASD patients and are particularly contributing to social impairments. In the present study we tested the hypothesis that altered neuronal development and plasticity, as seen in the mPFC of ASD individuals, may result from aberrant expression of functionally connected genes. Towards this end, we combined transcriptome sequencing and computational gene ontology analysis to identify the molecular networks impaired in the mPFC of a valproic acid (VPA) rat model of autism. This investigation identified two subsets of genes differentially expressed in the mPFC of VPA rats: one group of genes being functionally involved in the regulation of the circadian rhythm, while the second group encompasses a set of differentially expressed collagen genes acting within the extracellular matrix. Ultimately, our integrated transcriptome analysis identified a distinct subset of altered gene networks in the mPFC of VPA rats, contributing to our understanding of autism at the molecular level, thus providing novel insight into the genetic alterations associated with this neurodevelopmental disorder.

Contains fulltext : 175071.pdf (Publisher’s version ) (Open Access) Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar ("matching") adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA-axis hyper-reactivity in adulthood, as also found in major depression. This hyper-activity is related to increased corticotrophin-releasing hormone signaling and impaired glucocorticoid receptor-mediated negative feedback. In contrast, initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder, and future studies should investigate its neural/neuroendocrine foundation in further detail. Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.

Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula.

Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on the brain regions involved. In the present study, we determined how brain-wide inhibition of TrkB signaling affects cocaine intake, the motivation for the drug, and reinstatement of drug taking after extinction. To overcome the inability of TrkB ligands to cross the blood–brain barrier, the TrkB antagonist cyclotraxin-B was fused to the nontoxic transduction domain of the tat protein from human immunodeficiency virus type 1 (tat-cyclotraxin-B). Intravenous injection of tat-cyclotraxin-B dose-dependently reduced cocaine intake, motivation for cocaine (as measured under a progressive ratio schedule of reinforcement), and reinstatement of cocaine taking in rats allowed either short or long access to cocaine self-administration. In contrast, the treatment did not affect operant responding for a highly palatable sweet solution, demonstrating that the effects of tat-cyclotraxin-B are specific for cocaine reinforcement. Cocaine self-administration increased TrkB signaling and activated the downstream Akt pathway in the nucleus accumbens, and had opposite effects in the prefrontal cortex. Pretreatment with tat-cyclotraxin-B normalized protein levels in these two dopamine-innervated brain regions. Cocaine self-administration also increased TrkB signaling in the ventral tegmental area, where the dopaminergic projections originate, but pretreatment with tat-cyclotraxin-B did not alter this effect. Altogether, our data show that systemic administration of a brain-penetrant TrkB antagonist leads to brain region-specific effects and may be a potential pharmacological strategy for the treatment of cocaine addiction. SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors plays a well established role in cocaine reinforcement. However, local manipulation of BDNF signaling yields divergent effects, depending on the brain region, thereby questioning the viability of systemic TrkB targeting for the treatment of cocaine use disorders. Our study provides first-time evidence that systemic administration of a brain-penetrant TrkB antagonist (tat-cyclotraxin-B) reduces several behavioral measures of cocaine dependence, without altering motor performance or reinforcement by a sweet palatable solution. In addition, although cocaine self-administration produced opposite effects on TrkB signaling in the nucleus accumbens and prefrontal cortex, tat-cyclotraxin-B administration normalized these cocaine-induced changes in both brain regions.

Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety-like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction., Summary: Rats with a novel dopamine D1 receptor mutation, which causes reduced membrane Drd1 expression, display impaired social cognition, although their exploratory and anxiety-like behaviours are unaffected.

Fluoxetine (ProzacA (R)) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus. The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats. Pregnant rats were injected daily with 12 mg/kg fluoxetine or vehicle from gestational day 11 until birth, and the behavior of the offspring was monitored. Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0 mu g/g) were detected in the pup brain 5 h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day 7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4 weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT1A agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls. Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT1A receptor signaling.

Depression and abdominal obesity often co-occur, predominantly in women, and are associated with an increased risk for the development of glucose intolerance and subsequently type 2 diabetes. The underlying mechanisms are poorly understood. We found that female, but not male, depression-prone serotonin transporter knockout (SERT(-/-)) rats had a strong increase (54%) in abdominal fat, whereas no increases in plasma concentrations of glucose and insulin were observed. Surprisingly, application of a high-fat, high-sucrose (HFHS)-choice diet, which results in increased abdominal fat deposition and increased plasma glucose levels in wild-type rats, did not result in elevated plasma glucose levels in female SERT(-/-) rats. Our results show that serotonin transporter deficiency affects abdominal fat deposition in a sex-dependent way, but protects against rises in glucose levels, and thereby potentially glucose intolerance. The increased abdominal fat formation could result from serotonin-mediated developmental changes and provides heuristic value for understanding the effects of the depression-associated serotonin transporter promoter polymorphism in humans.Obesity (2009) doi:10.1038/oby.2009.139.

Contains fulltext : 81563.pdf (Publisher’s version ) (Closed access) Serotonin is well known for its role in affection, but less known for its role in cognition. The serotonin transporter (SERT) has an essential role in serotonergic neurotransmission as it determines the magnitude and duration of the serotonin signal in the synaptic cleft. There is evidence to suggest that homozygous SERT knockout rats (SERT(-/-)), as well as humans with the short SERT allele, show stronger cognitive effects than wild-type control rats (SERT(+/+)) and humans with the long SERT allele after acute tryptophan depletion. In rats, SERT genotype is known to affect brain serotonin levels, with SERT(-/-) rats having lower intracellular basal serotonin levels than wild-type rats in several brain areas. In the present study, it was investigated whether SERT genotype affects memory performance in an object recognition task with different inter-trial intervals. SERT(-/-), heterozygous SERT knockout (SERT(+/-)) and SERT(+/+) rats were tested in an object recognition test applying an inter-trial interval of 2, 4 and 8 h. SERT(-/-) and SERT(+/-) rats showed impaired object memory with an 8 h inter-trial interval, whereas SERT(+/+) rats showed intact object memory with this inter-trial interval. Although brain serotonin levels cannot fully explain the SERT genotype effect on object memory in rats, these results do indicate that serotonin is an important player in object memory in rats, and that lower intracellular serotonin levels lead to enhanced memory loss. Given its resemblance with the human SERT-linked polymorphic region and propensity to develop depression-like symptoms, our findings may contribute to further understanding of mechanisms underlying cognitive deficits in depression.