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[Display omitted] • Focal cortical cooling altered somatosensory evoked potentials (SEPs). • SEP amplitude was negatively correlated with cortical temperatures of 27.5−38.0 °C. • GABA A R but not AMPAR nor NMDAR antagonists eliminated the negative correlation. • GABAergic signaling is involved in the temperature dependency of SEPs. Although the focal brain cooling technique is widely used to examine brain function, the effects of cortical temperature at various levels on sensory information processing and neural mechanisms remain underexplored. To elucidate the mechanisms of temperature modulation in somatosensory processing, this study aimed to examine how P1 and N1 deflections of somatosensory evoked potentials (SEPs) depend on cortical temperature and how excitatory and inhibitory inputs contribute to this temperature dependency. SEPs were generated through electrical stimulation of the contralateral forepaw in anesthetized rats. The SEPs were recorded while cortical temperatures were altered between 17–38 °C either without any antagonists, with a gamma-aminobutyric acid type A (GABA A) receptor antagonist (gabazine), with an aminomethylphosphonic acid (AMPA) receptor antagonist (NBQX), or with an N -Methyl-D-aspartic acid (NMDA) receptor antagonist ([R]-CPP). The effects of different gabazine concentrations (0, 1, and 10 µM) were examined in the 35–38 °C range. The P1/N1 amplitudes and their peak-to-peak differences plotted against cortical temperature showed an inverted U relationship with a maximum at approximately 27.5 °C when no antagonists were administered. The negative correlation between these amplitudes and temperatures of ≥ 27.5 °C plateaued after gabazine administration, which occurred progressively as the gabazine concentration increased. In contrast, the correlation remained negative after the administration of NBQX and (R)-CPP. These results suggest that GABAergic inhibitory inputs contribute to the negative correlation between SEP amplitude and cortical temperature around the physiological cortical temperature. [ABSTRACT FROM AUTHOR]

[Display omitted] • Comparison of intracortical responses to three levels of electrical stimulation. • It was possible to distinguish between the three levels of electrical stimulation. • Investigated two different types of anesthesia to make the differentiation. Cortical responses have been proposed as a source for the extraction of unique and non-subjective sensory information. The present study aimed to investigate if it is possible to distinguish between non-noxious and noxious cortical responses with two different types of anesthesia. Sixteen rats were randomly allocated to receive either Hypnorm/Dormicum (HD) or isoflurane (ISO) anesthesia. Each animal had a custom-made microelectrode array implanted in the primary somatosensory cortex to record the local field potentials and a cuff electrode implanted around the sciatic nerve to deliver electrical stimulations. Three stimulation intensities were applied: 1x movement threshold (MT) (i.e., non-noxious activation), 5x MT (low intensity noxious activation), and 10x MT (high intensity noxious activation). The evoked potentials were assessed by extracting three features: 1) the negative peak (NP), 2) the positive peak (PP), and 3) the peak-to-peak (PtP) amplitudes. Our results showed that it was possible to distinguish between three levels of stimulation intensities based on the NP, PP, and PtP features for the HD group, whereas it was only possible to make the same differentiation with the use of PP and PtP when applying ISO. This work is believed to contribute to a basic understanding of how the cortical responses change in the hyperacute phase of pain and which cortical features may be suitable as objective measures of nociception. [ABSTRACT FROM AUTHOR]

Maternal deprivation (MDep) of neonatal rats significantly influences the hypothalamic-pituitary-adrenal (HPA) axis. This study hypothesized that GR-mRNA modulation constituted an early, critical mechanism for the acute effects of MDep on neuroendocrine stress-responses. GR-mRNA hybridization signal in hippocampal CA1, hypothalamic paraventricular nucleus (PVN) and frontal cortex was significantly reduced immediately following 24 h MDep. In amygdala, cingulate cortex, PVN and CA1, apparent gender-dependent MDep effects on GR-mRNA expression were observed, without significant differences in absolute levels. Thus, rapid, region-specific MDep effects on GR-mRNA expression in HPA-regulating areas are shown, consistent with involvement of GR-expression in mechanisms of MDep influence on HPA tone.

• Glucocorticoid receptor (GR) expression in the amygdala is altered by prenatal alcohol exposure (PAE). • PAE effects on amygdala GR expression were more pronounced during adolescence. • GR expression in the mPFC is altered by adolescent stress. • Adolescent stress effects on mPFC GR expression were more pronounced in adulthood. The dense expression of glucocorticoid receptors (GR) within the amygdala, medial prefrontal cortex (mPFC) and paraventricular nucleus of hypothalamus (PVN) mediates many aspects of emotional and stress regulation. Importantly, both prenatal alcohol exposure (PAE) and adolescent stress are known to induce emotional and stress dysregulation. Little is known, however, about how PAE and/or adolescent stress may alter the expression of GR in the amygdala, mPFC, and PVN. To fill this gap, we exposed PAE and control adolescent male and female rats to chronic mild stress (CMS) and assessed GR mRNA expression in the amygdala, mPFC, and PVN immediately following stress or in adulthood. We found that the effects of PAE on GR expression were more prevalent in the amygdala, while effects of adolescent stress on GR expression were more prevalent in the mPFC. Moreover, PAE effects in the amygdala were more pronounced during adolescence and adolescent stress effects in the mPFC were more pronounced in adulthood. GR expression in the PVN was affected by both PAE and adolescent stress. Finally, PAE and/or adolescent stress effects were distinct between males and females. Together, these results suggest that PAE and adolescent CMS induce dynamic alterations in GR expression in the amygdala, mPFC, and PVN, which manifest differently depending on the brain area, age, and sex of the animal. Additionally, these data indicate that PAE-induced hyperresponsiveness to stress and increased vulnerability to mental health problems may be mediated by different neural mechanisms depending on the sex and age of the animal. [ABSTRACT FROM AUTHOR]

• MCAO in the rat results in acute and chronic lingual weakness. • Changes in swallowing after MCAO include reduced bolus size and speed. • MCAO can be used to model post stroke dysphagia in the rat. Dysphagia is a common problem after stroke that is often associated with tongue weakness. However, the physiological mechanisms of post-stroke tongue muscle weakness and optimal treatments have not been established. To advance understanding of physiological mechanisms of post stroke dysphagia, we sought to validate the unilateral transient middle cerebral artery occlusion (MCAO) rat model of ischemic stroke as a translational model of post stroke dysphagia. Our goal was to establish clinically relevant measures and chronicity of functional deficits; criteria that increase the likelihood that findings will translate to the clinic. We hypothesized that MCAO would cause tongue weakness and functional swallowing changes. Maximum voluntary tongue forces and videofluoroscopic swallowing studies were collected in 8-week old male Sprague-Dawley rats prior to receiving either a left MCAO (N = 10) or sham (N = 10) surgery. Tongue forces and VFSS were reassessed at 1 and 8 weeks post-surgery. Maximum voluntary tongue force, bolus area, and bolus speed were significantly reduced in the MCAO group at the 1 and 8-week timepoints. Clinically relevant changes to swallowing and tongue force support the use of the MCAO rat model as a translational model of post stroke dysphagia. This model will allow for future studies to improve our understanding of the physiology contributing to these functional changes as well as the impact of therapeutic interventions on physiological targets and function. [ABSTRACT FROM AUTHOR]

• Objective parameters of the AEPs were identified in rats treated with SS. • Reduced sensory input was shown by hearing thresholds and ABR peak I amplitudes. • Reduced latencies were found in the ABR (8-24kHz), MLR and LLR in SS-induced tinnitus. • Central gain was reflected by increased amplitudes in ABR, MLR, and LLR. • Behavioral tinnitus was correlated to peak IV of ABR, and P2 and N2 of LLR. Early-response auditory evoked potentials (AEPs) in humans are significantly altered in tinnitus. These changes are closely related to that seen in animals, leading to new approaches to study tinnitus based on objective parameters. The purpose of this study was to characterize the AEPs in animals with tinnitus, by assessing early to late latency responses. For behavioral evaluation, rats were trained using positive reinforcement to press a lever in the presence of an auditory stimulus and to not press during silence. The auditory brainstem response (ABR), middle latency response (MLR) and auditory late latency response (LLR) were correlated to the false-positive responses (pressing the lever during silence), after oral administrations of Sodium Salicylate (SS, 350 mg/kg). In the present study, SS significantly increased the hearing thresholds and reduced ABR peak I amplitudes across the frequency range (4–32 kHz). In contrast, increased amplitudes were observed for several peaks in ABR, MLR, and LLR. Moreover, reduced ABR latencies in response to 8, 16 and 24 kHz tone bursts were observed after SS administration. Similarly, the central evaluation also revealed significantly reduced latencies in MLR and LLR during SS administration. In contrast, increased latencies were observed for ABR latencies in response to 32 kHz tone bursts, and at the P1-N1 component of LLR. Correlational analysis revealed that latencies and amplitudes of peaks II and IV (8 and 16 kHz) of ABR, and N2 latency and P2-N2 amplitude of LLR were associated with behavioral tinnitus. We suggest that AEPs can be used in the rat to evaluate the reduced sensory input and the increased central gain in SS-induced tinnitus, as well as reduced latencies (8–16 kHz) to distinguish between hearing loss and tinnitus. [ABSTRACT FROM AUTHOR]

• Dopamine (DA) signals are modulated by both appetitive and aversive events. • DA error signals increase and decrease to presence and absence of appetitive events. • DA error signals increase and decrease to avoidable and unavoidable aversive events. • Some dopamine neurons increase firing to salient events, both appetitive and aversive. Using environmental cues to acquire good and avoid harmful things is critical for survival. Rewarding and aversive outcomes both drive behavior through reinforcement learning and sometimes occur together in the environment, but it remains unclear how these signals are encoded within the brain and if signals for positive and negative reinforcement are encoded similarly. Recent studies demonstrate that the dopaminergic system and interconnected brain regions process both positive and negative reinforcement necessary for approach and avoidance behaviors, respectively. Here, we review these data with a special focus on behavioral paradigms that manipulate both expected reward and the avoidability of aversive events to reveal neural correlates related to value, prediction error encoding, motivation, and salience. [ABSTRACT FROM AUTHOR]

Highlights • Prescription psychostimulants are used as performance enhancing agents. • Psychostimulants exert their effects by increasing concentrations of DA and NE throughout the brain. • The LC-NE system regulates state dependent modulation of sensory processing. • NE-mediated sensory enhancement may be a component of these agents' performance enhancing effects. Abstract Prescription stimulants are used to treat attention deficit hyperactivity disorder (ADHD). Psychostimulants are also used off-label by non-ADHD patients as performance-enhancing agents across academic, occupational, athletic, and social settings. Extensive work has focused on the reinforcing effects and abuse liability of psychostimulants, but understanding the mechanisms through which these agents regulate neural circuit functions that govern cognitive and sensorimotor processes to result in their performance-enhancing effects has received less attention. Optimal detection of sensory information within complex, dynamic environments is critical for appropriate decision making and executive actions. As such, overall performance enhancement may significantly rely on improvements in the processing of incoming sensory stimuli. Psychostimulants enhance catecholamine neurotransmission through the blockade of dopamine and norepinephrine (NE) reuptake transporters. The ascending locus coeruleus (LC)-NE system regulates behavioral state and modulates state dependent transmission of sensory signals. LC stimulation and local administration of NE to sensory processing areas of the brain can change the dynamics of both cellular and circuit activity in response to incoming sensory information. Here we explore the LC-NE system's neuromodulatory role in altering sensory signal processing as a plausible mechanism through which psychostimulant agents amplify physiological responses to important sensory stimuli as a component of their performance-enhancing effects in both ADHD patients and otherwise healthy individuals. We further consider sensory enhancement as a desirable outcome that has not previously been explored as an element of therapeutic efficacy, as well as added motivation for otherwise healthy individuals to engage in off-label self-administration of psychostimulant drugs. [ABSTRACT FROM AUTHOR]

Highlights • The LC-NE system regulates neural coding linked to cognitive changes. • LC-NE activity levels and patterns drive different neurocomputational states. • LC-NE regulation of sensory system coding reflects perceptual changes. • LC-NE regulation of sensory function is relevant for context appropriate behaviors. Abstract Flexible and adaptive behaviors have evolved with increasing complexity and numbers of neuromodulator systems. The neuromodulatory locus coeruleus-norepinephrine (LC-NE) system is central to regulating cognitive function in a behaviorally-relevant and arousal-dependent manner. Through its nearly ubiquitous efferent projections, the LC-NE system acts to modulate neuron function on a cell-by-cell basis and exert a spectrum of actions across different brain regions to optimize target circuit function. As LC neuron activity, NE signaling, and arousal level increases, cognitive performance improves over an inverted-U shaped curve. Additionally, LC neurons burst phasically in relation to novel or salient sensory stimuli and top-down decision- or response-related processes. Together, the variety of LC activity patterns and complex actions of the LC-NE system indicate that the LC-NE system may dynamically regulate the function of target neural circuits. The manner in which neural networks encode, represent, and perform neurocomputations continue to be revealed. This has improved our ability to understand the optimization of neural circuits by NE and generation of flexible and adaptive goal-directed behaviors. In this review, the rat vibrissa somatosensory system is explored as a model neural circuit to bridge known modulatory actions of NE and changes in cognitive function. It is argued that fluid transitions between neural computational states reflect the ability of this sensory system to shift between two principal functions: detection of novel or salient sensory information and detailed descriptions of sensory information. Such flexibility in circuit function is likely critical for producing context-appropriate sensory signal processing. Nonetheless, many challenges remain including providing a causal link between NE mediated changes in sensory neural coding and perceptual changes, as well as extending these principles to higher cognitive functions including behavioral flexibility and decision making. [ABSTRACT FROM AUTHOR]

Highlights • HCN1-deficient rat strain was developed by TALEN mutagenesis. • The Hcn1 -deficient rats exhibited reduced hyperpolarization-activated currents. • The Hcn1 -deficient rats exhibited spontaneous SWDs accompanying behavioral arrest. • Both SWDs and behavioral arrest were suppressed by ethosuximide. • These findings demonstrate that deficiency of HCN1 caused absence epilepsy in rats. Abstract Hyperpolarized-activated cyclic nucleotide-gated (HCN) channels underlie hyperpolarization-activated current (I h) and are involved in controlling the excitability and electrical responsiveness of neurons. Absence epilepsy is clinically defined by a sudden, brief impairment of consciousness and behavioral arrest. Spike-and-wave discharges (SWDs) on electroencephalograms (EEG) are a diagnostic hallmark of absence epilepsy. In rat models of absence epilepsy, impaired function or expression of HCN1, a subtype of HCN channels, has been found. Here, to evaluate whether HCN1 deficiency causes absence epilepsy in rats, we developed Hcn1 -knockout rats by transcription activator-like effector nuclease mutagenesis. The cortical and hippocampal pyramidal neurons of these rats displayed a significant reduction of I h , a pronounced hyperpolarizing shift of the resting membrane potential, and increased input resistance, which indicated that the Hcn1 -knockout rats were deficient in HCN1 function. The Hcn1 -knockout rats were also more vulnerable to pentylenetetrazol-induced acute convulsions. More importantly, they exhibited spontaneous SWDs, which were accompanied by behavioral arrest, both of which were suppressed by ethosuximide. These results confirm the involvement of the HCN1 subunit in the regulation of input resistance and provide direct evidence that a deficiency of HCN1 caused absence epilepsy in rats. [ABSTRACT FROM AUTHOR]

Highlights • We examined how prior chemosensory experience impacted GC and PIR c-Fos expression. • Stimuli included taste (sucrose), odor (isoamyl acetate) and an odor-taste mix. • All novel chemosensory stimuli induced greater GC c-Fos expression. • Novel odor and odor-taste mix, but not taste, induced greater PIR c-Fos expression. Abstract Eating a new food is a unique event that guides future food choices. A key element for these choices is the perception of flavor (odor-taste associations), a multisensory process dependent upon taste and smell. The two primary cortical areas for taste and smell, gustatory cortex and piriform cortex, are thought to be crucial regions for processing and responding to odor-taste mixtures. To determine how previous experience impacts the primary chemosensory cortices, we compared the expression of the immediate early gene, c-Fos, between rats presented with a taste, an odor, or an odor-taste mixture for the first-time with rats that had many days of prior experience. Compared to rats with prior experience, we found that first-time sampling of all three chemosensory stimuli led to significantly greater c-Fos expression in gustatory cortex. In piriform cortex, only the novel chemosensory stimuli containing odors showed greater c-Fos expression. These results indicate that prior experience with taste, odor, or odor-taste stimuli habituates responses in the primary chemosensory cortices and adds further evidence supporting gustatory cortex as a fundamental node for the integration of gustatory and olfactory signals. [ABSTRACT FROM AUTHOR]

Corticotropin releasing hormone (CRH) produces age-dependent limbic seizures in the infant rat. Both the phenotype and the neuroanatomic matrix of CRH-induced seizures resemble the seizures induced by the rigid glutamate analogue, kainic acid (KA), and by rapid amygdala kindling. The experiments described in this study tested the hypothesis that the in vivo proconvulsant effects of CRH require activation of ionotropic glutamate receptors. Non-competitive (+MK-801) or competitive (CGP-39551) antagonists of N-methyl-d-aspartate (NMDA) receptors decreased or eliminated the motor effects of CRH, but electrographic CRH-induced seizures were unaffected. Administration of CRH antagonists did not affect the acquisition or the maintenance of rapid kindling, which are mediated by NMDA and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor activation, respectively. CRH receptor blockers failed to alter the latency or duration of seizures induced by activation of KA receptors, and threshold doses of CRH and KA had additive effects. CRH given repeatedly decreased the convulsant threshold dose of KA, probably via injury to hippocampal neurons. These results suggest that CRH and glutamate increase neuronal excitability via independent mechanisms. Because the proconvulsant effects of CRH are highly specific to the developmental period, glutamate-receptor-independent, CRH-receptor mediated excitation may account for some of the enhanced susceptibility to seizures during this period.

Corticotropin releasing factor (CRF) activates two known receptor types, CRF1, and CRF2. In the adult rat brain, CRF2 has a distinct distribution pattern, suggesting that it may mediate functions exclusive of CRF1. The goal of this study was to determine the age-dependent distribution of CRF2-messenger RNA (CRF2-mRNA) in the rat brain. Brains from rats sacrificed under stress-free conditions on fetal days (F) 15, 16, 17 and 19, and postnatal days 1, 3, 5, 7, 9, 12, 15, 25, 49, and 90 (adult) were analyzed using semiquantitative in situ hybridization histochemistry. The onset and distribution of CRF2-mRNA in the developing rat brain revealed important differences from the adult expression pattern: earliest expression of CRF2-mRNA was observed in the ventromedial hypothalamus (VMH) on F16. High levels of CRF2-mRNA were present in the fronto-parietal cortex in the fetal and early postnatal brain but not later. Conversely, no CRF2-mRNA was detectable in the ventroposterior (lateral and medial) thalamic nuclei prior to postnatal day 7. Distinct developmental profiles of CRF2-mRNA were also observed in the lateral septum, medial, basal and cortical amygdala nuclei, and in several hippocampal fields. In conclusion, CRF2 is expressed in the hypothalamus on F16, prior to the detection of CRF itself in the paraventricular nucleus. The differential levels and distributions of CRF2-mRNA in hypothalamic and limbic brain regions indicate a precise regulation of this receptor's expression during development, as shown for CRF1. Regulation of the levels of CRF2 may modulate the effects of CRF (and related ligands) on target neurons, consistent with differential maturation of the functions mediated by this receptor.

Seizures induced by fever are the most prevalent age-specific seizures in infants and young children. Whether they result in long-term sequelae such as neuronal loss and temporal lobe epilepsy is controversial. Prospective studies of human febrile seizures have found no adverse effects on the developing brain. However, adults with temporal lobe epilepsy and associated limbic cell loss frequently have a history of prolonged febrile seizures in early life. These critical issues may be resolved using appropriate animal models. Published models of hyperthermic seizures have used 'adolescent' and older rats, have yielded a low percentage of animals with actual seizures, or have suffered from a high mortality, rendering them unsuitable for long-term studies. This article describes the establishment of a model of febrile seizures using the infant rat. Hyperthermia was induced by a regulated stream of mildly heated air, and the seizures were determined by both behavioral and electroencephalographic (EEG) criteria. Stereotyped seizures were generated in 93.6% of 10-11-day-old rats. EEG correlates of these seizures were not evident in cortical recordings, but were clearly present in depth recordings from the amygdala and hippocampus. Prolonged febrile seizures could be induced without burns, yielding a low mortality (11%) and long-term survival. In summary, in infant rat paradigm of EEG-confirmed, hyperthermia-induced seizures which is suitable for long-term studies is described. This model should be highly valuable for studying the mechanisms and sequelae of febrile seizures.

[Display omitted] • Single and repeated infusions of MSCs were administered to rats with chronic SCI. • Repeated infusion of MSCs provided the greatest functional recovery. • The density of remyelinated axons was the greatest in the repeated MSC group. • Increased axonal sprouting and density were greatest in the repeated MSC group. • Repeated infusion of MSC could be promising in the treatment of SCI. Spinal cord injury (SCI) can cause paralysis with a high disease burden with limited treatment options. A single intravenous infusion of mesenchymal stem cells (MSCs) improves motor function in rat SCI models, possibly through the induction of axonal sprouting and remyelination. Repeated infusions (thrice at weekly intervals) of MSCs were administered to rats with chronic SCI to determine if multiple-dosing regimens enhance motor improvement. Chronic SCI rats were randomized and infused with vehicle (vehicle), single MSC injection at week 6 (MSC-1) or repeatedly injections of MSCs at 6, 7, and 8 weeks (MSC-3) after SCI induction. In addition, a single high dose of MSCs (HD-MSC) equivalent to thrice the single dose was infused at week 6. Locomotor function, light and electron microscopy, immunohistochemistry and ex vivo diffusion tensor imaging were performed. Repeated infusion of MSCs (MSC-3) provided the greatest functional recovery compared to single and single high-dose infusions. The density of remyelinated axons in the injured spinal cord was the greatest in the MSC-3 group, followed by the MSC-1, HD-MSC and vehicle groups. Increased sprouting of the corticospinal tract and serotonergic axon density was the greatest in the MSC-3 group, followed by MSC-1, HD-MSC, and vehicle groups. Repeated infusion of MSCs over three weeks resulted in greater functional improvement than single administration of MSCs, even when the number of infused cells was tripled. MSC-treated rats showed axonal sprouting and remyelination in the chronic phase of SCI. [ABSTRACT FROM AUTHOR]

The ontogeny of corticotropin-releasing hormone (CRH) receptor messenger ribonucleic acid (mRNA) in rat brain, using in situ hybridization, is the focus of this study. The developmental profile of CRH receptor using binding assays and receptor autoradiography has been reported, but may be confounded by the presence of a binding protein. The recent cloning of the rat CRH receptor gene has permitted the use of in situ hybridization histochemistry to map the distribution of cells expressing CRH receptor mRNA in the developing brain. We used antisense 35S-labeled oligodeoxynucleotide probes for the two reported splice-variants of the CRH receptor mRNA, which yielded essentially identical localization patterns. CRH receptor mRNA was clearly detectable in infant brain starting on the second postnatal day. Signal in hippocampal CA1, CA2 and CA3a increased to 300-600% of adult levels by postnatal day 6 with a subsequent gradual decline. In the amygdala, in contrast, CRH receptor mRNA abundance increased steadily between the second and the ninth postnatal days, to levels twice higher than those in the adult. In the cortex, CRH receptor mRNA levels were high on postnatal day 2 and decreased to adult levels by day 12. Transient signal over the hypothalamic paraventricular nucleus, observed on the second postnatal day, was not evident at older ages. These results demonstrate robust synthesis of CRH receptor as early as on the second postnatal day and unique region-specific developmental profiles for CRH receptor gene expression.

Mechanisms controlling the synthesis of corticotropin releasing hormone (CRH) in neonatal rats, and the ontogeny of glucocorticoid (GC) feedback control of hypothalamic CRH remain unknown. Specific issues are whether stress induces up-regulation of CRH gene expression during the first postnatal week, and the role of GC feedback, at the hypothalamic level, in the stress-hyporesponsive period. We studied the ontogeny of the negative feedback regulation of CRH gene expression by GC in the paraventricular nucleus (PVN). We implanted chronic cannulae containing a GC-receptor antagonist, RU 38486, in rats on postnatal days 3 to 13. Three days later, animals were sacrificed, and brains were analyzed for CRH-messenger RNA (CRH-mRNA), using semi-quantitative in situ hybridization. Animals implanted with cholesterol-containing cannulae served to evaluate the stressful effect of implantation on CRH-mRNA abundance. The presence of GC receptor messenger RNA (GR-mRNA) in the PVN of neonatal rats was also determined. RU 38486 did not increase CRH-mRNA abundance during the first postnatal week, despite the presence of GR-mRNA in the PVN. Chronic-implantation stress also failed to increase CRH synthesis. CRH gene expression in the PVN was enhanced in infant rats implanted with RU-38486 on postnatal day 9 or later. Cholesterol implantation on days 9, 10 (but not later), resulted in increased PVN-CRH-mRNA. Thus, CRH-mRNA is up-regulated by chronic blockade of GC receptors only subsequent to the eighth postnatal day. Furthermore, such blockade does not affect the response of CRH-mRNA to chronic stress in the neonatal rat.

A role for neutral endopeptidase 24.11 (NEP) in growth and development is supported by the demonstration that NEP hydrolyses and inactivates a number of peptide growth factors including atrial natriuretic peptide, endothelins, bombesin-like peptides, and opioid peptides, including the enkephalins. In the present study, suspensions of cells obtained from the ventral mesencephalon or cortex of rat embryos (ED14) were implanted into the striatum of the adult rat brain. Three to 15 weeks after transplantation the relative distribution of NEP-positive cellular elements was visualized histochemically. NEP staining in the transplants consistently appeared before NEP staining in the surrounding host striatum supporting a relative increase in NEP activity in the transplants. The NEP staining richly visualized cells of varying size and morphology which lacked the normal organization of the host striatum. The histochemical staining in the transplants and the surrounding host tissue was completely blocked by a 100 nM concentration of the selective NEP inhibitors phosphoramidon or JHF-26, supporting the exclusive localization of NEP by this method. NEP localization in the embryonic (ED14) cortex and ventral mesencephalon was also confirmed, suggesting one possible origin for the NEP-positive cells visualized in the transplants. Fluorescent double-labeling studies for NEP and glial fibrillary acidic protein (GFAP) or transforming growth factor alpha precursor (TGF alpha p) revealed the presence of rich glial labeling within the transplants for both GFAP and TGFap. NEP-labeled cells in the transplants were closely associated with glial elements, however, only occasional glial elements in the transplants stained for NEP; supporting a non-astrocytic localization for the NEP in the transplants. The marked enhancement of NEP staining in the transplants may have significance for controlling the rate or pattern of growth of the transplanted cells through inactivation of peptide growth factors produced by, or in response to, the transplants.

The kindling paradigm provides a powerful tool for studying the generation, propagation and generalization of seizures. Such reproducible quantitative paradigms are a prerequisite for the experimental study of epilepsy in the developing brain. Kindling has been extensively utilized as a model of limbic seizures in the adult rat; amygdala short-interval kindling has been studied in > or = 15-day-old rats. We applied the short-interval kindling method, i.e., stimulation at every 15 min, to 7-12-day-old rats. Stage-5 behavioral seizures were achieved even in 7-day-old rats; however, the progression of behavioral kindling differed somewhat from that of older rats. Correlation of electrographic discharges and behavioral phenomena was inversely related to age. Reliable progressive amygdala discharges were difficult to assess in most < or = 10-day-old rats. Spontaneous seizures occurred relatively frequently in younger age groups. The amygdala short-interval kindling paradigm is reproducibly and reliably applicable to rats during the 2nd postnatal week. The presence of progressive focal to bilateral-generalized seizures suggests a significant functional maturity of the amygdala-limbic circuitry at this age.

Corticotropin-releasing hormone (CRH) administered into the cerebral ventricles of rats during the first postnatal week caused a specific and stereotyped behavior sequence: rhythmic chewing and licking (jaw myoclonus) were followed by 'limbic'-type seizures. The onset of the seizures was much more rapid (2-45 min vs 3-7 h) than in adult rats, and the convulsant doses were much lower (50 x 10(-12) mol per gram brain weight vs 750 x 10(-12) mol per gram brain weight in adults). CRH potency in inducing seizures varied inversely with age. CRH-induced seizures occurred prior to any changes in serum corticosterone, and were eliminated by the administration of a CRH antagonist, as well as of phenytoin. Electrocorticographic correlates of CRH-induced behaviors in the infant rat were inconsistent, suggesting a subcortical origin of CRH-induced paroxysmal events in the immature brain.

Deep brain stimulation applied at high frequency (HFS) to the subthalamic nucleus (STN) is used to ameliorate the symptoms of Parkinson’s disease. The mechanism by which this is achieved remains controversial. In particular, it is uncertain whether HFS has a suppressive or excitatory action locally within the STN. Brief exposure of rats to ether anesthesia evokes pathological burst firing and associated expression of the immediate early gene c-Fos in STN neurons. We used this ether model of STN activation to test the effect of a range of HFS parameters on c-Fos expression evoked by the anesthetic. The elevated baseline of c-Fos expression afforded the possibility of detecting further excitatory, or suppressive effects of STN HFS. Four HFS protocols were examined; 130, 200 and 260 Hz with 60 µs, and 130 Hz with 90 µs pulse width (HFS intensity:150-300 µA). All HFS protocols were applied for 20 min while the animals were exposed to ether. Ether-evoked expression of c-Fos immunoreactivity was suppressed by HFS at 200 and 260 Hz with a pulse width of 60 µs, and by 130 Hz when the pulse width was increased to 90 µs. HFS at 130 Hz with the 60 µs pulse width had no significant effect and HFS alone caused negligible c-Fos expression in the STN. These findings suggest that HFS of the STN causes significant suppression of evoked neuronal activity. It remains to be determined whether this locally suppressive property of HFS is associated with the efficacy of STN deep brain stimulation to relieve the symptoms of Parkinson’s disease. [ABSTRACT FROM AUTHOR]

The upstream signal molecule modulating neuro-inflammation and synaptic changes during the pathogenesis of postoperative cognitive dysfunction (POCD) is still elusive. Here, we examined the effects and mechanisms of energy sensor AMP-activated protein kinase (AMPK) in the pathogenesis of POCD. Our data showed that surgery significantly increased the expression of p-AMPK in aged rats (p < 0.05), but not in adult rats (p > 0.05). Moreover, inhibiting AMPK activation via compound C during operation significantly improved surgery-induced impairment of the learning and memory of aged rats in water maze (p < 0.05). Further mechanism studies showed that corresponding to the impairment of learning and memory after surgery, surgery significantly increased the activation of microglia, decreased the expressions of NR2B and p-NR2B, and increased the expressions of Tau and p-Tau, which also were obviously restored by inhibiting AMPK during operation. In contrast, Inhibiting AMPK activation during operation didn’t change ATP level in the hippocampus of aged rats after surgery. These data suggest that surgery induced activation of AMPK in hippocampus in an age-dependent manner. AMPK plays important roles in POCD of aged rats via multiple mechanisms, and is a possible molecular target for the prevention and treatment of POCD. [ABSTRACT FROM AUTHOR]

To evaluate the role of afferent information from the salivary gland, we analyzed the neural activity of the sensory nerve innervating the submandibular gland in anesthetized rats. The sensory nerves running through the parasympathetic nerve supply responded to mechanical pressure applied to the surface of the main duct and the body of the gland, whilst those in the sympathetic nerve supply responded only to the body of the gland. The sensory nerves in the sympathetic and parasympathetic nerve routes responded to pressure in the duct system produced by a retrograde injection of saline into the main duct. The threshold pressure for production of afferent discharges was higher than the maximum secretory pressure evoked by electrical stimulation of the parasympathetic secretory nerve. The retrograde ductal injection of drugs related to the inflammatory process (capsaicin and bradykinin) evoked intense multi-unit discharges in the sensory nerves of both routes. The sensory nerve in the sympathetic route was responsive to ligation of the artery to the gland. These results suggest that sensory nerves in the sympathetic and parasympathetic routes mainly conduct noxious information, and that those in the sympathetic route are responsive to ischemia and may control blood flow of the gland. [ABSTRACT FROM AUTHOR]

To investigate the interaction between hippocampal γ-aminobutyric acid GABA A receptor (GABA A R) or GABA B receptor (GABA B R) and N-methyl-D-aspartate receptor (NMDAR) in the acquisition of passive avoidance memory in rats, we used GABA A or GABA B agents, D-AP5 (as a NMDAR antagonist), and a combination of the mentioned drugs in a step-through task. All agents were microinjected into the intra-CA1 regions at a volume of 1 µl/rat, prior to training. GABA A R agonist muscimol (0.2 µg/rat), selective GABA B R agonist baclofen (0.5 µg/rat) or NMDAR antagonist D-AP5 (0.25 µg/rat) decreased step-through latency, indicating a memory retention impairment. Neither GABA A R antagonist bicuculline (0.0625–0.25 µg/rat) nor GABA B R antagonist phaclofen (0.1–0.5 µg/rat) altered memory retrieval by itself. Moreover, the lower dose of muscimol (0.05 µg/rat) decreased D-AP5 (0.125 µg/rat) response on memory acquisition, but bicuculline did not alter the D-AP5 response. Furthermore, baclofen and phaclofen at the dose of 0.1 µg/rat potentiated D-AP5 response at the doses of 0.0625 and 0.125 µg/rat, but abolished memory impairment induced by D-AP5 at the higher dose (0.25 µg/rat). The results suggest that the microinjection of GABA A and GABA B agents into the CA1 region differently affects memory acquisition deficit induced by D-AP5. The activation of GABA A Rs increased the impairment effect of D-AP5 on passive avoidance memory, but their blockade did not have an effect. Also, the activation or blockade of GABA B Rs induced a similar and dual effect. [ABSTRACT FROM AUTHOR]

The functions of the claustrum are not well understood. Few studies explore its electrophysiological properties in awake animals. Here, we address this lacuna by recording spontaneous local field potential (LFP) activity in the anterior claustrum of rats freely exploring open field environments under differing conditions (light; dark; with, without an object present). We found three peaks in the LFP power spectral density (PSD) at 1–4 Hz, 4–7 Hz and 8–12 Hz. Two of those peaks, in the 1–4 Hz and 8–12 Hz bands, were present in almost all recordings and dominated the power spectrum. The power or frequency of detected peaks in some cases changed depending on the environmental context. The power of detected frequency bands of spontaneous LFPs showed varied patterns of distribution across the experimental arena. The 8–12 Hz band was predominantly found at running speeds of up to 6 cm/s. We suggest that spontaneous LFP activity in the anterior claustrum depends on the environmental context and running speed of the animal. [ABSTRACT FROM AUTHOR]

Ependymal cells have been considered one of prime targets for gene therapy in the central nervous system as they can secrete proteins directly into the cerebrospinal fluid. In this study, we have explored the probability of permanent exogenous gene expression using a combined adenovirus/transposon system. To this end, we created three adenoviruses; adenovirus #1 containing a CAG promoter-driven enhanced green fluorescent protein tagged with a palmitoylation site (palEGFP), whose DNA sequence was flanked by two different Tol2 ends, #2 containing a human FoxJ1 promoter-driven T2TP transposase, and #3 containing an EF-1 alpha promoter-driven T2TP transposase. We injected these adenoviruses into the lateral ventricles of adult rats to assess the duration of transgene expression, by which adenoviruses selectively infected to ependymal cells because they express the specific receptor. In animals injected with only adenovirus #1, we found palEGFP-expressing ependymal cells 1 week after injection, but these cells had disappeared by 2 weeks. In animals that received adenoviruses #1 and #2 in combination, despite detecting many palEGFP-expressing ependymal cells within the initial 2 weeks, transgene expression in ependymal cells was almost disappeared 1 month after injection. In contrast, many palEGFP-expressing astrocytes, oligodendrocytes, and neurons were found near the sites injected with adenoviruses #1 and #3, even 1 month after injection. There was no prominent infiltration of immunological cells during the observation period. These findings indicate that an adenovirus-mediated transposon gene transfer system can lead to prolonged, but not permanent, expression of exogenous genes in ependymal cells of adult rats. [ABSTRACT FROM AUTHOR]

Studies of the antidepressant vortioxetine have demonstrated beneficial effects on cognitive dysfunction associated with depression. To elucidate how vortioxetine modulates neuronal activity during cognitive processing we investigated the effects of vortioxetine (3 and 10 mg/kg) in rats performing an auditory oddball (deviant target) task. We investigated neuronal activity in target vs non-target tone responses in vehicle-treated animals using electroencephalographic (EEG) recordings. Furthermore, we characterized task performance and EEG changes in target tone responses of vortioxetine vs controls. Quantification of event-related potentials (ERPs) was supplemented by analyses of spectral power and inter-trial phase-locking. The assessed brain regions included prelimbic cortex, the hippocampus, and thalamus. As compared to correct rejection of non-target tones, correct target tone responses elicited increased EEG power in all regions. Additionally, neuronal synchronization was increased in vehicle-treated rats during both early and late ERP responses to target tones. This indicates a significant consistency of local phases across trials during high attentional load. During early sensory processing, vortioxetine increased both thalamic and frontal synchronized gamma band activity and EEG power in all brain regions measured. Finally, vortioxetine increased the amplitude of late hippocampal P3-like ERPs, the rodent correlate of the human P300 ERP. These findings suggest differential effects of vortioxetine during early sensory registration and late endogenous processing of auditory discrimination. Strengthened P3-like ERP response may relate to the pro-cognitive profile of vortioxetine in rodents. Further investigations are warranted to explore the mechanism by which vortioxetine increases network synchronization during attentive and cognitive processing. [ABSTRACT FROM AUTHOR]

Transient ischemic attack (TIA) has received only little attention in the experimental research field. Recently, we introduced a TIA model for mice, and here we set similar principles for simulating this human condition in Wistar rats. In the model: 1) transient nature of the event is ensured, and 2) 24 h after the event animals are free from any sensorimotor deficit and from any detectable lesion by magnetic resonance imaging (MRI). Animals experienced varying durations of ischemia (5, 10, 12.5, 15, 25, and 30 min, n = 6–8 per group) by intraluminal middle cerebral artery occlusion (MCAO). Ischemia severity and reperfusion rates were controlled by cerebral blood flow measurements. Sensorimotor neurological evaluations and MRI at 24 h differentiated between TIA and ischemic stroke. Hematoxylin and eosin staining and apoptotic cell counts revealed pathological correlates of the event. We found that already 12.5 min of ischemia was long enough to induce ischemic stroke in Wistar rats. Ten min or shorter durations induced neither gross neurological deficits nor infarcts visible on MRI, but histologically caused selective neuronal necrosis. A separate group of animals with 10 min of ischemia followed up to 1 week after reperfusion remained free of infarction and any MRI signal change. Thus, 10 min or shorter focal cerebral ischemia induced by intraluminal MCAO in Wistar rats provides a clinically relevant TIA the rat. This model is useful for studying molecular correlates of TIA. [ABSTRACT FROM AUTHOR]

Neural mechanism underlying memory retrieval has been extensively studied in the hippocampus and amygdala. However, little is known about the role of medial prefrontal cortex in long-term memory retrieval. We evaluate this issue in one-trial step-through inhibitory avoidance (IA) paradigm. Our results showed that, 1) inactivation of mPFC by local infusion of GABA A -receptor agonist muscimol caused severe deficits in retrieval of 1-day and 7-day but had no effects on 2-h inhibitory avoidance memory; 2) the protein level of phosphorylated-ERK1/2 in mPFC were significantly increased following retrieval of 1-day and 7-day IA memory, so did the numbers of phosphorylated-ERK (pERK) and phosphorylated-CREB (pCREB) labeled neurons; 3) intra-mPFC infusion of ERK kinase inhibitor PD98095 significantly reduced phosphorylated ERK1/2 levels and phosphorylated-ERK1/2 and phosphorylated-CREB labeled cells, and severely impaired retrieval of 7-day IA memory when the drugs were administrated 30 min prior to test. The present study provides evidence that retrieval of long-lasting memory for inhibitory avoidance requires mPFC and involves the ERK-CREB signaling cascade. [ABSTRACT FROM AUTHOR]

The thalamic reticular nucleus (TRN), a cluster of GABAergic cells, is thought to regulate bottom-up and top-down streams of sensory processing in the loop circuitry between the thalamus and cortex. Provided that sensory inputs of different modalities interact in the TRN, the TRN could contribute to fast and flexible cross-modal modulation of attention and perception that incessantly takes place in our everyday life. Indeed, diverse subthreshold interactions of auditory and visual inputs have been revealed in TRN cells (Kimura, 2014). To determine whether such sensory interaction could extend across modalities as a universal neural mechanism, the present study examined TRN cell activities elicited by auditory and cutaneous electrical stimulations in anesthetized rats. Juxta-cellular recording and labeling techniques were used. Recordings were obtained from 129 cells. Auditory or somatosensory responses were modulated by subthreshold electrical stimulation or sound (noise burst) in the majority of recordings (77 of 85 auditory and 13 of 15 somatosensory cells). Additionally, 22 bimodal cells and seven cells that responded only to combined stimulation were recognized. Suppression was predominant in modulation that was observed in both early and repeatedly evoked late responses. Combined stimulation also induced de novo cell activities. Further, response latency and burst spiking were modulated. Axonal projections of cells showing modulation terminated in first- or higher-order thalamic nuclei. Nine auditory cells projected to somatosensory thalamic nuclei. These results suggest that the TRN could regulate sensory processing in the loop circuitry between the thalamus and cortex through the sensory interaction pervasive across modalities. [ABSTRACT FROM AUTHOR]

Advances in our understanding of the human pain experience have shifted much of the focus of pain research from the periphery to the brain. Current hypotheses suggest that the progression of migraine depends on abnormal functioning of neurons in multiple brain regions. Accordingly, we sought to capture functional brain changes induced by the application of an inflammatory cocktail known as inflammatory soup (IS), to the dura mater across multiple brain networks. Specifically, we aimed to determine whether IS alters additional neural networks indirectly related to the primary nociceptive pathways via the spinal cord to the thalamus and cortex. IS comprises an acidic combination of bradykinin, serotonin, histamine and prostaglandin PGE2 and was introduced to basic pain research as a tool to activate and sensitize peripheral nociceptors when studying pathological pain conditions associated with allodynia and hyperalgesia. Using this model of intracranial pain, we found that dural application of IS in awake, fully conscious, rats enhanced thalamic, hypothalamic, hippocampal and somatosensory cortex responses to mechanical stimulation of the face (compared to sham synthetic interstitial fluid administration). Furthermore, resting state MRI data revealed altered functional connectivity in a number of networks previously identified in clinical chronic pain populations. These included the default mode, sensorimotor, interoceptive (Salience) and autonomic networks. The findings suggest that activation and sensitization of meningeal nociceptors by IS can enhance the extent to which the brain processes nociceptive signaling, define new level of modulation of affective and cognitive responses to pain; set new tone for hypothalamic regulation of autonomic outflow to the cranium; and change cerebellar functions. [ABSTRACT FROM AUTHOR]

The present study was conducted to investigate the expression of serine/threonine-kinase 33 (Stk33) in neuronal structures of the central nervous system in rat and hamster as well as the presence of the protein in the brain of higher mammals, using a polyclonal antibody on cryosections of fixed brains. We found a distinct immunostaining pattern that included intense fluorescence of the ependymal lining of cerebral ventricles, and of hypothalamic tanycytes and their processes. We further observed intense staining of magnocellular neurons in the hypothalamic paraventricular, supraoptic and accessory neurosecretory nuclei, in particular the circular nuclei, and less intense stained neurons in other diencephalic regions. Double-immunostaining experiments showed a partial colocalization of Stk33 with arginine-vasopressin, oxytocin or neuronal nitric oxide-synthase in a large number of neurons of the hypothalamic nuclear regions. Colocalization of Stk33 with substance P or the catecholamine-synthesizing enzyme tyrosine-hydroxylase was not observed. Immunofluorescence was not found in autonomic regions of the lateral horn, suggesting that Stk33 does not contribute to hypothalamo-spinal connections. However, large Stk33-immunoreactive axonal projections from magnocellular hypothalamus to the neurohypophysis were evident. These functionally important connections provide the bridge from neuronal to humoral regulation of the endocrine system. Additionally, Western blots from mouse brain showed two distinct bands representing two Stk33 isoforms. We also present first evidence for the presence of Stk33/STK33 in neuronal structures, ependymal cells and tanycytes in tree shrew, baboon, and human brain. [ABSTRACT FROM AUTHOR]

• Aging was associated with hippocampal β-AR dysregulation. • Hippocampal βArr1 and βArr2 levels were markedly reduced in aged rats. • Spatial memory, but not spatial learning, was impaired in aged rats. • Treadmill exercise significantly improved hippocampal β-AR dysregulation and spatial memory in aged rats. • Treadmill exercise markedly increased βArr2 levels, accompanied by a reduction in β1-AR level in aged rats. • Treadmill exercise via promoting βArr2 levels may contribute to the regulation of β1-AR levels. Hippocampal-dependent memory abilities including spatial memory decline with age. Exercise improves memory decline in aging brain, but, the precise mechanisms are still unknown. Learning and memory are recently hypothesized to be mediated by a β-arrestin (βArr)–dependent β-adrenergic pathway. Hence, we examined the effect of 8 weeks of treadmill exercise on hippocampal expression of β-adrenergic receptors (β-ARs; members of the G protein-coupled receptor family), and βArrs as well as spatial learning and memory in aged male rats to determine whether β-AR/βArr pathway could be involved in age-related memory decline. A total of 24 young (3-month-old) and aged (18-month-old) male Wistar rats were divided into young control, aged sedentary, and aged + exercise (n = 8 for each). Western blot for β1- and β2-ARs as well as βArr1 and βArr2 was performed. Spatial learning and memory were evaluated with the Morris water maze. The results showed significant up-regulation of β1-ARs as well as significant down-regulation of β2-AR and βArrs (βArr1 and βArr2) in the hippocampus of aged rats. Spatial memory, but not spatial learning, was impaired in aging, and treadmill exercise improved it. Notably, the improvement in spatial memory was accompanied by amelioration of β-ARs dysregulation and increase in βArr2 levels after exercise. There was a negative association between the expression of βArr2 and β1-AR, but not β2-AR, such that an increase in βArr2 by exercise was associated with reduced β1-AR expression, suggesting βArr2 may contribute to posttranslational down-regulation of β1-ARs. These data suggest that both G protein–dependent and β-arrestin–dependent β-AR pathways may regulate spatial learning and memory in aging brain. [ABSTRACT FROM AUTHOR]

[Display omitted] • Laser speckle flowmetry signals fluctuate less with head fixation. • An external standard can be used in in vivo laser speckle flowmetry experiments. • Semi-quantitation of CBF after carotid ligation provides side-by-side evaluation. Laser speckle flowmetry (LSF) can measure moving red blood cells in real time as changes in tissue blood flow; however, LSF values may not be sufficiently reproducible due to body movements and other factors. Therefore, it is difficult to compare absolute values of LSF directly. This study aimed to verify the influence of head fixation on improving the measurement accuracy and enabling the comparison of LSF values semi-quantitatively using an external standard. We first examined the effects of head fixation on LSF values obtained during cerebral blood flow (CBF) measurement through a bone window over the cerebrum in Sprague-Dawley rats. The LSF values in the bone window were semi-quantitated using the ratio of the external standard LSF values measured simultaneously in the same field of view in a unilateral common carotid artery ligation model to evaluate CBF. Head fixation halved the variability of LSF values when compared with measurements made without head fixation. The LSF laser focus position did not affect the LSF values provided the focus was positioned within the exposed cranium. Semi-quantitation of LSF values made it possible to monitor changes in CBF in each respective bone window over time in a model of unilateral carotid ligation. In conclusion, the stabilizing effect of head fixation on LSF values was clarified, and we observed that to improve measurement accuracy, the head should be immobilized. Semi-quantitation of LSF values was first introduced by using an external standard and appears to be useful in monitoring the CBF of each location separately. [ABSTRACT FROM AUTHOR]

Exercise mediates beneficial effects on the brain function and neural health, particularly in the hippocampus as the main area of memory. The hippocampus is a structure involved in exercise, which can improve synaptic plasticity and long-term potentiation (LTP). The present study investigated the effect of exercise, exercise withdrawal, and continued regular exercise on excitability and long-term potentiation in the dentate gyrus (DG) of hippocampus. Fifty male Wistar rats were randomly allocated to the five control, sham, exercise, exercise withdrawal, and continued regular exercise treatments. The experimental animals were forced to run on a treadmill one hour a day at a speed of 20–21 m/min over the two experimental periods of 21 and 42 days. While stimulating the medial perforant pathway, input–output (I/O) functions and LTP were recorded from the DG to evaluate synaptic potency and plasticity. The relevant responses in the DG were evaluated in all the groups from the slope and PS amplitude of the fEPSP. Results showed that the 21–day exercise treatment increased both the responsiveness and LTP in the DG of hippocampus. A 21–day withdrawal period after the exercise impaired the beneficial effects of the exercise, indicating the reversibility of these exercise-related hippocampal changes. Significant enhancements were also observed in cell responsiveness and LTP with the continued regular exercise (42–day) treatment. [ABSTRACT FROM AUTHOR]

Cilostazol(CTL) is a phosphodiesterase inhibitor, which has been widely used as anti-platelet agent. It also has preventive effects on various central nervous system (CNS) diseases, including ischemic stroke, Parkinson’s disease and Alzheimer disease. However, the molecular mechanism underlying the protective effects of CTL is still unclear, and whether CTL can prevent I/R induced cognitive deficit has not been reported. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The open field tasks and Morris water maze were used to assess the effect of CTL on anxiety-like behavioral and cognitive impairment after I/R. Western blotting were performed to examine the expression of related proteins, and HE-staining was used to detect the percentage of neuronal death in the hippocampal CA1 region. Here we found that CTL significantly improved cognitive deficits and the behavior of rats in Morris water maze and open field tasks ( P <0.05). HE staining results showed that CTL could significantly protect CA1 neurons against cerebral I/R ( P <0.05). Additionally, Akt1 phosphorylation levels were evidently up-regulated ( P <0.05), while the activation of JNK3, which is an important contributor to I/R-induced neuron apoptosis, was reduced by CTL after I/R ( P <0.05), and caspase-3 levels were also decreased by CTL treatment. Furthermore, all of CTL's protective effects were reversed by LY294002, which is a PI3K/Akt1 inhibitor. Taken together, our results suggest that CTL could protect hippocampal neurons and ameliorate the impairment of learning/memory abilities and locomotor/ exploratory activities in ischemic stroke via a PI3K-Akt1/JNK3/caspase-3 dependent mechanism. [ABSTRACT FROM AUTHOR]

The influence of the duration of vaginocervical stimulation (VCS) on the electroencephalographic activity (EEG) of medial amygdala (MeA) and prefrontal cortex (PFC) in rats during proestrus-estrus (P-E) and diestrus (D) was examined. Using a glass syringe plunger, a constant force of 300 g was exerted against the cervix during 60 s. Relative power (RP) and correlation of three EEG band frequencies were compared between the first and last 30 s intervals of VCS. A higher RP of the 4–7 Hz band and a lower RP of the fast frequencies were observed in the MeA and PFC in P-E females during the first 30 s of VCS as compared to the last 30 s. Only during P-E, a higher interamygdaline correlation in the 8–12 Hz band and a lower correlation in the 13–21 Hz band during the first 30 s were observed. Similarly, a higher interamygdaline correlation in the 8–12 Hz band was observed during the first 30 s of VCS during P-E as compared to D. During the last 30 s of VCS there was no difference between phases. The VCS evoked EEG changes in the MeA that varied between phases of the estrous cycle and depended on the duration of the stimulation. These effects could be associated with the quantification processes of VCS that has been proposed to occur in the amygdala. These findings show differential responsiveness of the MeA and PFC according to the amount of VCS received, and that the response varies according to the estrous cycle. [ABSTRACT FROM AUTHOR]

[Display omitted] • We examined c-Fos expression in the central gustatory system and related structures after either novel or familiar saccharin was consumed. • The novel taste induced higher levels of c-Fos expression than familiar taste in BLA, CNA, GT, GC, mPBN, and lPBN. • The potentiated c-Fos expression induced by novel tastes was not found in the BNST, MeA, rNST, LH, NAc, NAcS, NBM and the PrC. Taste neophobia, the rejection of novel tastes or foods, involves an interplay of various brain regions encompassing areas within the central gustatory system, as well as nuclei serving other functions. Previous findings, utilising c-Fos imaging, identified several brain regions which displayed higher activity after ingestion of a novel taste as compared to a familiar taste. The present study extends this analysis to include additional regions suspected of contributing to the neurocircuitry involved in evoking taste neophobia. Our data show increased c-Fos expression in the basolateral amygdala, central nucleus of the amygdala, gustatory portion of the thalamus, gustatory portion of the insular cortex and the medial and lateral regions of the parabrachial nucleus. These results confirm the contribution of areas previously identified as active during ingestion of novel tastes and expose additional areas that express elevated levels of c-Fos under these conditions, thus adding to the neural network involved in the detection and initial processing of taste novelty. [ABSTRACT FROM AUTHOR]

[Display omitted] • Morphine administration induced significant CPP. • Microinjection of AMPA into the LHb reduced the acquisition phase of CPP. • Bilateral injections of AMPA into the LHb significantly inhibited locomotor activity in the expression phase. • Intra-LHb injection of NBQX increased the acquisition phase. • NBQX affects AMPA-induced CPP scores in a dose-dependent manner. The lateral habenula (LHb), known as the brain structure of the epithalamic, plays the main role in depression and drug addiction. The glutamatergic system influences morphine reward. The effect of activation/inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) in the LHb on different phases of morphine-induced conditioned place preference (CPP) remains unknown. In this research, the effect of bilateral intra-LHb microinjection of AMPARs agonist and antagonist on the acquisition and expression phases of CPP in male rats has been investigated. Different doses of NBQX, the antagonist of AMPARs, in combination with the effective dose of morphine, increased the CPP score during the acquisition phase. While AMPA, the agonist of AMPARs, significantly reduced the conditioning scores in the acquisition phase. Pretreatment with NBQX (0.5 and 1 μg/rat) reversed the inhibitory effect of AMPA (1 μg/rat) on the acquisition phase of morphine-induced CPP. The antagonist (1 μg/rat) increased the effect of a high dose of agonist (2 μg/rat) on CPP. On the other hand, NBQX significantly increased CPP scores during the expression phase. AMPA did not significantly affect CPP scores in the expression phase, but significantly reduced locomotor activity in the test phase. These results confirmed the importance of AMPARs in the LHb in morphine reward. Our data also suggest that injection of an AMPARs antagonist into the LHb may alter the AMPA-induced morphine response in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

We utilized proton magnetic resonance spectroscopy to evaluate the metabolic profile of the hippocampus and anterior cingulate cortex of the developing rat brain from postnatal days 14–70. Measured metabolite concentrations were modeled using linear, exponential, or logarithmic functions and the time point at which the data reached plateau (i.e. when the portion of the data could be fit to horizontal line) was estimated and was interpreted as the time when the brain has reached maturity with respect to that metabolite. N-acetyl-aspartate and myo-inositol increased within the observed period. Gluthathione did not vary significantly, while taurine decreased initially and then stabilized. Phosphocreatine and total creatine had a tendency to increase towards the end of the experiment. Some differences between our data and the published literature were observed in the concentrations and dynamics of phosphocreatine, myo-inositol, and GABA in the hippocampus and creatine, GABA, glutamine, choline and N-acetyl-aspartate in the cortex. Such differences may be attributed to experimental conditions, analysis approaches and animal species. The latter is supported by differences between in-house rat colony and rats from Charles River Labs. Spectroscopy provides a valuable tool for non-invasive brain neurochemical profiling for use in developmental neurobiology research. Special attention needs to be paid to important sources of variation like animal strain and commercial source. [ABSTRACT FROM AUTHOR]

The role of dorsal hippocampus (DH) serotonin 6 (5-HT 6 ) receptors in memory is unknown, particularly in memory impairment of Parkinson's disease. We tested here effects of activation and blockade of DH 5-HT 6 receptors on working and hippocampus-dependent memories in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced working and hippocampus-dependent memory impairments as measured by the T-maze rewarded alternation and hole-board tests, and decreased dopamine (DA) levels in the striatum, medial prefrontal cortex (mPFC), DH and amygdala. Intra-DH injection of 5-HT 6 receptor agonist WAY208466 (1.5, 3 and 6 µg/rat) did not change choice accuracy and the number of head-dippings when re-exposure to hole-board in sham-operated rats, while 5-HT 6 receptor antagonist SB258585 (4 µg/rat) increased choice accuracy and decreased the number of head-dippings. In the lesioned rats, both WAY208466 (3 and 6 µg/rat) and SB258585 (2 and 4 µg/rat) increased choice accuracy and decreased the number of head-dippings. Neurochemical results showed that intra-DH injection of WAY208466 or SB258585 produced significant effects on DA and noradrenaline (NA) levels in the mPFC (WAY208466: sham-operated, NA −44%; lesioned, DA 522%, NA −47%; SB258585: sham-operated, DA 72%, NA 85%; lesioned, DA −68%), DH (WAY208466: lesioned, DA 427%; SB258585: sham-operated, DA 119%, NA 206%) and amygdala (WAY208466: sham-operated, NA −28%; lesioned, DA 302%; SB258585: sham-operated, NA 183%); however, 5-HT levels in these brain regions were not changed. These findings suggest DA depletion plays a key role in working and hippocampus-dependent memory impairments, and 5-HT 6 receptors in the DH are involved in the regulation of the memories. [ABSTRACT FROM AUTHOR]

Current experimental research on the therapeutic effects of galvanic vestibular stimulation (GVS) has mainly focused on neurodegenerative disorders. However, it primarily stimulates the vestibular nuclei and could be potentially effective in modulating imbalance between them in the case of unilateral labyrinthectomy (UL). Fifty male Wistar rats (180–220 g) were used in 5 groups of 10: intact, sham, right-UL (RUL; without intervention), and two other right-UL groups with GVS intervention [one group treated with low rate GVS (GVS.LF; 6–7 Hz), and the other treated with high rate GVS (GVS.HF; 17–18 Hz)]. The UL models were prepared by intratympanic injection of sodium arsanilate. GVS protocols were implemented 30 min/day and continued for 14 days via ring-shaped copper electrodes inserted subcutaneously over each mastoid. Functional recovery was assessed by several postural tests including support surface area, landing and air-righting reflexes, and rotarod procedure. Immunohistochemical investigations were performed on ipsi- and contra-lesional medial vestibular nuclei (MVN) using bromodeoxyuridine (BrdU) and Ki67, as markers of cell proliferation. Behavioral evaluations showed significant functional recovery of GVS-treated groups compared to RUL group. The percent of marked cells with BrdU and Ki67 were significantly higher in the ipsilesional MVN of both GVS-treated groups compared with other groups. Our findings confirmed the effectiveness of GVS-intervention in accelerating static and dynamic vestibular compensation. This could be explained by the cell proliferation in ipsilesional MVN cells and rapid rebalancing of the VNs and the modulation of their motor outputs. Therefore, GVS could be promising for rehabilitating patients with unilateral vestibular weakness. [ABSTRACT FROM AUTHOR]

As anorexigenic hormones bombesin and nucleobindin2 (NUCB2)/nesfatin-1 decrease food intake in rodents. Both hormones have been described in brain nuclei that play a role in the modulation of hunger and satiety, like the paraventricular nucleus of the hypothalamus (PVN) and the nucleus of the solitary tract (NTS). However, the direct interaction of the two hormones is unknown so far. The aim of study was to elucidate whether bombesin directly interacts with NUCB2/nesfatin-1 neurons in the PVN and NTS. Therefore, we injected bombesin intraperitoneally (ip) at two doses (26 and 32 nmol/kg body weight) and assessed c-Fos activation in the PVN, arcuate nucleus (ARC) and NTS compared to vehicle treated rats (0.15 M NaCl). We also performed co-localization studies with oxytocin or tyrosine hydroxylase. Bombesin at both doses increased the number of c-Fos positive neurons in the PVN (p<0.05) and NTS (p<0.05) compared to vehicle, while in the ARC no modulation was observed (p>0.05). In the PVN and NTS the number of c-Fos positive neurons colocalized with NUCB2/nesfatin-1 increased after bombesin injection compared to vehicle treatment (p<0.05). Moreover, an increase of activated NUCB2/nesfatin-1 immunoreactive neurons that co-expressed oxytocin in the PVN (p<0.05) or tyrosine hydroxylase in the NTS (p<0.05) was observed compared to vehicle. Our results show that peripherally injected bombesin activates NUCB2/nesfatin-1 neurons in the PVN and NTS giving rise to a possible interaction between bombesin and NUCB2/nesfatin-1 in the modulation of food intake. [ABSTRACT FROM AUTHOR]

The neural pathways underlying the respiratory variation dependent on vigilance states remain unsettled. In the present study, we examined the orexinergic innervation of Kölliker-Fuse nucleus (KFN) neurons sending their axons to the rostral ventral respiratory group (rVRG) and phrenic nucleus (PhN) as well as to the hypoglossal nucleus (HGN) by using a combined retrograde tracing and immunohistochemistry. After injection of cholera toxin B subunit (CTb) into the KFN, CTb-labeled neurons that are also immunoreactive for orexin (ORX) were found prominently in the perifornical and medial regions and additionally in the lateral region of the hypothalamic ORX field. After injection of fluorogold (FG) into the rVRG, PhN or HGN, we found an overlapping distribution of ORX-immunoreactive axon terminals and FG-labeled neurons in the KFN. Within the neuropil of the KFN, asymmetrical synaptic contacts were made between these terminals and neurons. We further demonstrated that many neurons labeled with FG injected into the rVRG, PhN, or HGN are immunoreactive for ORX receptor 2. Present data suggest that rVRG-, PhN- and HGN-projecting KFN neurons may be under the excitatory influence of the ORXergic neurons for the state-dependent regulation of respiration. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a disease of complex etiology, involving multiple risk factors. When these risk factors are presented concomitantly, cognition and brain pathology are more severely compromised than if those risk factors were presented in isolation. Reduced cholinergic tone and elevated amyloid-beta (Aβ) load are pathological hallmarks of AD. The present study sought to investigate brain pathology and alterations in learning and memory when these two factors were presented together in rats. Rats received either sham surgeries, cholinergic depletions of the medial septum, intracerebroventricular Aβ 25–35 injections, or both cholinergic depletion and Aβ 25–35 injections (Aβ+ACh group). The Aβ+ACh rats were unimpaired in a striatal dependent visual discrimination task, but had impaired acquisition in the standard version of the Morris water task. However, these rats displayed normal Morris water task retention and no impairment in acquisition of a novel platform location during a single massed training session. Aβ+ACh rats did not have exacerbated brain pathology as indicated by activated astroglia, activated microglia, or accumulation of Aβ. These data suggest that cholinergic depletions and Aβ injections elicit subtle cognitive deficits when behavioural testing is conducted shortly after the presentation of these factors. These factors might have altered hippocampal synaptic plasticity and thus resemble early AD pathology. [ABSTRACT FROM AUTHOR]

Preclinical studies indicate that serotonin 7 (5-HT 7 ) receptors may regulate depressive-like behaviors. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT 7 receptors in the lateral habenular nucleus (LHb) involve in the regulation of PD-related depression. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-LHb injection of 5-HT 7 receptor agonist AS19 (1, 2 and 4 μg/rat) induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra-LHb injection of 5-HT 7 receptor antagonist SB269970 (1.5, 3 and 6 μg/rat) produced antidepressant effects in the two groups of rats. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-LHb injection of AS19 (4 μg/rat) decreased dopamine and 5-HT levels in the medial prefrontal cortex, habenula and hippocampus in sham-operated and the lesioned rats; whereas SB269970 (6 μg/rat) increased dopamine and 5-HT levels in these structures. In addition, noradrenaline levels in these structures were not changed after intra-LHb injection of AS19 or SB269970 in the two groups of rats. These findings suggest that activation or blockade of 5-HT 7 receptors in the LHb may change the activity of LHb glutamate neurons, and then decreases or increases dopamine and 5-HT levels in the limbic and limbic-related brain regions, which are involved in the regulation of depressive-like behaviors. [ABSTRACT FROM AUTHOR]

Experimental traumatic brain injury (TBI) is known to produce an acute increase in cerebral glucose utilization, followed rapidly by a generalized cerebral metabolic depression. The current studies determined effects of single or multiple treatments with sodium pyruvate (SP; 1000 mg/kg, i.p.) or ethyl pyruvate (EP; 40 mg/kg, i.p.) on cerebral glucose metabolism and neuronal injury in rats with unilateral controlled cortical impact (CCI) injury. In Experiment 1 a single treatment was given immediately after CCI. SP significantly improved glucose metabolism in 3 of 13 brain regions while EP improved metabolism in 7 regions compared to saline-treated controls at 24 h post-injury. Both SP and EP produced equivalent and significant reductions in dead/dying neurons in cortex and hippocampus at 24 h post-CCI. In Experiment 2 SP or EP were administered immediately (time 0) and at 1, 3 and 6 h post-CCI. Multiple SP treatments also significantly attenuated TBI-induced reductions in cerebral glucose metabolism (in 4 brain regions) 24 h post-CCI, as did multiple injections of EP (in 4 regions). The four pyruvate treatments produced significant neuroprotection in cortex and hippocampus 1 day after CCI, similar to that found with a single SP or EP treatment. Thus, early administration of pyruvate compounds enhanced cerebral glucose metabolism and neuronal survival, with 40 mg/kg of EP being as effective as 1000 mg/kg of SP, and multiple treatments within 6 h of injury did not improve upon outcomes seen following a single treatment. [ABSTRACT FROM AUTHOR]

Rhynchophylline (Rhy) has been demonstrated protective effects on some neurological diseases. However, the roles of Rhy in the subarachnoid hemorrhage (SAH) are still to be cleared. In the present study, the effects of Rhy on attenuation of early brain injury (EBI) after SAH have been evaluated. The adult male Sprague-Dawley rats (280–300 g) were used to establish the SAH models using endovascular perforation method. Rhy was administered by intraperitoneal injection immediately following SAH. Brain edema was assessed by magnetic resonance imaging (MRI) at 24 h after SAH. Neurological deficits, brain water content, malondialdehyde (MDA) concentration, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) content in hippocampus were also evaluated. Immunofluorescence and western blot were used to explore the underlying protective mechanism of Rhy. The results showed that, following 10 mg/kg Rhy treatment, the brain edema and neurological deficits, and blood-brain barrier (BBB) disruption were significantly attenuated at 24 h after SAH. Additionally, in hippocampus, MDA concentration, MPO activity and ROS content were markedly decreased. Meanwhile, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO-1) were increased, while the expressions of p-p53, cleaved-caspase-3 and tumor necrosis factor-α (TNF-α) were significantly decreased. Our results indicated that Rhy could attenuate early brain injury by reducing inflammation and apoptosis in hippocampus after SAH. [ABSTRACT FROM AUTHOR]

The anorectic neuropeptide nesfatin-1 has recently been characterized as a potential mood regulator, but the accurate effect of nesfatin-1 on anxiety and learning and memory behavior and the possible mechanisms remains unknown. In the present study, to test the hypothesis that nesfatin-1 might affect the anxiety-like and learning and memory behaviors in rats via ERK/CREB/BDNF pathway, nesfatin-1 was administered intraperitoneally to rats with the doses (10, 20, 40 μg/kg), and the behavioral performance was tested using the open field task, the Morris water maze (MWM), and the Y maze. Moreover, the protein expression of brain-derived neurotrophic factor (BDNF), total and phosphorylated-ERK in the hippocampus and the prefrontal cortex (PFC) were evaluated. The results showed that chronic administration of nesfatin-1 could decrease the moving distance, the duration in the center, and the frequencies of rearing and grooming in the open field task, decrease the moving distance, frequency, and the preference index of new arm in the Y maze, although there was no significant difference of the performance in the MWM task among groups. Furthermore, 3 weeks’ consecutive administration of nesfatin-1 resulted in the decrease of protein expression of BDNF and phosphorylated-ERK in the hippocampus and the PFC. These results provided evidence that exogenous nesfatin-1 could decrease exploration and induce anxiety-like behavior in rats, the mechanism of which might be related to the reduced protein expression of BDNF and phosphorylated-ERK in the hippocampus and the PFC. [ABSTRACT FROM AUTHOR]

Lead (Pb) exposure during development is associated with impaired cognitive function and long-term potentiation (LTP). Vitamin E (VE) is an antioxidant that could have protective effects against Pb intoxication. In this study, we examined the protective effects of vitamin E against Pb-induced LTP impairments. Forty-six adult male Wistar rats were randomly divided into 6 treatment groups: (1) control; (2) Pb exposure; (3) VE; (4) Pb +VE; (5) Pb exposure followed by VE 2 months after exposure; (6) VE followed by Pb exposure 1 month after treatment. Rats were exposed to Pb through daily consumption of Pb-contaminated distilled water; VE was administered by daily gavage for 3 months. After this period, the population spike (PS) amplitudes and the slopes of excitatory postsynaptic potentials (EPSPs) were measured in the dentate gyrus (DG) area of the hippocampus in adult rats in response to electrical stimulation applied to the perforant pathway in vivo. Blood samples were also collected to evaluate malondialdehyde (MDA) levels, total antioxidant capacity (TAC), and total oxidant status (TOS). Biochemical analyses demonstrated significant increases in plasma MDA and TOS levels in the Pb-exposed group compared to the control group. VE–protected groups revealed significant increases in TAC levels. Our results demonstrate that Pb decreased EPSP slopes and PS amplitudes compared to the control group, whereas VE increased these parameters compared to the control group. Co-administration of VE with Pb exposure inhibited Pb-induced effects. These findings suggest that VE via its antioxidant activity reverses Pb-induced impairments of synaptic plasticity in the DG. [ABSTRACT FROM AUTHOR]