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Background: The amygdala plays a critical role in the development of anxiety and the regulation of stress hormone secretion. Reciprocally, stress and stress hormones can induce amygdala hypertrophy, a phenomenon related to enhanced anxiety. As such, modulating amygdaloid function can potentially reduce maladaptive features of the stress response. The amygdala contains two kind of receptor for corticosteroids, the adrenal steroid hormone released during stress: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). Although high-affinity MRs are heavily occupied during basal conditions, low-affinity GRs are heavily occupied only by stress levels of glucocorticoids. Prolonged and heavy occupancy of GRs tends to mediate the deleterious effects of glucocorticoids on neurons, whereas MR occupancy tends to mediate beneficial effects. Methods: In this report, we overexpress MR in neurons of adult rat basolateral amygdala, with a herpes simplex viral vector coding for two copies of MR. Results: Such overexpression reduced anxiety, as measured on an elevated plus-maze, and reduced the magnitude of glucocorticoid secretion after an acute stressor. Conclusions: Thus, increasing MR signaling in basolateral amygdala could be valuable in management of stress disorders. [Copyright &y& Elsevier]

Abstract: Stress results in the release of glucocorticoids (GCs) which at high levels, impair performance on hippocampus-dependent tasks. Estrogen is neurotrophic and can rescue stress-induced memory impairments. Here we report the use of a viral vector to overexpress a chimeric gene (ER/GR) that converts the deleterious effects of glucocorticoids into beneficial estrogenic effects. A short immobilization stress regimen was sufficient to impair non-spatial memory. In contrast, viral vector-mediated overexpression of ER/GR in the dentate gyrus of the hippocampus protected against stress-induced impairments of non-spatial memory. These data add to the growing evidence that increasing estrogenic signaling can protect against the impairing effects of stress on non-spatial memory. [Copyright &y& Elsevier]

While acute and chronic d-amphetamine (AMPH) treatments produce greater scores for locomotor activity in female rats in comparison with male rats, little is known about AMPH-induced gender differences on cognition. The objectives of the present study were to (1) investigate during a withdrawal period following chronic AMPH treatment whether performance of two memory tasks, object recognition (OR) and object placement (OP) are altered, and (2) determine if an AMPH challenge dose after a withdrawal period amplifies previously reported gender differences in locomotor activity and neurochemistry. Sprague–Dawley male and female adult rats were included in a chronic AMPH treatment (10 injections, 1 every other day; males: 3 mg/kg, females 2.6 mg/kg). Locomotor activity was quantified (acute, chronic, and after a 16-day withdrawal period). Neurotransmitter levels in brain areas were evaluated after an AMPH challenge dose on the 16th withdrawal day. During the withdrawal period, OR (2- and 4-h delays) was impaired in AMPH-treated males but they did not show any impairment in OP; AMPH females also showed impairments in OR (only 4-h delay). AMPH females showed more locomotion after acute and chronic treatment but AMPH-induced hyperactivity was comparable for females and males after a challenge dose. Following a challenge dose of AMPH after a withdrawal period, gender differences in dopaminergic and serotonergic neurotransmission in the striatum were found. These gender differences elicited by AMPH in monoaminergic pathways may be related to sex differences on behavioral components involved in locomotion and OR memory. [Copyright &y& Elsevier]

Major depression and anxiety disorders are significant causes of disability and socioeconomic burden. Despite the prevalence and considerable impact of these affective disorders, their pathophysiology remains elusive. Thus, there is an urgent need to develop novel therapeutics for these conditions. We evaluated the role of SIRT1 in regulating dysfunctional processes of reward by using chronic social defeat stress to induce depression- and anxiety-like behaviors. Chronic social defeat stress induces physiological and behavioral changes that recapitulate depression-like symptomatology and alters gene expression programs in the nucleus accumbens, but cell type–specific changes in this critical structure remain largely unknown. We examined transcriptional profiles of D1-expressing medium spiny neurons (MSNs) lacking deacetylase activity of SIRT1 by RNA sequencing in a cell type–specific manner using the RiboTag line of mice. We analyzed differentially expressed genes using gene ontology tools including SynGO and EnrichR and further demonstrated functional changes in D1-MSN–specific SIRT1 knockout (KO) mice using electrophysiological and behavioral measurements. RNA sequencing revealed altered transcriptional profiles of D1-MSNs lacking functional SIRT1 and showed specific changes in synaptic genes including glutamatergic and GABAergic (gamma-aminobutyric acidergic) receptors in D1-MSNs. These molecular changes may be associated with decreased excitatory and increased inhibitory neural activity in Sirt1 KO D1-MSNs, accompanied by morphological changes. Moreover, the D1-MSN–specific Sirt1 KO mice exhibited proresilient changes in anxiety- and depression-like behaviors. SIRT1 coordinates excitatory and inhibitory synaptic genes to regulate the GABAergic output tone of D1-MSNs. These findings reveal a novel signaling pathway that has potential for the development of innovative treatments for affective disorders. [ABSTRACT FROM AUTHOR]

Background: The kappa opioid receptor (KOR) system contributes to the prodepressive and aversive consequences of stress and is implicated in the facilitation of conditioned fear and anxiety in rodents. Here, we sought to identify neural circuits that mediate KOR system effects on fear and anxiety in rats. Methods: We assessed whether fear conditioning induces plasticity in KOR or dynorphin (the endogenous KOR ligand) messenger RNA (mRNA) expression in the basolateral (BLA) and central (CeA) nuclei of the amygdala, hippocampus, or striatum. We then assessed whether microinfusions of the KOR antagonist JDTic (0–10 μg/side) into the BLA or CeA affect the expression of conditioned fear or anxiety. Finally, we examined whether fear extinction induces plasticity in KOR mRNA expression that relates to the quality of fear extinction. Results: Fear conditioning upregulated KOR mRNA in the BLA by 65% and downregulated it in the striatum by 22%, without affecting KOR levels in the CeA or hippocampus, or dynorphin levels in any region. KOR antagonism in either the BLA or CeA decreased conditioned fear in the fear-potentiated startle paradigm, whereas KOR antagonism in the BLA, but not the CeA, produced anxiolytic-like effects in the elevated plus maze. Effective fear extinction was associated with a 67% reduction in KOR mRNA in the BLA. Conclusions: These findings suggest that fear conditioning and extinction dynamically regulate KOR expression in the BLA and provide evidence that the BLA and CeA are important neural substrates mediating the anxiolytic-like effects of KOR antagonists in models of fear and anxiety. [ABSTRACT FROM AUTHOR]

Little is known about changes in brain function that may occur during pregnancy. Studies in rodents and sheep suggest that several brain neurotransmitter and neurohormonal systems known to modulate anxiety may be altered during pregnancy.Cerebrospinal fluid (CSF) and plasma samples were obtained from 21 women (during weeks 38–39 of pregnancy) who were undergoing elective cesarean section and from 22 healthy nonpregnant women.The CSF levels of g-aminobutyric acid (GABA) and 3-methoxy-4-hydroxyphenylglycolwere reduced in pregnant women. There were no changes in CSF glutamate, 5-hydroxyindoleactic acid, and homovanillic acid. There was a large increase in CSF prolactin in pregnant women and also a trend toward an elevation in CSF oxytocin. Levels of prolactin, but not oxytocin, in CSF and plasma were correlated in pregnant women.These results suggest that pregnancy alters regulation of brain GABA, norepinephrine, and prolactin, which may play a role in changes in vulnerability to anxiety and depression during pregnancy and postpartum. Prolactin circulating in the bloodstream seems to be the major source of CSF prolactin during pregnancy. [Copyright &y& Elsevier]