Though the GluK4 kainate receptor subunit shows limited homology and a restricted expression pattern relative to other kainate receptor subunits, its ablation results in distinct behavioral and molecular phenotypes. GluK4 knockout mice demonstrated impairments in memory acquisition and recall in a Morris water maze test, suggesting a previously unreported role for kainate receptors in spatial memory. GluK4 knockout mice also showed marked hyperactivity and impaired pre-pulse inhibition, thereby mirroring two of the hallmark endophenotypes of patients with schizophrenia and bipolar disorder. Furthermore, we found that GluK4 is a key mediator of excitotoxic neurodegeneration: GluK4 knockout mice showed robust neuroprotection in the CA3 region of the hippocampus following intrahippocampal injection of kainate and widespread neuroprotection throughout the hippocampus following hypoxia-ischemia. Biochemical analysis of kainate- or sham-treated wild-type and GluK4 knockout hippocampal tissue suggests that GluK4 may act through the JNK pathway to regulate the molecular cascades that lead to excitotoxicity. Together, our findings suggest that GluK4 may be relevant to the understanding and treatment of human neuropsychiatric and neurodegenerative disorders.

Sounds, like music and noise, are capable of reliably affecting individuals' mood and emotions. However, these effects are highly variable across individuals. A putative source of variability is genetic background. Here we explored the interaction between a functional polymorphism of the dopamine D2 receptor gene (DRD2 rs1076560, G>T, previously associated with the relative expression of D2S/L isoforms) and sound environment on mood and emotion-related brain activity. Thirty-eight healthy subjects were genotyped for DRD2 rs1076560 (G/G=26; G/T=12) and underwent functional magnetic resonance imaging (fMRI) during performance of an implicit emotion-processing task while listening to music or noise. Individual variation in mood induction was assessed before and after the task. Results showed mood improvement after music exposure in DRD2GG subjects and mood deterioration after noise exposure in GT subjects. Moreover, the music, as opposed to noise environment, decreased the striatal activity of GT subjects as well as the prefrontal activity of GG subjects while processing emotional faces. These findings suggest that genetic variability of dopamine receptors affects sound environment modulations of mood and emotion processing.

Disturbance of the daily cycles in sleep and wakefulness induced by conditions such as shift work and jet lag can increase the risk of affective disorders including anxiety and depression. The way such circadian disorganization disrupts the regulation of mood, however, is not well understood. More specifically, the impact of circadian disorganization on the daily rhythms of the neuronal function that controls mood remains unclear. We therefore investigated the effects of circadian disorganization on expression rhythms of clock genes as well as immediate early genes (IEGs) in several mood-controlling regions of the brain. To introduce circadian disorganization of behaviors, we exposed male C57BL/6J mice to chronic reversal of the light-dark cycle and we found a marked negative mood phenotype in these mice. Importantly, the most adverse effect of circadian disorganization on expression rhythms of clock and IEGs was observed in the prefrontal cortex (PFC) when compared to that in other mood-related areas of the brain. Dysregulation of molecular rhythms in the PFC is therefore suggested to be associated with the development of mood disorders in conditions including shift work and jet lag.

Age-associated changes in cognition are mirrored by impairments in cellular models of memory and learning, such as long-term potentiation (LTP) and long-term depression (LTD). In young rodents, environmental enrichment (EE) can enhance memory, alter LTP and LTD, as well as reverse cognitive deficits induced by aging. Whether short-term EE can benefit cognition and synaptic plasticity in aged rodents is unclear. Here, we tested if short-term EE could overcome age-associated impairments in induction of LTP and LTD. LTP and LTD could not be induced in the CA1 region of hippocampal slices in control, aged rats using standard stimuli that are highly effective in young rats. However, exposure of aged littermates to EE for three weeks enabled successful induction of LTP and LTD. EE-facilitated LTP was dependent upon N-methyl-d-aspartate receptors (NMDARs). These alterations in synaptic plasticity occurred with elevated levels of phosphorylated cAMP response element-binding protein and vascular endothelial growth factor, but in the absence of changes in several other synaptic and cellular markers. Importantly, our study suggests that even a relatively short period of EE is sufficient to alter synaptic plasticity and molecular markers linked to cognitive function in aged animals.

Increases in cell proliferation in the hippocampus have been robustly demonstrated in animal models of neurodegenerative diseases like Huntington's disease (HD). However, in the subventricular zone, animal models of HD have demonstrated no change in cell proliferation compared to wild types, while in humans there is a distinct increase in cell proliferation in HD cases. Interestingly, there have been no reports on cell proliferation in the human subgranular zone (SGZ) of the hippocampus in HD, despite numerous transgenic mouse models of HD showing decreased proliferation in the SGZ. Furthermore, HD can be divided into those with mainly mood and mainly motor symptomatology. We hypothesized that HD cases with mainly mood symptomatology would show a greater change in hippocampal proliferation, which has previously been implicated in mood disorders such as depression. Therefore, in the current study we examined and compared proliferation in the SGZ in normal vs. HD, HD mood, and HD motor affected cases. However, our results revealed no significant differences in SGZ proliferation between normal and HD cases, and no differences when divided into groups based on mood and motor symptomatology. Our results were confirmed using a range of cell-cycle protein markers and, overall, were comparable with previous studies of the human hippocampus, where very little proliferation was detected in the adult SGZ. These results demonstrate that in humans the SGZ is far less proliferative than the SVZ, and suggests that hippocampal plasticity in humans does not primarily involve cell proliferation.

Peripheral inflammation often causes changes in mood and emergence of depressive behavior, and is characterized by a group of physical manifestations including lethargy, malaise, listlessness, decreased appetite, anhedonia, and fever. These behavioral changes are induced at the molecular level by pro-inflammatory cytokines like interleukin (IL)-1β, IL-6 and TNF-α. The basolateral amygdala (BLA) is a key brain region involved in mood and may mediate some of the behavioral effects of inflammation. However, it is unknown whether peripheral inflammatory state affects the activity of BLA neurons. To test this, adult male Sprague-Dawley rats were treated with IL-1β (1 μg, intraperitoneal (i.p.)), and behavioral and electrophysiological measures were obtained. IL-1β reduced locomotion in the open-field test and also reduced home-cage mobility, consistent with features of sickness-like behavior. Using in vivo single-unit extracellular electrophysiological recordings from anesthetized rats, we found that spontaneous BLA neuronal firing was acutely (<30 min) increased after IL-1β, followed by a return to baseline level, particularly in the basal nucleus of the BLA complex. To verify and expand on effects of peripheral inflammation, we tested whether another, long-lasting inflammagen also changes BLA neuronal firing. Lipopolysaccharide (250 μg/kg, i.p.) increased BLA firing rate acutely (<30 min) and persistently. The findings demonstrate a rapid effect of peripheral inflammation on BLA activity and suggest a link between BLA neuronal firing and triggering of behavioral consequences of peripheral inflammation. These findings are a first step toward understanding the neuronal basis of depressive behavior caused by acute peripheral inflammation.

Altered activity of corticolimbic brain regions is a hallmark of stress-related illnesses, including mood disorders, neurodegenerative diseases, and substance abuse disorders. Acute stress adaptively recruits brain region-specific functions for coping, while sustained activation under chronic stress may overwhelm feedback mechanisms and lead to pathological cellular and behavioral responses. The neural mechanisms underlying dysregulated stress responses and how they contribute to behavioral deficits are poorly characterized. Here, we tested whether prior exposure to chronic restraint stress (CRS) or unpredictable chronic mild stress (UCMS) in mice could alter functional response to acute stress and whether these changes are associated with chronic stress-induced behavioral deficits. More specifically, we assessed acute stress-induced functional activation indexed by c-Fos+ cell counts in 24 stress- and mood-related brain regions, and determined if changes in functional activation were linked to chronic stress-induced behavioral impairments, summarized across dimensions through principal component analysis (PCA). Results indicated that CRS and UCMS led to convergent physiological and anxiety-like deficits, whereas working and short-term memory were impaired only in UCMS mice. CRS and UCMS exposure exacerbated functional activation by acute stress in anterior cingulate cortex (ACC) area 24b and ventral hippocampal (vHPC) CA1, CA3, and subiculum. In dysregulated brain regions, levels of functional activation were positively correlated with principal components reflecting variance across behavioral deficits relevant to stress-related disorders. Our data supports an association between a dysregulated stress response, altered functional corticolimbic excitation/inhibition balance, and the expression of maladaptive behaviors.

Early life stress can permanently alter functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress response and influences the perception of pain. Chronic pelvic pain patients commonly report having experienced childhood neglect or abuse, which increases the likelihood of presenting with comorbid chronic pain and/or mood disorders. Animal models of neonatal stress commonly display enhanced anxiety-like behaviors, colorectal hypersensitivity, and disruption of proper neuro-immune interactions in adulthood. Here, we tested the hypothesis that early life stress impacts vaginal sensitivity by exposing mice to neonatal maternal separation (NMS) for 3h/day during the first two (NMS14) or three (NMS21) postnatal weeks. As adults, female mice underwent vaginal balloon distension (VBD), which was also considered an acute stress. Before or after VBD, mice were assessed for anxiety-like behavior, hindpaw sensitivity, and changes in gene and protein expression related to HPA axis function and regulation. NMS21 mice displayed significantly increased vaginal sensitivity compared to naïve mice, as well as significantly reduced anxiety-like behavior at baseline, which was heightened following VBD. NMS21 mice exhibited significant thermal and mechanical hindpaw hypersensitivity at baseline and following VBD. NMS14 mice displayed no change in anxiety-like behavior and only exhibited significantly increased hindpaw mechanical and thermal sensitivity following VBD. Centrally, a significant decrease in negative regulation of the HPA axis was observed in the hypothalamus and hippocampus of NMS21 mice. Peripherally, NMS and VBD affected the expression of inflammatory mediators in the vagina and bladder. Corticotropin-releasing factor (CRF) receptor and transient receptor potential (TRP) channel protein expression was also significantly, and differentially, affected in vagina, bladder, and colon by both NMS and VBD. Together these data indicate that NMS affects both central and peripheral aspects of the HPA axis, which may drive changes in vaginal sensitivity and the development of comorbid chronic pain and mood disorders.

Serotonin (5-hydroxytryptamine; 5-HT) has an important role in mood regulation, and its dysfunction in the central nervous system (CNS) is associated with depression. Reports of mood and immune disorder co-morbidities indicate that immune-5-HT interactions may mediate depression present in immune compromised disease states including HIV/AIDS, multiple sclerosis, and Parkinson's disease. Chemokines, immune proteins that induce chemotaxis and cellular adhesion, and their G-protein coupled receptors distribute throughout the CNS, regulate neuronal patterning, and mediate neuropathology. The purpose of this study is to investigate the neuroanatomical and neurophysiological relationship between the chemokine fractalkine/CX3CL1 and its receptor CX3CR1 with 5-HT neurons in the rat midbrain raphe nuclei (RN). Immunohistochemistry was used to examine the colocalization of CX3CL1 or CX3CR1 with 5-HT in the RN, and whole-cell patch-clamp recordings in rat brain slices were used to determine the functional impact of CX3CL1 on 5-HT dorsal raphe nucleus (DRN) neurons. Greater than 70% of 5-HT neurons colocalize with CX3CL1 and CX3CR1 in the RN. CX3CL1 localizes as discrete puncta throughout the cytoplasm, whereas CX3CR1 concentrates to the perinuclear region of 5-HT neurons and exhibits microglial expression. CX3CL1 and CX3CR1 also colocalize with one another on individual RN cells. Electrophysiology studies indicate a CX3CL1-mediated enhancement of spontaneous inhibitory postsynaptic current (sIPSC) amplitude and dose-dependent increase of evoked IPSC (eIPSC) amplitude without affecting eIPSC paired-pulse ratio, a finding observed selectively in 5-HT neurons. CX3CL1's effect on eIPSC amplitude is blocked by pretreatment with an anti-CX3CL1 neutralizing antibody. Thus, CX3CL1 enhances postsynaptic GABA receptor number or sensitivity on 5-HT DRN neurons under conditions of both spontaneous and synaptically-evoked GABA release. CX3CL1 may indirectly inhibit 5-HT neurotransmission by increasing the sensitivity of 5-HT DRN neurons to GABA inputs. Therapies targeting CX3CL1 may treat serotonin related mood disorders, including depression experienced by patients with compromised immune systems.

Regulator of G protein signaling (RGS) proteins are negative regulators of heterotrimeric G proteins that act by accelerating Gα-mediated GTPase activity to terminate G protein-coupled receptor-associated signaling. RGS8 is expressed in several brain regions involved with movement and mood. To investigate the role of RGS8 in vivo, we generated transgenic mice overexpressing brain RGS8 (RGS8tg). RGS8 gene and protein expressions were examined by real-time PCR and immunohistochemistry, respectively, and a significant increase in RGS8 protein was detected in the hippocampal CA1 region compared with wild-type mice (WT). We characterized the phenotypic traits, and found that RGS8tg showed decreased depressive-like behavior in the forced swimming test (FST). Previously, RGS8 was identified as a potent negative regulator of melanin-concentrating hormone receptor 1 (MCHR1), whose activation is mainly involved in energy homeostasis and emotional processing. Interestingly, acute oral administration of MCHR1 antagonist SNAP94847 did not have antidepressant-like effects on RGS8tg in the FST, but did show antidepressant effects on WT. In contrast, selective noradrenaline reuptake inhibitor desipramine had a significant effect on RGS8tg in the FST. MCHR1 is enriched in a subset of primary cilia, as sensory organelles that mediate extracellular signaling. Immunohistochemical analyses revealed significant elongation of MCHR1-positive cilia in the CA1 region of RGS8tg compared with WT. Taken together, these findings suggest that RGS8 participates in modulation of depression-like behavior through ciliary MCHR1 expressed in the CA1 region. The present study may support the possible modulation of RGS8 function in mood disorders.

Cannabinoid 1 receptors (CB(1)) are highly expressed on presynaptic terminals in the brain where they are importantly involved in the control of neurotransmitter release. Alteration of CB(1) expression is associated with a variety of neurological and psychiatric disorders. There is now compelling evidence that peripheral inflammatory disorders are associated with depression and cognitive impairments. These can be modeled in rodents with peripheral administration of lipopolysaccharide (LPS), but central effects of this treatment remain to be fully elucidated. As a reduction in endocannabinoid tone is thought to contribute to depression, we asked whether the expression of CB(1) in the CNS is altered following LPS treatment. CD1 mice received LPS (0.1-1mg/kg, ip) and 6h later activated microglial cells were observed only in circumventricular organs and only at the higher dose. At 24h, activated microglial cells were identified in other brain regions, including the hippocampus, a structure implicated in some mood disorders. Immunohistochemistry and real-time polymerase chain reaction (PCR) were utilized to evaluate the change of CB(1) expression 24h after inflammation. LPS induced an increase of CB(1) mRNA in the hippocampus and brainstem. Subsequent immunohistochemical analysis revealed reduced CB(1) in the hippocampus, especially in CA3 pyramidal layer. Analysis of co-localization with markers of excitatory and inhibitory terminals indicated that the decrease in CB(1) expression was restricted to glutamatergic terminals. Despite widespread microglial activation, these results suggest that peripheral LPS treatment leads to limited changes in CB(1) expression in the brain.

Serotonin is a neurotransmitter that plays a role in regulating activities such as sleep, appetite, mood and substance abuse disorders; serotonin receptors 5-HT2AR and 5-HT2CR are active within pathways associated with substance abuse. It has been suggested that 5-HT2AR and 5-HT2CR may form a dimer that affects behavioral processes. Here we study the coevolution of residues in 5-HT2AR and 5-HT2CR to identify potential interactions between residues in both proteins. Coevolution studies can detect protein interactions, and since the thus uncovered interactions are subject to evolutionary pressure, they are likely functional. We assessed the significance of the 5-HT2AR/5-HT2CR interactions using randomized phylogenetic trees and found the coevolution significant (p-value = 0.01). We also discuss how co-expression of the receptors suggests the predicted interaction is functional. Finally, we analyze how several single nucleotide polymorphisms for the 5-HT2AR and 5-HT2CR genes affect their interaction. Our findings are the first to characterize the binding interface of 5-HT2AR/5-HT2CR and indicate a correlation between this interface and location of SNPs in both proteins.

Desensitization of post-synaptic serotonin1A (5-HT1A) receptors may underlie the clinical improvement of neuropsychiatric disorders. In the hypothalamic paraventricular nucleus, Galphaz proteins mediate the 5-HT1A receptor-stimulated increases in hormone release. Regulator of G protein signaling-Z1 (RGSZ1) is a GTPase-activating protein selective for Galphaz proteins. RGSZ1 regulates the duration of interaction between Galphaz proteins and effector systems. The present investigation determined the levels of RGSZ1 in the hypothalamic paraventricular nucleus of rats subjected to four different treatment protocols that produce desensitization of 5-HT1A receptors. These protocols include: daily administration of beta estradiol 3-benzoate (estradiol) for 2 days; daily administration of fluoxetine for 3 and 14 days; daily administration of cocaine for 7 or 14 days; and acute administration of (+/-)-1-(2,5 dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI; a 5-HT2A/2C receptor agonist). Estradiol treatment was the only protocol that increased the levels of RGSZ1 protein in the hypothalamic paraventricular nucleus in a dose-dependent manner (46%-132% over control). Interestingly, previous experiments indicate that only estradiol produces a decreased Emax of 5-HT1A receptor-stimulation of hormone release, whereas fluoxetine, cocaine and DOI produce a shift to the right (increased ED50). Thus, the desensitization of 5-HT1A receptors by estradiol might be attributable to increased levels of RGSZ1 protein. These findings may provide insight into the adaptation of 5-HT1A receptor signaling during pharmacotherapies of mood disorders in women and the well-established gender differences in the vulnerability to depression.

The behavioral phenotype of a transgenic mouse overexpressing a galanin receptor 2 (GalR2)-enhanced, green fluorescent protein (EGFP)-construct under the platelet-derived growth factor-B promoter, and of controls, was assessed in various behavioral tests, such as the Porsolt forced swim test, as well as the open field, elevated plus maze and passive avoidance tests. In addition, the distribution of GalR2-EGFP expressing cell bodies and processes was studied in the brain of these mice using histochemical methods. Three age groups of the transgenic mice demonstrated decreased levels of immobility in the forced swim test, indicative of antidepressive-like behavior and/or increased stress resistance. Anxiety-like behaviors, measured in two different tests, did not differ between the GalR2-overexpressing and the wild-type mice, nor did motor activity levels, emotional learning or memory behaviors. High levels of GalR2 mRNA and protein expression were observed in the presubiculum, subiculum, cingulate cortex, retrosplenial granular and agranular cortices, subregions of prefrontal cortex, and the olfactory bulb, regions which are directly or indirectly implicated in depression-like behavior. These results may contribute to the understanding of the pathophysiology of major depressive disorder and the role of GalR2 in the regulation of mood, and suggest a potential therapeutic effect by targeting the GalR2 for treatment of depressive disorders.

Retinoids, a family of molecules that is derived from vitamin A, are involved in a complex signaling pathway that regulates gene expression and controls neuronal differentiation in the central nervous system. The physiological actions of retinoids are mainly mediated by retinoic acid receptors. Here we describe the distribution of retinoic acid receptor α (RARα) in the human hypothalamus by immunohistochemistry. RARα immunoreactivity showed a widespread pattern throughout the hypothalamus, with high density in the suprachiasmatic nucleus (SCN), paraventricular nucleus (PVN), supraoptic nucleus (SON), infundibular nucleus and medial mamillary nucleus. No staining was observed in the sexually dimorphic nucleus of preoptic area, tuberomamillary nucleus and lateral hypothalamic area. RARα was co-localized with vasopressin (AVP) neurons in the SCN, PVN and SON, and co-localized with corticotropin releasing hormone (CRH) neurons in the PVN. These findings provide a neurobiological basis for the participation of retinoids in the regulation of various hypothalamic functions. As shown earlier, the co-localization of RARα in CRH neurons suggests that retinoids might directly modulate the hypothalamus-pituitary-adrenal axis in the PVN, which may have implications for the stress response and its involvement in mood disorders. Functional studies in the other sites of RARα localization have to follow in the future.

Ferulic acid (4-hydroxy-3-methoxycinnamic acid; FA) is a plant constituent and is contained in several medicinal plants for clinical use. In this paper, we investigated the effects of FA on the proliferation of neural stem/progenitor cells (NSC/NPCs) in vitro and in vivo. FA significantly increased the proliferation of NSC/NPCs cultured from the telencephalon of embryonic day-14 rats, and increased the number and size of secondary formed neurospheres. An in vitro differentiation assay showed that FA did not affect the percentage of either neuron-specific class III beta-tubulin (Tuj-1)-positive cells or glial fibrillary acidic protein (GFAP)-positive cells in the total cell population. Oral administration of FA increased the number of newly generated cells in the dentate gyrus (DG) of the hippocampus of corticosterone (CORT)-treated mice, indicating that FA enhances the proliferation of adult NSC/NPCs in vivo. We also found that oral administration of FA increased cAMP response element binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) mRNA level in the hippocampus of CORT-treated mice, and ameliorated the stress-induced depression-like behavior of mice. These novel pharmacological effects of FA may be useful for the treatment of mood disorders such as depression.

Autism spectrum disorder (ASD) is a developmental brain disorder characterized by restricted and repetitive patterns of behavior, social and communication defects, and is commonly associated with difficulties with motor coordination. The etiology of ASD, while mostly idiopathic, has been linked to hereditary factors and teratogens, such as valproic acid (VPA). VPA is used clinically to treat epilepsy, mood disorders, and in the prevention of migraines. The use of VPA during pregnancy significantly increases the risk of ASD in the offspring. Neuropathological studies show decreased cerebellar function in patients with ASD, resulting in gait, balance and coordination impairments. Herein, we have exposed pregnant rats to a repeated oral dose of VPA on embryonic days 10 and 12 and performed a detailed investigation of the structure and function of the cerebellar vermis. We found that throughout all ten lobules of the cerebellar vermis, Purkinje cells were significantly smaller and expression of the calcium binding protein calbindin (CB) was significantly reduced. We also found that dendritic arbors of Purkinje cells were shorter and less complex. Additionally, animals exposed to a repeated dose of VPA performed significantly worse in a number of motor tasks, including beam walking and the rotarod. These results suggest that repeated embryonic exposure to VPA induces significant cerebellar dysfunction and is an effective animal model to study the cerebellar alterations in ASD.

Tianeptine (Tian) has been widely used in treating mood and anxiety disorders, and recently as a nootropic to improve cognitive performance. However, its mechanisms of action are insufficiently clear. We used a comparative proteomic approach to identify sub-proteome changes in hippocampal cytosol and non-synaptic mitochondria (NSM) following chronic Tian treatment (3 weeks, 10 mg/kg/day) of adult male Wistar rats and rats exposed to chronic social isolation stress (CSIS) (6 weeks), an animal model of depression. Behavioural assessment of depressive and anxiety-like behaviours was based on sucrose preference, forced swim test and marble burying. Selected differently expressed proteins were validated by Western blot and/or immunohistochemical analysis. Tian normalized the behavioural alternations induced by CSIS, indicating its antidepressant and anxiolytic efficacy. Proteomic data showed that Tian increased the expression of proteasome system elements and redox system enzymes, enhanced energy metabolism and increased glyceraldehyde-3-phosphate dehydrogenase expression bound to NSM in control rats. Tian-treatment of CSIS-stressed rats resulted in a minor suppression of the increase in proteasome elements and antioxidative enzymes, except for an increase in Cu-Zn superoxide dismutase, and increased the level of Lactate dehydrogenase. Our results indicate on an increased NSM functionality in controls and suppression of the CSIS-induced impairment of NSM functionality by Tian treatment as well as on the CSIS-caused discrepancy in Tian effects relative to controls.

Aim of this systematic review is to assess short- and long-lasting effects of antenatal exposure to untreated maternal depressive symptoms. Pertinent articles were identified through combined searches of Science.gov, Cochrane library, and PubMed databases (through August 2015). Forty-three, selected articles revealed that untreated gestational depression and even depressive symptoms during pregnancy may have untoward effects on the developing fetus (hyperactivity, irregular fetal heart rate), newborns (increased cortisol and norepinephrine levels, decreased dopamine levels, altered EEG patterns, reduced vagal tone, stress/depressive-like behaviors, and increased rates of premature deaths and neonatal intensive care unit admission), and children (increased salivary cortisol levels, internalizing and externalizing problems, and central adiposity). During adolescence, an independent association exists between maternal antenatal mood symptoms and a slight increase in criminal behaviors. In contrast, the relationship between gestational depression and increased risks of prematurity and low birth weight remains controversial. Given this background, when making clinical decisions, clinicians should weigh the growing evidences suggesting the detrimental and prolonged effects in offspring of untreated antenatal depression and depressive symptoms during pregnancy against the known and emerging concerns associated with in utero exposure to antidepressants.

Stressful social experiences during early-life can increase the risk of developing neuropsychiatric disorders associated with anxiety, mood, and personality. Early neglect also alters peripheral arginine vasopression (AVP) and oxytocin (OXT). We hypothesized that a lack of social stimuli should adversely affect developmental AVP and OXT systems. To test this idea, we examined changes of central AVP- and OXT-immunoreactive (ir) cell number as well as its related behaviors in socially isolated rats. Animals were weaned at 23 days of age, divided into group- or isolation-reared conditions, and maintained for at least 2 weeks. At 38-48 days of age, animals were sacrificed for immunohistochemistry, or used for two behavioral tests: elevated plus-maze test and social recognition test. The results from immunohistochemistry showed that isolation-reared males have decreased AVP-ir cells in the paraventricular nucleus hypothalamus (PVH), medial parvicellular part, ventral zone, and that isolation-reared females have decreased OXT-ir cells in the PVH, medial parvicellular part, dorsal zone, when compared with group-reared counterparts. The results from behavioral assessment showed that isolation-reared animals have difficulty with social recognition, and that isolation-reared males, but not females, have anxiogenic profile. The present study demonstrates that post-weaning social isolation results in decrease of male AVP-ir cells and female OXT-ir cells in the PVH parvocellular divisions, and supports the idea that juvenile social environment may play a critical role in neuronal and behavioral development.