Background Multiple neuropsychiatric disorders, e.g., depression, are linked to imbalances in excitatory and inhibitory neurotransmission and prefrontal cortical dysfunction, and are concomitant with chronic stress. Methods We used electrophysiologic (n = 5–6 animals, 21–25 cells/group), neuroanatomic (n = 6–8/group), and behavioral (n = 12/group) techniques to test the hypothesis that chronic stress increases inhibition of medial prefrontal cortex (mPFC) glutamatergic output neurons. Results Using patch clamp recordings from infralimbic mPFC pyramidal neurons, we found that chronic stress selectively increases the frequency of miniature inhibitory postsynaptic currents with no effect on amplitude, which suggests that chronic stress increases presynaptic gamma-aminobutyric acid release. Elevated gamma-aminobutyric acid release under chronic stress is accompanied by increased inhibitory appositions and terminals onto glutamatergic cells, as assessed by both immunohistochemistry and electron microscopy. Furthermore, chronic stress decreases glucocorticoid receptor immunoreactivity specifically in a subset of inhibitory neurons, which suggests that increased inhibitory tone in the mPFC after chronic stress may be caused by loss of a glucocorticoid receptor–mediated brake on interneuron activity. These neuroanatomic and functional changes are associated with impairment of a prefrontal-mediated behavior. During chronic stress, rats initially make significantly more errors in the delayed spatial win-shift task, an mPFC-mediated behavior, which suggests a diminished impact of the mPFC on decision making. Conclusions Taken together, the data suggest that chronic stress increases synaptic inhibition onto prefrontal glutamatergic output neurons, limiting the influence of the prefrontal cortex in control of stress reactivity and behavior. Thus, these data provide a mechanistic link among chronic stress, prefrontal cortical hypofunction, and behavioral dysfunction.

Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominantnegative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH-seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxidative stress. Furthermore, deficits were observed in well-defined tests for the cognitive control of adaptive behavior using reversal learning and reinforcer devaluation paradigms. These deficits occurred even though DN-DISC1 mice showed intact performance in simple associative learning and normal responses in consumption of reward. In an additional series of assessments, motivational functions also were impoverished in DN-DISC1 mice, including tests of the dynamic modulation of reward value by effortful action, progressive ratio performance, and social behavior. Augmentation of an oxidative stress-associated cascade (e.g., a nuclear GAPDH cascade) points to an underlying condition that may contribute to the profile of cognitive and motivational impairments in DN-DISC1 mice by affecting the functional integrity of the prefrontal cortex and dysfunction within its connected networks. As such, this model should be useful for further preclinical research and drug discovery efforts relevant to the burden of prefrontal dysfunction in neuropsychiatric illness.cognition | depression | orbitofrontal cortex I t has long been noted that the cognitive impairments in patients with major mental illness, such as schizophrenia and mood disorders, point to dysfunction of the frontal lobe (1-3). More recent translational studies based on cognitive and affective neuroscience approaches suggest the associated deficits in neuropsychiatric populations reflect abnormal functioning of prefrontal-subcortical circuitry responsible for cognitive and emotional control (4-7). By examining disorders of brain circuitry, these studies offer the potential to advance therapeutic treatment (7,8).The impaired integrity affecting prefrontal circuitry in schizophrenia and mood disorders in part reflects neuropathology associated with decreased parvalbumin immunoreactivity (9-11), a marker for fast-spiking inhibitory interneurons, which are critical for cognitive function (9, 10). One possible cause of impaired integrity affecting that interneuron population comes from evidence that decreased parvalbumin immunoreactivity is elicited by oxidative stress in mouse models relevant to neuropsychiatric illness (12-15). Oxidative stress can be driven by a deficiency in antioxidant defenses, which leads to increased oxidative signaling resulting in damage to DNA, proteins, and fatty acids (16). Central nervous system cells are particularly vulnerable to these effects because of reduced antioxidant levels and elevated metabolic rate (13).Genetic studies also are contribu...

Pregnancy and parturition are intricately regulated to ensure successful reproductive outcomes. However, the factors that control gestational length in humans and other anthropoid primates remain poorly defined. Here, we show the endogenous retroviral long terminal repeat transposon-like human element 1B (THE1B) selectively controls placental expression of corticotropin-releasing hormone (CRH) that, in turn, influences gestational length and birth timing. Placental expression of CRH and subsequently prolonged gestational length were found in two independent strains of transgenic mice carrying a 180-kb human bacterial artificial chromosome (BAC) DNA that contained the full length of CRH and extended flanking regions, including THE1B. Restricted deletion of THE1B silenced placental CRH expression and normalized birth timing in these transgenic lines. Furthermore, we revealed an interaction at the 5′ insertion site of THE1B with distal-less homeobox 3 (DLX3), a transcription factor expressed in placenta. Together, these findings suggest that retroviral insertion of THE1B into the anthropoid primate genome may have initiated expression of CRH in placental syncytiotrophoblasts via DLX3 and that this placental CRH is sufficient to alter the timing of birth.

Postpartum depression (PPD) affects up to 20% of mothers and has negative consequences for both mother and child. Although exposure to psychosocial stress during pregnancy and abnormalities in the hypothalamic pituitary adrenal (HPA) axis have been linked to PPD, molecular changes in the brain that contribute to this disease remain unknown. This study utilized a novel chronic psychosocial stress paradigm during pregnancy (CGS) to investigate the effects of psychosocial stress on maternal behavior, neuroendocrine function, and gene expression changes in molecular regulators of the HPA axis in the early postpartum period. Postpartum female mice exposed to CGS display abnormalities in maternal behavior, including fragmented and erratic maternal care patterns, and the emergence of depression and anxiety-like phenotypes. Dysregulation in postpartum HPA axis function, evidenced by blunted circadian peak and elevation of stress-induced corticosterone levels, was accompanied by increased CRH mRNA expression and a reduction in CRH receptor 1 in the paraventricular nucleus of the hypothalamus (PVN). We further observed decreased PVN expression of nuclear steroid hormone receptors associated with CRH transcription, suggesting these molecular changes could underlie abnormalities in postpartum HPA axis and behavior observed. Overall, our study demonstrates that psychosocial stress during pregnancy induces changes in neuroendocrine function and maternal behavior in the early postpartum period and introduces our CGS paradigm as a viable model that can be used to further dissect the molecular defects that lead to PPD.

Neuronal nitric oxide synthase (nNOS) forms nitric oxide (NO), which functions as a signaling molecule via S-nitrosylation of various proteins and regulation of soluble guanylate cyclase (cGC)/cyclic guanosine monophosphate (cGMP) pathway in the central nervous system. nNOS signaling regulates diverse cellular processes during brain development and molecular mechanisms required for higher brain function. Human genetics have identified nNOS and several downstream effectors of nNOS as risk genes for schizophrenia. Besides the disease itself, nNOS has also been associated with prefrontal cortical functioning, including cognition, of which disturbances are a core feature of schizophrenia. Although mice with genetic deletion of nNOS display various behavioral deficits, no studies have investigated prefrontal cortex-associated behaviors. Here, we report that nNOS knockout (KO) mice exhibit hyperactivity and impairments in contextual fear conditioning, results consistent with previous reports. nNOS KO mice also display mild impairments in object recognition memory. Most importantly, we report for the first time working memory deficits, potential impairments in prefrontal cortex mediated cognitive function in nNOS KO mice. Furthermore, we demonstrate Disrupted-in-Schizophrenia 1 (DISC1), another genetic risk factor for schizophrenia that plays roles for cortical development and prefrontal cortex functioning, including working memory, is a novel protein binding partner of nNOS in the developing cerebral cortex. Of note, genetic deletion of nNOS appears to increase the binding of DISC1 to NDEL1, regulating neurite outgrowth as previously reported. These results suggest that nNOS KO mice are useful tools in studying the role of nNOS signaling in cortical development and prefrontal cortical functioning.

Sleep disturbances are common in psychiatric disorders, but the causal relationship between the two and the underlying genetic factors is unclear. The DISC1 gene is strongly linked to mood disorders and schizophrenia in a Scottish pedigree. In an earlier study we found a sleep homeostasis disturbance in a Drosophila model overexpressing wild-type human DISC1. Here we aimed to explore the relationship between sleep and the DISC1 gene in a mammalian model, a novel transgenic mouse model expressing full-length human DISC1.We assessed circadian rhythms by monitoring wheel running activity under normal 24-h light:dark conditions and in constant darkness and found the DISC1 mice to have normal circadian photoentrainment and normal intrinsic circadian period. We also assessed sleep duration and quality in the DISC1 mice and found that they were awake longer than wild-type controls at baseline with a tendency for lower rebound of delta activity during recovery from a short sleep deprivation. Thus we suggest that DISC1 may be involved in sleep regulation.

The pericentriolar material (PCM) is composed of proteins responsible for microtubule nucleation/anchoring at the centrosome, some of which have been associated with genetic susceptibility to schizophrenia. Here, we show that mice haploinsufficient for Pericentriolar material 1 (Pcm1+/−), which encodes a component of the PCM found to bear rare loss of function mutations in patients with psychiatric illness, manifest neuroanatomical phenotypes and behavioral abnormalities. Using ex-vivo magnetic resonance imaging of the Pcm1+/− brain, we detect reduced whole brain volume. Pcm1 mutant mice show impairment in social interaction, specifically in the social novelty phase, but not in the sociability phase of the three-chamber social interaction test. In contrast, Pcm1+/− mice show normal preference for a novel object, suggesting specific impairment in response to novel social stimulus. In addition, Pcm1+/− mice display significantly reduced rearing activity in the open field. Pcm1+/− mice behave normally in the elevated plus maze, rotarod, prepulse inhibition, and progressive ratio tests. Together, our results suggest that haploinsufficiency at the Pcm1 locus can induce a range of neuroanatomical and behavioral phenotypes that support the candidacy of this locus in neuropsychiatric disorders.

Prenatal stress (PS) is associated with increased vulnerability to affective disorders. Transplacental glucocorticoid passage and stress-induced maternal environment alterations are recognized as potential routes of transmission that can fundamentally alter neurodevelopment. However, molecular mechanisms underlying aberrant emotional outcomes or the individual contributions intrauterine stress versus maternal environment play in shaping these mechanisms remain unknown. Here, we report anxiogenic behaviors, anhedonia, and female hypothalamic-pituitary-adrenal axis hyperactivity as a consequence of psychosocial PS in mice. Evidence of fetal amygdala programming precedes these abnormalities. In adult offspring, we observe amygdalar transcriptional changes demonstrating sex-specific dysfunction in synaptic transmission and neurotransmitter systems. We find these abnormalities are primarily driven by in-utero stress exposure. Importantly, maternal care changes postnatally reverse anxiety-related behaviors and partially rescue gene alterations associated with neurotransmission. Our data demonstrate the influence maternal environment exerts in shaping offspring emotional development despite deleterious effects of intrauterine stress.