Humans exhibit a remarkable degree of resilience in the face of extreme stress, with most resisting the development of neuropsychiatric disorders. Over the past 5 years, there has been increasing interest in the active, adaptive coping mechanisms of resilience; however, in humans, the majority of published work focuses on correlative neuroendocrine markers that are associated with a resilient phenotype. In this review, we highlight a growing literature in rodents that is starting to complement the human work by identifying the active behavioral, neural, molecular, and hormonal basis of resilience. The therapeutic implications of these findings are important and can pave the way for an innovative new approach to drug development for a range of stress–related syndromes.

Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting an important, novel circuit-specific mechanism in depression.

We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10 d) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2 week), but not acute (single dose), treatments with the antidepressant medication fluoxetine (20 mg/kg). Chronic social defeat stress increased hyperpolarization-activated cation current (I h ) in VTA dopamine neurons, an effect that was also normalized by chronic treatment with fluoxetine. As well, local infusion of I h inhibitors ZD7288 (0.1 g) or DK-AH 269 (0.6 g) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individual's responses to chronic stress and antidepressant action.

Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety-and anhedonia-like symptoms and decreased cAMP response element-binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K + channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety-and depression-like behavioral phenotypes, establish a selective role of NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.Depression and anxiety are common forms of mental illness in the general population. Although they are classified as distinct syndromes by the Diagnostic and Statistical Manual (American Psychiatric Association), symptoms of depression and anxiety often occur together and to widely varying extents in different subtypes of the illnesses. Despite the importance of these clinical phenomena, very little is known about the distinctions between depression-and anxiety-like symptoms in animal models 1 . Models of 'active' stress, such as foot shock, restraint stress, social defeat and learned helplessness, produce depression-and anxiety-like phenotypes; the molecular mechanisms of these models have been extensively studied, but specific molecular mediators of depression versus anxiety symptoms have not yet been described [2][3][4] . Even less well studied, however, is a 'passive' model of stress and social isolation in adulthood, which, as with active stress, mimics aspects of human depression and anxiety 5,6 . This lack of attention is unfortunate, as social isolation would appear to be particularly relevant to certain subtypes of human depression and anxiety disorders 7,8 .Although social isolation has been studied, most models to date have focused on adulthood behaviors after isolation rearing early in life, either as pups or adolescents, which is a very different model than adulthood social isolation 5 . Reports on adulthood isolation provide evidence for a strong anxiety-like phenotype 9,10 , an increase in alcohol intake 11 , modulation of responses to rewarding stimuli 9,10,12 , changes in circadian rhythms 13 and a dampening in running-induced neurogenesis 14 . Although reports on changes in neurochemistry are often conflicting, there appears to be decreased serotonergic and noradrenergic function and metabolism in several brain regi...

Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we show that chronic atypical antipsychotics down-regulate the expression of mGlu2, an effect that is associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurs in concert with a 5-HT2A receptor-dependent up-regulation and increased binding of HDAC2 to the mGlu2 promoter. Viral-mediated over-expression of HDAC2 in frontal cortex decreases mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevent the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augment their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target to improve schizophrenia treatment.

Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns. Here we show that PRC2, which supports neuron specification during differentiation, contributes to the suppression of a transcriptional program that is detrimental for adult neuron function and survival. We show that PRC2 deficiency in striatal neurons leads to the de-repression of selected, predominantly bivalent PRC2 target genes that are dominated by self-regulating transcription factors normally suppressed in these neurons. The transcriptional changes in PRC2-deficient neurons lead to progressive and fatal neurodegeneration in mice. Our results point to a key role of PRC2 in protecting neurons against degeneration.

Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3′-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants.

Numerous studies have employed repeated social defeat stress (RSDS) to study the neurobiological mechanisms of depression in rodents. An important limitation of RSDS studies to date is that they have been conducted exclusively in male mice due to the difficulty of initiating attack behavior directed toward female mice. Here, we establish a female mouse model of RSDS by inducing male aggression toward females through chemogenetic activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate that females susceptible to RSDS display social avoidance, anxiety-like behavior, reduction of body weight, and elevated levels of circulating interleukin 6. In contrast, a subset of mice we term resilient only display anxiety-like behaviors after RSDS. This model allows for investigation of sex differences in the neurobiological mechanisms of defeat‒induced depression‒like behaviors. A robust female social defeat model is a critical first step in the identification and development of novel therapeutic compounds to treat depression and anxiety disorders in women.