Stressors motivate an array of adaptive responses ranging from “fight or flight” to an internal urgency signal facilitating long-term goals1. However, traumatic or chronic uncontrollable stress promotes the onset of Major Depressive Disorder where acute stressors lose their motivational properties and are perceived as insurmountable impediments2. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal3. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry4. Here we report that corticotropin releasing factor (CRF), a neuropeptide released in response to acute stressors5 and other arousing environmental stimuli6, acts in the nucleus accumbens of naïve mice to increase dopamine release through co-activation of CRF R1 and R2 receptors. Remarkably, severe stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF’s capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

SUMMARY The striatum contains neurochemically defined compartments termed patches and matrix. Previous studies suggest patches preferentially receive limbic inputs and project to dopamine neurons in substantia nigra (SNc), whereas matrix neurons receive sensorimotor inputs and do not innervate SNc. Using BAC-Cre transgenic mice with viral tracing techniques we mapped brain-wide differences in the input-output organization of the patch/matrix. Findings reveal a displaced population of striatal patch neurons termed “exo-patch”, which reside in matrix zones but have neurochemistry, connectivity, and electrophysiological characteristics resembling patch neurons. Contrary to previous studies, results show patch/exo-patch and matrix neurons receive both limbic and sensorimotor information. A novel inhibitory projection from bed nucleus of the stria terminalis to patch/exo-patch neurons was revealed. Projections to SNc were found to originate from patch/exo-patch and matrix neurons. These findings redefine patch/matrix beyond traditional neurochemical topography and reveal new principles about their input-output connectivity, providing a foundation for future functional studies.

Background Generalized Social Phobia (GSP) and Generalized Anxiety Disorder (GAD) are both associated with emotion dysregulation. In healthy subjects, research implicates dorsal anterior cingulate (dACC) in both explicit emotion regulation and top-down attentional control. While studies have examined these processes in GSP or GAD, no work compares findings across the two disorders. Moreover, no work examines functioning in cases comorbid for both disorders (GSP/GAD). Here we compare the neural correlates of explicit emotion regulation (EER) and top-down attentional control (TAC) in GSP, GAD, and GSP/GAD. Method Medication-free adults with GSP (EER n=19; TAC n=18), GAD (EER n=17; TAC n =17), GSP/GAD (EER n=17; TAC=15), or no psychopathology (EER n=18; TAC n=18). During EER, individuals alternatively viewed, up-regulated, and down-regulated responses to emotional pictures. During TAC, they performed an emotional Stroop task. Results For both tasks, significant group-by-condition interactions emerged in dACC and parietal cortices. Healthy adults showed significantly increased recruitment during emotion regulation, relative to emotion-picture viewing. GAD, GSP, and GSP/GAD subjects showed no such increases, with all three groups differing from healthy adults but not from each other. Evidence of emotion-related disorder-specificity emerged in medial prefrontal cortex (MPFC) and amygdala. This disorder-specific responding varied as a function of stimulus emotion content but not emotion-regulatory demands. Conclusions GSP and GAD both involve reduced capacity for engaging emotion-regulation brain networks, whether explicitly or via top-down attentional control. A reduced ability to recruit regions implicated in top-down attention might represent a general risk factor for anxiety disorders.