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.

Context Generalized social phobia (GSP) is characterized by fear/avoidance of social situations. Previous studies have examined the neural responses in GSP to one class of social stimuli, facial expressions. However, studies have not examined the neural response in GSP to another equally important class of social stimuli, the communication of praise or criticism. Objective To examine the neural response to receipt of praise or criticism in GSP; specifically, to determine whether patients with GSP show an increased response to the receipt of both praise and criticism and whether self-relevance modulates this relationship. Design Case-control study. Setting Government clinical research institute. Participants Unmedicated individuals with GSP (n=17) and age-, IQ-, and sex-matched healthy comparison individuals (n=17). Main Outcome Measure Blood oxygenation level–dependent signal, as measured via functional magnetic resonance imaging. During functional magnetic resonance imaging scans, individuals read positive (eg, You are beautiful), negative (eg, You are ugly), and neutral (eg, You are human) comments that could be either about the self or about somebody else (eg, He is beautiful). Results Hypothesized significant group×valence×referent interactions were observed within regions of the medial prefrontal cortex and bilateral amygdala. In these regions, the patients with GSP showed significantly increased blood oxygenation level–dependent responses, relative to comparison individuals, to negative comments (criticism) referring to themselves. However, in contrast, there were no significant group differences with respect to negative comments referring to others or neutral or positive comments referring to self or others. Conclusions These results implicate the medial prefrontal cortex, involved in the representation of the self, together with the amygdala, in the pathophysiology of GSP. Further, findings demonstrate a meaningful effect of psychological context on neural-circuitry hyperactivity in GSP.

Rats emit ultrasonic vocalizations (USVs) that are thought to serve as situation-dependent affective signals and accomplish important communicative functions. In appetitive situations, rats produce 50 kHz USVs, whereas 22 kHz USVs occur in aversive situations. Reception of 50 kHz USVs induces social approach behavior, while 22 kHz USVs lead to freezing behavior. These opposite behavioral responses are paralleled by distinct brain activation patterns, with 50 kHz USVs, but not 22 kHz USVs, activating neurons in the nucleus accumbens (NAcc). The NAcc mediates appetitive behavior and is critically modulated by dopaminergic afferents that are known to encode the value of reward. Therefore, we hypothesized that 50 kHz USVs, but not 22 kHz USVs, elicit NAcc dopamine release. While recording dopamine signaling with fast-scan cyclic voltammetry, freely moving rats were exposed to playback of four acoustic stimuli via an ultrasonic speaker in random order: (1) 50 kHz USVs, (2) 22 kHz USVs, (3) time-and amplitude-matched white noise, and (4) background noise. Only presentation of 50 kHz USVs induced phasic dopamine release and elicited approach behavior toward the speaker. Both of these effects, neurochemical and behavioral, were most pronounced during initial playback, but then declined rapidly with subsequent presentations, indicating a close temporal relationship between the two measures. Moreover, the magnitudes of these effects during initial playback were significantly correlated. Collectively, our findings show that NAcc dopamine release encodes pro-social 50 kHz USVs, but not alarming 22 kHz USVs. Thus, our results support the hypothesis that these call types are processed in distinct neuroanatomical regions and establish a functional link between pro-social communicative signals and reward-related neurotransmission.

The "endowment effect" refers to the tendency to place greater value on items that one owns-an anomaly that violates the reference-independence assumption of rational choice theories. We investigated neural antecedents of the endowment effect in an event-related functional magnetic resonance imaging (fMRI) study. During scanning, 24 subjects considered six products paired with 18 different prices under buying, choosing, or selling conditions. Subjects showed greater nucleus accumbens (NAcc) activation for preferred products across buy and sell conditions combined, but greater mesial prefrontal cortex (MPFC) activation in response to low prices when buying versus selling. During selling, right insular activation for preferred products predicted individual differences in susceptibility to the endowment effect. These findings are consistent with a reference-dependent account in which ownership increases value by enhancing the salience of the possible loss of preferred products.

The anterior insula has been implicated in both the experience and the anticipation of negative outcomes. Although individual differences in insular sensitivity have been associated with selfreport measures of chronic anxiety, previous research has not examined whether individual differences in insular sensitivity predict learning to avoid aversive stimuli. In the present study, insular sensitivity was assessed as participants anticipated monetary losses while undergoing functional magnetic resonance imaging. We found that insular responsiveness to anticipated losses predicted participants' ability to learn to avoid losses (but not to approach gains) in a behavioral test several months later. These findings suggest that in addition to correlating with self-reported anxiety, heightened insular sensitivity may promote learning to avoid loss.Detecting and avoiding threats arguably are the most basic of survival skills. In humans, avoidance learning is necessary not only to ensure survival in the face of basic threats (e.g., predators, rotten food), but also to promote optimal responses to more abstract threats in social (e.g., enemies) and economic (e.g., risky investments) domains. Although the ability to anticipate and avoid danger is critical to survival, excessive anticipatory anxiety may contribute to psychopathology.

Environmental stimuli guide value-based decision making, but can do so through cognitive representation of outcomes or through general-incentive properties attributed to the cues themselves. We assert that these differences are conferred through the use of alternative associative structures differing in computational intensity. Using this framework, we review scientific evidence to discern the neural substrates of these assumed separable processes. We suggest that the contribution of the mesolimbic dopamine system to Pavlovian valuation is restricted to an affective system that is only updated through experiential feedback of stimulus-outcome pairing, whereas the orbitofrontal cortex contributes to an alternative system capable of inferential reasoning. Finally we discuss the interactions and convergence of these systems and their implications for decision making and its pathology.