BACKGROUND: Stress is a major risk factor for depression, but not everyone responds to stress in the same way. Identifying why certain individuals are more susceptible is essential for targeted treatment and prevention. In rodents, nucleus accumbens (NAc) afferents from the ventral hippocampus (vHIP) are implicated in stress-induced susceptibility, but little is known about how this pathway might encode future vulnerability or specific behavioral phenotypes. METHODS: We used fiber photometry to record in vivo activity in vHIP-NAc afferents during tests of depressive-and anxiety-like behavior in male and female mice, both before and after a sex-specific chronic variable stress protocol, to probe relationships between prestress neural activity and behavior and potential predictors of poststress behavioral adaptation. Furthermore, we examined chronic variable stress-induced alterations in vHIP-NAc activity in vivo and used ex vivo slice electrophysiology to identify the mechanism of this change. RESULTS: We identified behavioral specificity of the vHIP-NAc pathway to anxiety-like and social interaction behavior. We also showed that this activity is broadly predictive of stress-induced susceptibility in both sexes, while prestress behavior is predictive only of anxiety-like behavior. We observed a stress-induced increase in in vivo vHIP-NAc activity coincident with an increase in spontaneous excitatory postsynaptic current frequency. CONCLUSIONS: We implicate vHIP-NAc in social interaction and anxiety-like behavior and identify markers of vulnerability in this neural signal, with elevated prestress vHIP-NAc activity predicting increased susceptibility across behavioral domains. Our findings indicate that individual differences in neural activity and behavior play a role in predetermining susceptibility to later stress, providing insight into mechanisms of vulnerability.

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Making decisions is fundamental to how we navigate, survive, and thrive in our environment. The quality of information used to support decisions is rarely perfect. Many decisions are made under conditions of uncertainty, arising from ambiguous or conflicting information. Conflict and ambiguity, though conceptually distinct, both generate uncertainty, a commonality that has led to overlapping and inconsistent terminology in the literature. Evidence from human and animal research suggests a behavioral dissociation in responding to conflict and ambiguity. This dissociation can be studied through the implementation of spatial or operant tasks in rodents which find close parallels in gambling tasks in humans. Pharmacological manipulations in rodents and fMRI studies in humans further suggest a dissociation in the neural processing of conflict and ambiguity such that fronto-striato-parietal circuits may be most important for interpreting ambiguous information, while the ventral striatum and ventral hippocampus are critical for resolving conflicting information. Overall, the neural representation and resolution of conflict and ambiguity remain relatively understudied despite the fundamental importance of these processes to understanding decisionmaking. We highlight the need for further research to differentiate these related yet distinct processes through implementation of carefully designed behavioral tasks with neural circuit-dissection techniques and the potential to pursue translational research between rodents and humans.

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Learning to predict threat is essential but equally important yet often overlooked is learning about the absence of threat. Interrogating neural activity in two nucleus accumbens afferents in male and female mice during aversive and neutral cues reveals sex-specific encoding of cue discrimination and cue-mediated suppression of reward behavior. Sexual dimorphisms in neural bases of threat discrimination may reflect sex differences in behavioral strategy relevant to differential psychiatric risk.

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