Ventral Hippocampal Afferents to Nucleus Accumbens Encode Both Latent Vulnerability and Stress-Induced Susceptibility

Abstract

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.

Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes

“…This result provides electrophysiological evidence for early life adversity influencing glutamate transmission within the NAcC and complements previous work demonstrating that maternal separation stress leads to decreased GluA2 AMPA subunit expression in the NAc of males but not of females (29). Of note, many other studies have demonstrated stress-induced increases in glutamate transmission within the NAc, but those studies focused on recordings in the NAc shell and primarily examined the influence of stress exposure during adulthood (30)(31)(32).…”

Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice

“…Although pharmacological inactivation of the VTA completely abolishes the 4 Hz NAc oscillation, other circuit elements, including excitatory inputs or local interneurons, may modulate the amplitude of 4 Hz NAc oscillations 44 . For example, there is evidence that vHPC projections to the NAc are activated by aversive stimuli and mediate stress susceptibility 15,47,48 . Future studies will determine how other inputs and local microcircuitry contribute to the 4 Hz NAc oscillation.…”

Sex Differences in the Development of the Rodent Corticolimbic System

“…Future work dissecting subregion-and axisspecific hippocampal maturation in both sexes is necessary to identify possible mechanisms underlying the emergence of sex differences in hippocampal-dependent behavior. Finally, recent research tying adult sex-specific stress susceptibility to changes in the ventral hippocampus-nucleus accumbens circuit (Muir et al, 2020;Williams et al, 2020) further asserts a pressing need to expand these efforts toward the identification of sex-and circuit-specific maturation trajectories within sensitive circuits, as a means to search for potential contributions to both stress sensitivity and behavioral emergence in males and females.…”