Behavioral and dopaminergic signatures of resilience

Abstract

Chronic stress can have lasting adverse consequences in some individuals, yet others are resilient to the same stressor1,2. While previous work found differences in the intrinsic properties of mesolimbic dopamine (DA) neurons in susceptible and resilient individuals after stress was over;3-10 the causal links between DA activity during stress, dynamic stress-evoked behavior, and individual differences in susceptibility and resilience are not known. Here, we record behavior and neural activity in DA projections to the nucleus accumbens (NAc, signals reward11-14) and to the tail striatum (TS, signals threat15-18) during a multiday chronic social defeat paradigm and discover behavioral and neural signatures of resilience. Using supervised and unsupervised behavioral quantification, we find that resilient and susceptible individuals employ different behavioral strategies during stress. In addition, NAc-DA (but not TS-DA) activity is higher in the proximity of the aggressor in resilient mice, consistent with a greater subjective value of the aggressor. Moreover, NAc-DA tends to be elevated at the onset of fighting back in resilient mice and at the offset of attacks in susceptible mice. To test whether DA activation during defeat can generate resilience, and if its timing with respect to behavior is critical, we performed optogenetic stimulation of NAc-DA in open-loop (randomly timed) during defeat or timed to specific behaviors using real-time pose-tracking and behavioral classification. We find that both open-loop DA activation and fighting-back-timed activation promote resilience, in both cases reorganizing behavior during defeat toward resilience-associated patterns. Attack offset-timed activation promotes avoidance during defeat but does not promote susceptibility afterwards. Together, these data suggest a model whereby, during stress, DA in the NAc can increase resilience primarily by elevating the subjective value of the stressor rather than by reinforcing particular stress-responsive behaviors.

Responses and functions of dopamine in nucleus accumbens core during social behaviors

“…When we artificially increased DA release during defeat and thus altered the valence associated with defeat, animals showed reduced social avoidance to the aggressor after defeat. This result is consistent with a recent study showing that increasing DA level in NAc but not in tail striatum during 10-day chronic defeat led to increased resilience of defeated animals, measured as decreased social avoidance ( Willmore et al, 2022 ). In a separate study, Xie et al found that optogenetic inhibition of VTA reduced “rewarding history” of pup interaction and slowed the emergence of parental behaviors ( Xie et al, 2022 ).…”

Overlapping representations of food and social stimuli in VTA dopamine neurons

“…R. Lee, Chen, and Tye 2021;Matthews et al 2016;Tomova et al 2020;Mumtaz et al 2018;Tenk et al 2009;Whitten 1956;Remedios et al 2017; S. X. McHenry et al 2017;Willmore et al 2022;Dai et al 2022). If social and food representations overlap in VTA DA neurons, one would predict that a change in social experience that affects social motivation might reorganize responses across both social-and food-responsive VTA DA neurons.…”

“…Dopaminergic neurons in the midbrain are essential for motivated behaviors mediated by a range of unconditioned stimuli, including both palatable rewards (Schultz, Dayan, and Montague 1997;Cohen et al 2012;Fernandes et al 2020;Grove et al 2022;Martel and Fantino 1996;Mazzone et al 2020) and social stimuli (Gunaydin et al 2014;Willmore et al 2022;Solié et al 2021;Louilot et al 1991;Bariselli et al 2018). However, whether the same or different dopamine subpopulations encode such different unconditioned stimuli is unclear.…”