Sex Differences in Contributions of Mesolimbic Dopamine to Stress Coping and Avoidance Behaviors
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Stress is an unavoidable, ubiquitous feature of life. While stress and its resultant responses are popularly associated with negative experiences, affect, and outcomes, the stress response is required for growth and adaptation. A critical phase of the stress response is stress coping, comprised of behavioral and cognitive strategies that aim to minimize and manage the impacts of stress on the mind and body. Although stress and an adaptive stress response are necessary for development, chronic stress that surpasses adaptive capacity significantly increases vulnerability for developing stress-associated conditions such as major depression and generalized anxiety disorder. The choice of coping strategy is a highly variable, context-dependent process that can directly mediate stress-associated outcomes. Avoidant, passive, or aggressive coping styles during stress can dysregulate assessments of threat and safety after stress, which contribute to symptomatology of stress-linked disorders. In humans, women experience a higher incidence of stress-linked conditions, which is hypothesized to be driven in part by sex-biased differences in coping styles during stress. The relationship between stress coping strategies and behavior after stress is not fully known, but is suspected to be mediated by sex through a complex interaction of genetic, neurobiological, and psychosocial factors. Activity of dopaminergic (DA) neurons in the ventral tegmental area (VTA) and subsequent release in the nucleus accumbens (NAc) are likely mediators of relationships between stress coping and avoidance behaviors through their role in stress and reward processing, action selection, motivation, and exploratory behaviors. However, the role of sex in dynamics of DAergic activity across stress and avoidance remains elusive due to decades of stress models being developed and tested exclusively in males. The work in this dissertation characterizes sex-biased outcomes of stress exposure on activity of VTA DA neurons and DA release in the NAc. In Aim 1, male and female mice were exposed to subchronic variable stress (SCVS), a stress paradigm that models female-specific stress vulnerability to explore dynamics of stress coping behaviors and their relationship to avoidance after stress. Females were found to engage in more active coping than males. Greater active coping during stress was associated with more avoidance in females and less avoidance in males, indicating that the influence of coping strategy on post-stress avoidance is mediated by sex. In light of ongoing research demonstrating sex-biased changes in mesolimbic activity after SCVS, Aim 2 investigates the relationship between post-stress VTA DA activity, stress coping, and avoidance behaviors. After stress, there was no sex or stress-induced difference in spontaneous activity of VTA DA neurons, but there was increased inhibitory synaptic tone and reduced Ih amplitude in cells from stressed animals. Interestingly, greater VTA DA firing rates predicted greater avoidance in control females and stressed males, suggesting that stress engages a sex-biased relationship between DA activity and avoidance. Finally, Aim 3 uses fiber photometry recordings of DA release in the NAc core to assess dynamics of NAc DA activity across stress coping and avoidance behaviors. During TSS, NAc release increased in males and females at the onset of immobility, but at greater magnitudes in males. The magnitude of DA release at immobility onset predicted immobility behavior at the beginning of stress, but the magnitude of DA release at immobility onset diminished over time and did not predict immobility at the end of stress. Recordings in avoidance tasks demonstrated that NAc DA release is greater in females than males during the EPM assay, and is increased by the presentation of a rewarding stimulus across all animals. Together, these findings demonstrate that stress coping behavior, a sex-biased predictor of avoidance behavior, engages the mesolimbic system in a sex-biased manner. DA activity is also dynamically altered by transitions between coping styles and by the assessment of salient stimuli in an anxiogenic environment. This demonstrates a sex-biased role for mesolimbic DA in assessing salience during stress and avoidance tasks to direct behavioral adaptation.
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