Neurocircuitry of motivated reward-seeking after stress

Project Summary/Abstract Stress is a risk factor for the development of neuropsychiatric disorders. Over recent years, it is becoming increasingly clear that dopaminergic circuitry originating in the ventral tegmental area, which is the most well studied in the context of motivation, is also critical for the behavioral response to stress suggesting an interaction

between stress, motivation, and stress-coping behaviors. Recent studies have determined that the medial habenulo-interpeduncular nucleus (MHb-IPN) axis, and particularly the IPN responds to aversive stimuli, contributes to avoidance behavior, and modulates anxiety-like behavior as a component of the extrahypothalamic

stress network. However, the MHb-IPN axis also controls nicotine intake in rodent models, receives dopamine input from the VTA, and contributes to novelty preference suggesting a role for this pathway in reward seeking and motivation. Interestingly, we have determined that the IPN GABAergic neurons are activated by acute

stressors; whereas, rewarding stimuli including sucrose reduces activity, which, when mimicked using optogenetics, reduces stress-induced anxiety-like behavior in mice. These data suggest that one critical function of the IPN and associated circuitry may be in motivating reward seeking as a stress-coping strategy. However,

neuronal sub-populations underlying this effect are unknown as are the IPN efferents and afferents that mediate effects of stress on motivated reward seeking. Thus, the goal of this application is to build off these data and test the hypothesis that IPN neuronal sub-populations, IPN efferents, and IPN afferents drive reward seeking as a

coping mechanism for stress reduction. In Aim 1, we will combine GCaMP expression with fiber photometry and optogenetics to test if an IPN GABAergic neuron sub-population activated by acute stressors exhibits reduced activity during reward behaviors and contributes to stress-induced increased motivation for sucrose seeking.

Aim 2 will test if a sub-population of IPN neurons that project to the laterodorsal tegmental area contributes to reward seeking during stress through modulation of dopaminergic reward circuits. Aim 3 will test the hypothesis that acute stress engages IPN afferents that are critical for the effects of stressors on reward behavior and

seeking. It is anticipated that elucidating circuitry and mechanisms underlying coping behaviors and effects of stressors on reward seeking and consumption in an understudied brain region will yield great insights into behaviors that may be dysregulated in neuropsychiatric disorders and set the foundation for therapeutic

strategies for new treatment.