. The primary goal of this proposal is to investigate the motivational role of excitation of neurons that release corticotropin releasing factor (CRF) in brain limbic structures. CRF neural circuitry is the brain's master stress trigger1. The activation of CRF neurons is traditionally believed to generate aversive motivational states including aversive withdrawal states after discontinuation of drug use in addicts1,2,3. Specifically, excitation of CRF neurons in both the central amygdala (CeA) and in the bed nucleus of the stria terminalis (BNST) are hypothesized to generate aversive withdrawal states1,2,4 according to opponent-process models (also called hedonic homeostasis, hedonic dysregulation and allostasis hypotheses of addiction). However, other research, including my own pilot studies, demonstrates that activation of CRF neurons in CeA, as well as NAc, may also contribute to intensifying positive incentive motivation for rewards, without inducing any aversive states5,6,7. If so, this would help explain why stress continues to precipitate relapse in recovering addicts even after withdrawal symptoms are gone. My pilot evidence suggests that only CRF neurons in BNST cause a traditional aversive state when activated. The current proposal aims to investigate the surprising positive incentive motivation roles of CRF neurons in CeA and NAc, using selective optogenetic tools to specifically activate CRF-expressing neurons in CRH-Cre rats, via Cre-targeted optogenetic channelrhodopsin. The predicted positive incentive motivation effects of CRF-neuron stimulation in NAc and CeA will be contrasted to predicted negative aversive effects of CRF-neuron stimulation in BNST. Motivation effects of inhibiting CRF neurons will also be examined in these structures. Incentive motivation amplification will be measured using laser self-stimulation of CRF neurons and an operant 2-choice task earning sensory rewards, which models narrowly focused intense pursuit, similar to addiction8,9. In this choice task, rats earn either sucrose rewards or intravenous drug rewards: one of the two reward choices always earn a reward accompanied by laser that modulates CRF neuronal activity, while the other choice earns the reward alone. Finally, distributed neural circuitry recruited by stimulation of CRF neurons that mediate incentive motivation for CeA or NAc sites, or aversive motivation for BNST sites, will be mapped and compared by measuring distant Fos expression in other brain structures, and specific causal projections will be examined using optogenetic tools. Through the proposed training, I will learn new techniques including intravenous drug self-administration procedures and behavioral economics analysis, and advanced optogenetic and immunohistochemistry techniques needed for CRF neuron imaging and tract tracing, and for mapping anatomical activation patterns. This training will help me to develop into a productive, independent research scientist. The results may also provide insights for understanding clinical roles of CRF neuronal circuitry of CeA, NAc, and BNST in incentive motivation vs. aversive motivation, relevant to the roles of stress activation of CRF neurons in addiction and relapse.
Stress is an important factor that contributes to drug addiction, relapse, and other disorders, and the brain?s master stress trigger is the corticotropin releasing factor (CRF) system1. While CRF neurons are often thought to act in addiction primarily by generating aversive stress states, new evidence indicates that CRF and CRF- containing neurons in the nucleus accumbens and amygdala may also directly amplify incentive motivation to pursue and consume rewards, without necessarily causing aversive states5,6,7. The current proposal aims to use selective optogenetic and other tools to specifically activate CRF-expressing neurons in targeted brain structures that amplify intense incentive motivation, in order to elucidate new neurobiological mechanisms through which stress can contribute to addiction and relapse, and lead to potential therapeutic targets.
