The Role of Limbic Corticotropin Releasing Factor Neural Systems in Motivation and Addiction

Abstract

Corticotropin releasing factor (CRF) is a key regulator of behavioral and physiological responses to stress and is typically associated with anxiety and distress (Gray, 1993). In opponent process theories of addiction, CRF-driven anxiety acts as a negative reinforcer during withdrawal to cause relapse as a means of reducing distress due to hedonic homeostatic dysregulation (George et al., 2012a; G. F. Koob, 2010). However, evidence suggests an alternative role for CRF in positive incentive motivation without distress (Baumgartner et al., 2021, 2022; Lemos et al., 2012; Merali et al., 1998a; Peciña et al., 2006a; Xu et al., 2024). Specifically, optogenetic activation of CRF neurons in central amygdala (CeA) and nucleus accumbens (NAc) generate positive incentive motivation and reward pursuit without distress in Crh-cre rats. However, it is unclear whether CRF itself versus other co-released neurotransmitters from CRF neurons, such as GABA, contributes to the appetitive effects of CRF neuron stimulation. Chapters 2 and 3 investigate whether NAc and CeA CRF neuronal activation requires CRF receptor activation for incentive motivation. Using optogenetics and pharmacology, I activate these neurons while blocking CRF receptors during behavioral tests of motivation. Results show CRF receptor activation is crucial for both regions to enhance reward pursuit. Moreover, blocking CRF receptors diminishes self-stimulation of CRF neurons, implicating CRF signaling in motivation without distress. Next, the circuitry underlying the incentive effects of CeA CRF neuronal activation is unknown. Chapter 4 presents pilot data on CeA CRF neuron projections to dorsal medial striatum (DMS), mid-anterior lateral hypothalamus (LH), and posterior LH or substantia nigra (SN). CeA CRF projections to the LH may exhibit a rostrocaudal gradient: those to mid-anterior LH bias rats against laser-paired rewards, while those to posterior LH or SN bias rats toward laser-paired rewards, potentially supporting self-stimulation. However, activation of fibers into the DMS are ineffective in influencing motivation. Finally, it is possible that extensive drug experience flips the valence of CeA CRF neurons, given opponent process predictions of CRF's role in mediating aversive distress in withdrawal. Chapter 5 explores the impact of long access cocaine self-administration (LgA) on the valence of CeA CRF neuronal activation. Following 14 days of 6-hour daily cocaine self-administration, rats showed altered motivation patterns: males displayed aversion to laser-paired sucrose while females intensified sucrose pursuit. After abstinence, males reverted to preferring laser-paired sucrose, and both sexes increased overall reward pursuit compared to drug-naïve and control rats. Notably, some rats self-stimulated CeA CRF neurons during withdrawal and post-abstinence, suggesting sustained positive incentive motivation. Moreover, CeA CRF neuron activation did not induce aversion post-cocaine exposure. These findings reveal sex-dependent differences in CRF signaling during withdrawal as well as augmented incentive sensitization post-abstinence in both sexes. This dissertation expands upon conventional views of CRF as a driver of distress by exploring its role in incentive motivation. We provide further evidence for an incentive role for limbic CRF systems, particularly within CeA and NAc. Importantly, CeA CRF neurons can still generate positive incentive motivation, potentially facilitating incentive sensitization, and fail to become aversive following extensive cocaine consumption. Finally, pilot data exploring CeA CRF neuronal projections hint at the specific circuitry underlying CeA CRF driven incentive motivation. This work adds nuance to mechanisms involved in stress-induced relapse and motivation and provides important insights into stress-associated affective disorders related to motivation.