Activating corticotropin releasing factor (CRF) systems in nucleus accumbens, amygdala, and bed nucleus of stria terminalis: Incentive motivation or aversive motivation?

Abstract Background Corticotropin releasing factor (CRF) neural systems are important stress mechanisms in central amygdala (CeA), bed nucleus of stria terminalis (BNST), nucleus accumbens (NAc) and related structures. CRF-containing neural systems are traditionally posited to generate aversive distress states that motivate over-consumption of rewards and relapse in addiction. However, CRF-containing systems may alternatively promote incentive motivation to increase reward pursuit and consumption, without requiring aversive states. Methods We optogenetically stimulated CRF-expressing neurons in CeA, BNST or NAc, using Crh-Cre+ rats (n=37 female, n=34 male) to investigate roles in incentive motivation versus aversive motivation. We paired CRF-expressing neuronal stimulations with earning sucrose rewards in two-choice and progressive ratio tasks and investigated recruitment of distributed limbic circuitry. We further assessed valence with CRF-containing neuron laser self-stimulation tasks. Results Channelrhodopsin excitation of CRF-containing neurons in CeA and NAc amplified and focused incentive motivation and recruited activation of mesocorticolimbic reward circuitry. CRF systems in both CeA and NAc supported laser self-stimulation, amplified incentive motivation for sucrose in a breakpoint test, and focused ‘wanting’ on laser-paired sucrose over a sucrose alternative in a two-choice test. Conversely, stimulation of CRF-containing neurons in BNST produced negative-valence or aversive effects and recruited distress-related circuitry, as stimulation was avoided and suppressed motivation for sucrose. Conclusions CRF-containing systems in NAc and CeA can promote reward consumption by increasing incentive motivation, without involving aversion. By contrast, stimulation of CRF-containing systems in BNST is aversive but suppresses sucrose reward pursuit and consumption, rather than increase as predicted by traditional hedonic self-medication hypotheses.