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Activating Corticotropin-Releasing Factor Systems in the 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 the 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 overconsumption 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 the 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 the CeA and NAc amplified and focused incentive motivation and recruited activation of mesocorticolimbic reward circuitry. CRF systems in both the 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 the 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 the NAc and CeA can promote reward consumption by increasing incentive motivation without involving aversion. In contrast, stimulation of CRF-containing systems in the BNST is aversive but suppresses sucrose reward pursuit and consumption rather than increase, as predicted by traditional hedonic self-medication hypotheses.

      Keywords

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      Linked Article

      • Love it or Leave it: Differential Modulation of Incentive Motivation by Corticotropin-Releasing Factor Neurons
        Biological PsychiatryVol. 89Issue 12
        • Preview
          Corticotropin-releasing factor (CRF) is a neuropeptide critical to behavioral and physiological responses to stressors. CRF was originally discovered as an initiator of the hypothalamic-pituitary-adrenal axis, where it is released from neurons of the paraventricular nucleus of the hypothalamus into the pituitary gland. CRF was subsequently detected in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) and was found to mediate negative valence associated with stress, anxiety, and drug withdrawal.
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