Striatal-level structures such as the nucleus accumbens (NAc) and central amygdala (CeA) are capable of generating intense incentive and aversive motivated behaviors (Baumgartner et al. 2020; Warlow et al. 2020). NAc may have two modes for motivation, as inhibition and excitation of NAc can both produce motivated behaviors. For example, NAc medial shell inhibition through AMPA receptor antagonist (DNQX) microinjections can produce both intense eating and defensive behaviors (Baumgartner et al., 2020). Chapter 2 of this dissertation investigates the inhibition hypothesis of accumbens motivation generation by testing whether local pairing of optogenetic excitation can disrupt ‘desire’ and ‘dread’ behaviors generated by DNQX microinjections.

Incentive and aversive motivation generated by NAc and other limbic structures are flexible and able to respond to external stressors. Chapter 3 therefore investigates a previously untested neuronal population in NAc that expresses corticotropin-releasing factor (CRF), a stress-related peptide heavily implicated in aversive motivation and distressing drug-withdrawal states in CeA and bed nucleus of stria terminalis (BNST). Like NAc, the CeA is also capable of producing intense positive and negative motivated behaviors and we investigate the flexibility of incentive or aversive motivation in CRF neurons using new Crh-Cre+ rats to optogenetically stimulate NAc, CeA, or BNST CRF-containing neurons. This work finds that excitation of CRF-expressing neurons is capable of biasing and amplifying motivation for sucrose rewards in both NAc shell and lateral CeA (Baumgartner et al. 2021). Conversely, it also demonstrates that optogenetic excitation of pallidal-like bed nucleus of stria terminalis (BNST) CRF-containing neurons produces only negative affect and aversive motivation, filling the traditional role that CRF has been hypothesized to play in aversive withdrawal and affect (Koob 2013).

Following the demonstrated positive role of NAc and CeA CRF-containing neurons for sucrose rewards, Chapter 4 of this dissertation examines whether this influence on incentive motivation also applies to drug rewards. CRF in CeA and BNST is posited to underlie aversive withdrawal states, causing negative distress that leads to addictive relapse through attempts at hedonic self-medication to relieve this state (Koob 2013). Chapter 4 therefore tests whether optogenetic excitation of CRF neurons in NAc, CeA, and BNST are capable of biasing and amplifying motivation for self-administered intravenous cocaine infusions. Understanding whether CRF-mediated incentive motivation also can drive drug motivation is therefore integral. We find that NAc and CeA CRF-expressing neurons are indeed capable of biasing motivation for cocaine infusions, while rats given the option between BNST CRF-containing neuron-paired cocaine and cocaine alone show no drug escalation or preferences between cocaine options.

Altogether this dissertation demonstrates the limbic generation of intense motivation in structures such as NAc and CeA, and how both incentive and aversive motivation can be modulated by stress and brain CRF systems. The neural mechanisms underlying these different motivational valences provide important insight into cases where motivation can become pathological, such as in addiction, schizophrenia, and other psychological disorders.