Mesocorticolimbic Generation of Desire and Dread along a Rostrocaudal Gradient in Medial Shell of Nucleus Accumbens.

Abstract

Behaviors related to desire versus dread are generated by localized inhibitions along a rostrocaudal anatomical gradient within medial shell of nucleus accumbens of the rat. Either GABA receptor-mediated inhibitions, via microinjections of the GABAA agonist muscimol, or corticolimbic glutamate disruption, via microinjections of the AMPA antagonist DNQX, generate intense eating at rostral sites and fearful behaviors at more caudal sites. Importantly, local endogenous dopamine is needed for eating and fear generation by glutamate blockade. Additionally, environmental ambience can retune the valence of behavior produced by glutamate disruption, promoting appetitive behavior in a familiar environment, and promoting fearful behavior in a stressful environment. Here, I investigated what signals might contribute to desire versus dread. In Chapter 2 I found that behaviors generated by GABAergic inhibition of accumbens resist environmental retuning, and do not need endogenous dopamine. These results suggest that subcortical GABAergic generation of motivation is more robust, autonomous and anatomically biased than glutamatergic generation in accumbens. In Chapter 3 I found that only endogenous local signaling at D1 dopamine receptors is needed for generation of excessive eating by glutamate disruptions, whereas fear generation requires both D1 and D2 dopamine signaling simultaneously. Furthermore, when motivation valence generated by glutamate disruptions was flipped by manipulating environmental ambience, the roles of local D1 versus D2 signaling also switched dynamically to match the motivation valence generated at the moment. The experiments in Chapter 4 examined whether medial prefrontal cortex can modulate intense motivations generated by accumbens shell glutamate disruptions. I found that activation of medial orbitofrontal cortex biased intense bivalent motivation in an appetitive direction by amplifying generation of eating behavior by middle to caudal accumbens disruptions, without altering fear. In contrast, activation of infralimbic prefrontal cortex powerfully and generally suppressed both appetitive eating and fearful behaviors generated by accumbens shell disruptions. As a whole, these experiments demonstrate that flips in motivational valence based on environmental cues may involve changes in dopamine signaling, or changes in top-down corticolimbic inputs. These findings carry important implications for the relationship between appetitive desire and aversive dread.