Friday, July 26, 2024
7/26/2024
Project Summary/Abstract Impulsivity is implicated in many neuropsychiatric disorders1 and food-directed impulsivity is associated with both obesity and binge-eating disorder2–4. Impulsive behaviors can be roughly divided into two distinct subtypes: behaviors resulting from a failure to suppress an inappropriate action (impulsive action) and behaviors wherein a choice between two or more responses is made without proper consideration of the consequences (impulsive choice). While the neural processes regulating impulsive responding are poorly understood, evidence exists that impulsive actions and impulsive choices may be modulated by both overlapping and distinct neural substrates5. The hippocampus (HPC), a brain region crucial for mnemonic function, has recently been identified as a critical region mediating the higher-order control of appetite and food intake6,7 . Our recent findings have further shown that the ventral subregion of the HPC (vHPC) plays a critical role in mediating impulsivity directed towards palatable food8,9. However, the neural processes and circuitry through which the vHPC modulates impulsive responding for palatable foods remain unknown. In addition to the vHPC, The nucleus accumbens (ACB) is also known to regulate impulsivity10–13, and ACB-projecting hippocampal neurons have been shown to enhance food palatability14. Deep brain stimulation (DBS) of the ACB shell subregion (ACBsh) increases impulsive responding in rats15, and a pilot study of responsive DBS in the ACB for patients with BED improved lose-of-control eating frequency and was associated with weight-loss16. Previous research on HPC-to-ACB circuitry has focused its role in neuropsychiatric disorders17 and on non-food related reward processing, such as drugs of abuse18,19. Despite both the HPC and ACB being implicated in food-motivated behavior and impulsivity, it is unknown whether HPC-to-ACB communication modulates behavioral inhibition for food-motivated responding. We hypothesize that the vHPC regulates impulsivity for palatable foods via downstream connections to ACBsh. Preliminary data presented herein reveal increased calcium-dependent activity in both the vHPC and ACBsh in rats immediately prior to a non-impulsive relative to an impulsive lever press. Aim 1 experiments build off these findings by using pathway-specific in vivo fiber photometry to record calcium-dependent activity in the ACBsh-projecting vHPC neurons during impulsive responding. Our preliminary findings further show that chemogenetic vHPC-to-ACBsh inhibition increases impulsive action for palatable foods in males. Aim 2 will build on these findings by exploring the effects of pathway-specific inhibition on impulsive action in females, as well as impulsive choice in both males and females. Finally, Aim 3 uses multi-synaptic neural pathway tracing and in situ hybridization to identify the neurochemical phenotype and downstream targets of the vHPC-to-ACBsh pathway. Overall, improved understanding of the neurobiology underlying food-directed impulsivity can shed greater light on the role of food motivation and behavioral inhibition in obesity.
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