Chronic Chemogenetic Manipulation of Ventral Pallidum Targeted Neurons in Rats Fed an Obesogenic Diet

Abstract

Current treatments for obesity are unable to reliably reduce weight over time and alternative treatments need to address this challenge. New interventions that target the nervous system could manipulate brain networks underlying reward, metabolic rate and behavior. Here, the ventral pallidum was evaluated as a target of manipulation due to its established role in the networks underlying motivation, pleasure and behavioral output. Chronic inhibitory or excitatory chemogenetic activation was used to modulate the activity of ventral pallidum (VP) targeted neurons in rats on an obesogenic diet. We hypothesized that inhibition of VP activity would decrease the salience of the rats' high-sugar, high-fat diet and lead to reduced food consumption and weight gain over time. Paradoxically, measurements of weight, water and food consumption revealed significantly increased weight gain in both groups receiving VP targeted manipulation that was not readily explained by food or water consumption. We theorize that the complex reciprocal feedback between ventral striatal structures (e.g., VP) and metabolic centers of the hypothalamus and brainstem, demonstrated by prior research, likely underpin our findings. This study suggests that the treatment of appetitive disorders (e.g., obesity) with chronic neuromodulation-based interventions could be burdened by the delayed onset of outcomes that are difficult to predict from related prior studies that used acute interventions.