Chronic chemogenetic manipulation of ventral pallidum targeted neurons in male rats fed an obesogenic diet

Abstract

Current treatments for obesity do not reliably reduce body weight over time. New interventional strategies, including chemogenetics, carry promise based on preclinical animal studies. Here, we focused on the ventral pallidum (VP) due to its clearly established role in eating behavior. Chronic inhibitory or excitatory chemogenetic activation was used to modulate the activity of VP-targeted neurons in rats on an obesogenic diet. Based on studies using acute VP manipulations, we hypothesized that VP inhibition would decrease weight gain, while VP stimulation would increase weight. Instead, both manipulations caused weight gain over time, and in a manner not clearly linked to consumption levels. We theorize that the complex reciprocal feedback between ventral striatal structures and metabolic centers likely underpin our unexpected findings. Regardless, this study suggests that the result of strategies to prevent obesity with chronic neuromodulation could be difficult to predict from prior preclinical studies that have used acute interventions.

Keywords: DREADDs; Food; Motivation; Reward.

Figure 1.. Chronic activation of Gi and Gq in ventral pallidum targeted neurons increases weight gain.

Panel A illustrates the experimental design and timeline. B. The expression of the fluorescent marker mCherry/eYFP for each animal is overlaid in three representative sections along the A-P axis (Bregma: 0.36, 0.00, −0.36) with a separate column and color for each group (Gi - Blue, Gq - Red, control - Green). C. Average weight (grams) of the three cohorts (Gi, Gq, and control [crl]) at postnatal day (PND) 90 ± 1 standard deviation. For comparison the average weight of rats on normal chow at PND 90 from the vendor (VC), Charles River, is shown in black. D. The effect of chronic CNO delivery on weight, food and water consumption is displayed with line color matching that of panel. E. Days are graphed as two-day averages. Error bars = ±1 standard deviation.