Ventral Pallidal GABAergic Neurons Drive Consumption in Male, But Not Female, Rats

Abstract

Food intake is controlled by multiple converging signals: hormonal signals that provide information about energy homeostasis and hedonic and motivational aspects of food and food cues that can drive nonhomeostatic or "hedonic" feeding. The ventral pallidum (VP) is a brain region implicated in the hedonic and motivational impact of food and food cues, as well as consumption of rewards. Disinhibition of VP neurons has been shown to generate intense hyperphagia, or overconsumption. While VP GABA neurons have been implicated in cue-elicited reward-seeking and motivation, the role of these neurons in the hyperphagia resulting from VP activation remains unclear. Here, we used designer receptors exclusively activated by designer drugs to activate VP GABA neurons in nonrestricted male and female rats during chow and sucrose consumption. We found that activation of VP GABA neurons increases consumption of chow and sucrose in male rats, but not female rats. Together, these findings suggest that activation of VP GABA neurons can stimulate consumption of routine or highly palatable rewards selectively in male rats.

Keywords: chemogenetic; consumption; sex differences; sucrose; ventral pallidum.

Figure 1.

Characterization of DREADD localization and functional impact. A Representative section from the striatum (top), ventral pallidum (middle), and septum (bottom), used for analysis in QUINT workflow. B, Output results of QUINT workflow (n = 8), showing all brain regions where mCherry (DREADD virus reporter) was detected in rats that received 600 nl (n = 4, circles) and 800 nl (n = 4, triangles) injections. LME showed a significant effect of brain region (F_(3,28) = 113.34, p < 0.001), on viral particles, with follow-up comparisons indicating that significantly more expression was found in VP compared with other brain regions where expression was seen. C, Percent of DREADD-positive cells expressing c-Fos after 0, 0.05, or 0.5 mg/kg J60 in male (circles) and female (triangles) rats expressing Gq or Gi DREADD. *p < 0.05 (left). D, Representative VP images from a Gq male (left) and a Gi male (right) injected with 0.5 mg/kg J60. E, Representative traces from neurons expressing mCherry (left) or Gi DREADD (right) during the baseline period and 0–5 and 5–10 min after J60 application. F, Normalized firing rate (% of baseline) of neurons expressing mCherry (black; 9 cells/3 rats) and Gi DREADD (red; 15 cells/3 rats) at baseline and following J60 wash-on (0–10 min). Lines and shading indicate mean ± SEM.

Figure 2.

Effects of chemogenetic activation of VP GABA neurons on sucrose consumption. A, A mixture of GAD1-cre and DIO-hM3Dq-mCherry or DIO-mCherry was injected bilaterally into the VP. B, Colormaps show hM3Dq viral placement (brightest point of expression) in a horizontal cross section of the VP and behavioral changes from baseline following a high dose (0.5 mg/kg) of J60, for all Gq (hM3Dq) rats (left), female Gq rats (middle), and male Gq rats (right). C, Sucrose consumption following injections of saline (light green), low-dose J60 (medium green), and high-dose J60 (dark green) for all Gq rats (left), Gq females (middle), and Gq males (right). D, Sucrose consumption following injections of saline (light green), low-dose J60 (medium green), and high-dose J60 (dark green) for all mCherry control rats (left), mCherry females (middle), and mCherry males (right). Bar plots and error bars indicate mean ± SEM. Dots and lines represent individual rats. Asterisks indicate p < 0.05 for Sidak-corrected pairwise comparisons.

Figure 3.

Effects of chemogenetic activation of VP GABA neurons on sucrose preference. A, Sucrose preference following injections of saline (light green), low-dose J60 (medium green), and high-dose J60 (dark green) for all Gq rats (left), Gq females (middle), and Gq males (right). B, Sucrose preference following injections of saline (light green), low-dose J60 (medium green), and high-dose J60 (dark green) for all mCherry control rats (left), mCherry females (middle), and mCherry males (right). Bar plots and error bars indicate mean ± SEM. Dots and lines represent individual rats. Asterisks indicate p < 0.05 for Sidak-corrected pairwise comparisons.

Figure 4.

Effects of chemogenetic activation of VP GABA neurons on chow consumption. A, Chow consumption following injections of saline (light green), low-dose J60 (medium green), and high-dose J60 (dark green) for all Gq rats (left), Gq females (middle), and Gq males (right). B, Chow consumption following injections of saline (light green), low-dose J60 (medium green), and high-dose J60 (dark green) for all mCherry control rats (left), mCherry females (middle), and mCherry males (right). Bar plots and error bars indicate mean ± SEM. Dots and lines represent individual rats. Asterisks indicate p < 0.05 for Sidak-corrected pairwise comparisons.