Enhanced food motivation in obese mice is controlled by D1R expressing spiny projection neurons in the nucleus accumbens

Abstract

Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. In addition to homeostatic feeding mechanisms, there is growing recognition of the involvement of food reward and motivation in the development of obesity. However, it remains unclear how brain circuits that control food reward and motivation are altered in obese animals. Here, we tested the hypothesis that signaling through pro-motivational circuits in the core of the nucleus accumbens (NAc) is enhanced in the obese state, leading to invigoration of food seeking. Using a novel behavioral assay that quantifies physical work during food seeking, we confirmed that obese mice work harder than lean mice to obtain food, consistent with an increase in the relative reinforcing value of food in the obese state. To explain this behavioral finding, we recorded neural activity in the NAc core with both in vivo electrophysiology and cell-type specific calcium fiber photometry. Here we observed greater activation of D1-receptor expressing NAc spiny projection neurons (NAc D1SPNs) during food seeking in obese mice relative to lean mice. With ex vivo slice physiology we identified both pre- and post-synaptic mechanisms that contribute to this enhancement in NAc D1SPN activity in obese mice. Finally, blocking synaptic transmission from D1SPNs decreased physical work during food seeking and attenuated high-fat diet-induced weight gain. These experiments demonstrate that obesity is associated with a selective increase in the activity of D1SPNs during food seeking, which enhances the vigor of food seeking. This work also establishes the necessity of D1SPNs in the development of diet-induced obesity, identifying a novel potential therapeutic target.

A molecularly defined NAcSh D1 subtype controls feeding and energy homeostasis

“…In recent years, several studies have analyzed the role of the mediodorsal NAcSh in feeding 20, 23, 24 and revealed that activation of the dopamine receptor 1 expressing medium spiny neurons (D1-MSNs) 25, 26 projecting to the lateral hypothalamus (LH) 21, 24 or ventral tegmental area (VTA) 27 stops ongoing food consumption. However, other studies showed that D1-MSNs activity was enhanced during appetitive phase 28 as well as consumption 29 . Although temporally distinct phases of feeding behavior, such as food seeking, food evaluation and consumption, could potentially account for such discrepancy, the heterogeneity of NAc neurons 30 could underlie the discrepancies considering that different studies might have manipulated different neuron subtypes with opposing functions.…”

“…The NAc is a critical component of the basal ganglion circuitry, which receives and integrates information from cortical and limbic regions for actions. Previous studies have linked feeding behavior to the NAcSh 20, 21, 24, 27, 28, 36 . D1-MSNs, but not D2-MSNs, provide the dominant source of accumbal inhibition to the LH and regulate complex feeding behaviors through LH GABA neurons 20, 28 .…”

“…This further indicates that finer granularity and cell type-specific approaches are needed to dissect the function of different neuron subtypes in NAc. For example, although the D2 + neuronal activity as a whole is not altered during food consumption 19,22 , the D2 receptors are indeed downregulated in obese rodent as well as human 55,56 , whether certain D2-MSN subtypes are involved in regulating food intake remains to be determined.…”

“…Although temporally distinct phases of feeding behavior, such as food seeking, food evaluation and consumption, could potentially account for such discrepancy, the neuronal heterogeneity of NAc 24 could underlie the seemingly conflict feeding behavior as the different studies might have manipulated different neuron subtypes with opposing functions. With the application of single cell RNA-seq and spatial transcriptome techniques to decipher the neuron heterogeneity of different brain regions [25][26][27][28][29] , we could focus on different neuron subtypes located in the NAcSh implicated in feeding behavior 9,10,19,22,30,31 to identify the neuron subtype(s) responsible for regulating feeding behavior.…”

“…1a). Since D1-MSNs, but not D2-MSNs, provide the dominant source of accumbal inhibition to LH with rapid control over feeding via LH GABA neurons 19,22 , we focused our effort on the Tac2 and Serpinb2 D1-MSN subtypes. tSNE plots of scRNA-seq result indicated that the Tac2 + neurons are mainly enriched in the D1-MSN subclusters 6 and 8, while Serpinb2 + neurons are enriched in D1-MSN subcluster 2 24 (Fig.…”