Nucleus Accumbens D1 Receptor–Expressing Spiny Projection Neurons Control Food Motivation and Obesity

Matikainen‐Ankney, Bridget A.; Legaria, Alex A.; Pan, Yiyan A; Vachez, Yvan; Murphy, Caitlin; Schaefer, Robert F.; McGrath, Quinlan J; Wang, Justin G; Bluitt, Maya N.; Ankney, Kevin C.; Norris, Aaron J.; Creed, Meaghan C.; Kravitz, Alexxai V.

doi:10.1016/j.biopsych.2022.10.003

Cited by 19 publications

(12 citation statements)

References 76 publications

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“…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 . Giving the controversial findings of D1-MSNs in feeding 20, 29, 37 , it is critical to examine neuron subtype effect of NAcSh as the discrepancy could be caused by manipulation of different neuronal subtypes of NAcSh in the different studies.…”

Section: Resultsmentioning

confidence: 99%

A molecularly defined NAcSh D1 subtype controls feeding and energy homeostasis

Liu

Zhao

Xie

et al. 2023

Preprint

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Understanding the mechanism of energy homeostasis is expected to lead to effective treatment to obesity and metabolic diseases1,2. However, energy homeostasis is a complicated process largely controlled by neuronal circuits in the hypothalamus and brainstem3-5, whereas reward and motivation of food intake are mainly controlled by the limbic regions6and cerebral cortex7,8. Although the limbic and hypothalamus connection like Nucleus Accumbens shell (NAcSh) to the lateral hypothalamus (LH) circuit has been reported to regulate feeding9,10, the neuron subtypes involved, and how do the humoral/neuronal signals coordinate to direct feeding behavior remain unknown. Here we show that the projection from dopamine receptor D1(Drd1)- andSerpinb2-expressing subtype to leptin receptor (LepR) expressing neurons in LH modulates food seeking and consumption. We demonstrate that theSerpinb2+neuronal activity is dynamically modulated during feeding. Conversely, chemo/optogenetics-mediated modulation ofSerpinb2+neurons bidirectionally regulate food seeking and consumption. Importantly, circuitry stimulation revealed the NAcShSerpinb2→LHLepRprojection controls refeeding and overcomes leptin-mediated feeding suppression. Ablation of NAcShSerpinb2neurons could decrease body weight. Together, our study reveals a molecularly distinct accumbal-to-lateral hypothalamic neural circuit that controls internal state-dependent food consumption, which provides a promising therapeutic target for anorexia and obesity.

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Section: Resultsmentioning

confidence: 99%

A molecularly defined NAcSh D1 subtype controls feeding and energy homeostasis

Liu

Zhao

Xie

et al. 2023

Preprint

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“…DIO mice have been tested in Pavlovian and operant training paradigms, and have displayed deficits in motivation and learning, particularly in the progressive ratio task (Cordner & Tamashiro, 2015; Huwart et al, 2022; Kanoski et al, 2007; Sharma et al, 2013). In one notable exception, mice were trained to increase the level of force to obtain food rewards rather than number of operant responses (Matikainen-Ankney et al, 2023). In this case, DIO mice exerted more effort to obtain food rewards, suggesting that their lack of performance in the task is not due to low motivation, but rather due to a devaluation of delayed rewards.…”

Section: Discussionmentioning

confidence: 99%

Conditioned overconsumption is dependent on reinforcer type in lean, but not obese, mice

Lewis-Sanders,

Bullich,

Olvera

et al. 2024

Preprint

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Associative learning can drive many different types of behaviors, including food consumption. Previous studies have shown that cues paired with food delivery while mice are hungry will lead increased consumption in the presence of those cues at later times. We previously showed that overconsumption can be driven in male mice by contextual cues, using chow pellets. Here we extended our findings by examining other parameters that may influence the outcome of context-conditioned overconsumption training. We found that the task worked equally well in males and females, and that palatable substances such as high-fat diet and Ensure chocolate milkshake supported learning and induced overconsumption. Surprisingly, mice did not overconsume when sucrose was used as the reinforcer during training, suggesting that nutritional content is a critical factor. Interestingly, we also observed that diet-induced obese mice did not learn the task. Overall, we find that context-conditioned overconsumption can be studied in lean males and female mice, and with multiple reinforcer types.

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“…SST + GABAergic neurons exist in the hypothalamus and regulate food intake 32 . D1 medium spiny neurons are a type of GABAergic neuron in the human striatum that expresses D1-type dopamine receptors; these neurons have been implicated in food motivation and the development of diet-induced obesity in mice 33 .…”

Section: Regulatory Processes Underlying Clustersmentioning

confidence: 99%

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Suzuki,

Hatzikotoulas,

Southam

et al. 2024

Nature

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Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10−8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

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Nucleus Accumbens D1 Receptor–Expressing Spiny Projection Neurons Control Food Motivation and Obesity

Cited by 19 publications

References 76 publications

A molecularly defined NAcSh D1 subtype controls feeding and energy homeostasis

A molecularly defined NAcSh D1 subtype controls feeding and energy homeostasis

Conditioned overconsumption is dependent on reinforcer type in lean, but not obese, mice

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

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