The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons

Chao

Ansoult

et al. 2023

Preprint

Self Cite

Brain circuits involved in metabolic control and reward-associated behaviors are potent drivers of feeding behavior and are both dramatically altered in obesity, a multifactorial disease resulting from genetic and environmental factors. In both mice and human, exposure to calorie-dense food has been associated with increased astrocyte reactivity and pro-inflammatory response in the brain. Although our understanding of how astrocytes regulate brain circuits has recently flourish, whether and how striatal astrocytes contribute in regulating food-related behaviors and whole-body metabolism is still unknown. In this study, we show that exposure to enriched food leads to profound changes in neuronal activity and synchrony. Chemogenetic manipulation of astrocytes activity in the dorsal striatum was sufficient to restore the cognitive defect in flexible behaviors induced by obesity, while manipulation of astrocyte in the nucleus accumbens led to acute change in whole-body substrate utilization and energy expenditure. Altogether, this work reveals a yet unappreciated role for striatal astrocyte as a direct operator of reward-driven behavior and metabolic control.

Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Diet Induced Obesity Leads To Increased Strength and Decreas...mentioning

confidence: 99%

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Dual role of striatal astrocytes in behavioral flexibility and metabolism in the context of obesity

Chao

Ansoult

et al. 2023

Preprint

Self Cite

“…Data in rodents also support a role of D2R in the development of some features of obesity (2, 39). Recent findings in mice highlight a particular sensitivity of D2SPNs to circulating lipids (75, 76), and point to a role of D2R and D2SPNs in the regulation of energy output (77, 78). Interestingly GO pathways and gene networks downregulated in NAc D2SPNs of mHP mice included signaling and synaptic functions, while those upregulated were related to DNA and transcription, possibly indicating long-term adaptive modification of these neurons.…”

Section: Discussionmentioning

confidence: 99%

Operant training for highly palatable food alters translating mRNA in nucleus accumbens D2 neurons and reveals a modulatory role ofNeurochondrin

Giralt

Taing

et al. 2023

Preprint

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BACKGROUND: Highly palatable food triggers behavioral alterations reminiscent of those induced by addictive drugs. These effects involve the reward system and dopamine neurons, which modulate neurons in the nucleus accumbens (NAc). The molecular mechanisms underlying the effects of highly palatable food on feeding behavior are poorly understood. METHODS: We studied the effects of 2-week operant conditioning of mice with standard or isocaloric highly palatable food. We investigated the behavioral effects and dendritic spine modifications in the NAc. We compared the translating mRNA in NAc neurons identified by the type of dopamine receptors they express, depending on the type of food and training. We tested the consequences of invalidation of an abundant downregulated gene,Ncdn(Neurochondrin). RESULTS: Operant conditioning for highly palatable food increases motivation for food even in well-fed mice. In control mice, free access to regular or highly palatable food results in increased weight as compared to regular food only. Highly palatable food increases spine density in the NAc. In animals trained for highly palatable food, translating mRNAs are modified in NAc dopamine D2-receptor-expressing neurons, mostly corresponding to striatal projection neurons, but not in those expressing D1-receptors. Knock-out ofNcdn, an abundant down-regulated gene, opposes the conditioning-induced changes in satiety-sensitive feeding behavior and apparent motivation for highly palatable food, suggesting down-regulation may be a compensatory mechanism. CONCLUSIONS: Our results emphasize the importance of mRNA alterations D2 striatal projection neurons in the NAc in the behavioral consequences of highly palatable food conditioning and suggest a modulatory contribution ofNcdndownregulation.

“…We next explored the functional outcome of DS astrocytes manipulation onto obesity-induced cognitive alteration. Reversal learning is a form of cognitive exibility highly dependent on to the integrity of the DS and that was shown to be impaired in human and rodent obesity (Foldi et al, 2021;Montalban et al, 2023). Neuroimaging studies in humans show that reversal learning requires the integrity of the ventral prefrontal cortex and the DS (Jocham et al, 2009).…”

Section: Activation Of Ds Astrocytes Rescues Neuronal Synchronization...mentioning

confidence: 99%

Dual role of striatal astrocytes in behavioral flexibility and metabolism in the context of obesity

Chao

Ansoult

et al. 2023

Preprint

Self Cite

Brain circuits involved in metabolic control and reward-associated behaviors are potent drivers of feeding behavior and are both dramatically altered in obesity, a multifactorial disease resulting from genetic and environmental factors. In both mice and humans, exposure to calorie-dense food has been associated with increased astrocytes reactivity and pro-inflammatory response in the brain. Although our understanding of how astrocytes regulate brain circuits has recently flourish, whether and how striatal astrocytes contribute in regulating food-related behaviors and whole-body metabolism is still unknown. In this study, we show that exposure to enriched food leads to profound changes in neuronal activity and synchrony. Chemogenetic manipulation of astrocytes activity in the dorsal striatum was sufficient to restore the defect in flexible behaviors induced by obesity, while manipulation of astrocytes in the nucleus accumbens led to acute change in whole-body substrate utilization and energy expenditure. Altogether, this work reveals a yet unappreciated role for striatal astrocyte as a direct operator of reward-driven behavior and metabolic control.