How does the brain implement decision-making to eat? Implication of the serotonin 4 receptors
Feeding behavior is a typical motivated and survival-related behavior but individuals with anorexia nervosa self-impose food restriction often to the point of death. In drug addiction, the prospect of hedonic experience prevails over the risk of death and incapacity, suggesting commonalities between anorexia and dependence. We found that anorexia may have a rewarding effect via neural substrates of drug addiction1. Indeed, stimulation of the serotonin 4 receptors (5-HT4Rs) in the nucleus accumbens (NAc), a central structure of the brain’s reward system, favors both anorexia and motor hyperactivity by activating the anorectic peptide called cocaine- and amphetamine-regulated transcript (CART) through a cAMP / protein kinase A signaling pathway in mice. Since anorexia and hyperactivity are two hallmarks of anorexia nervosa, these results suggest a critical implication of the 5-HT4Rs. This could be conserved in humans because (i) the levels of 5-HT4Rs vary in the NAc in both rats and humans with obesity and, (ii) male mice with NAc-5-HT4R overexpression self-restrict. We then tested whether the 5-HT4Rs were implicated in an essential feature of anorexia, namely the persistence of anorexia in the face of negative consequences, a characteristic of dependence.
We first found that the 5-HT4Rs in the medial prefrontal cortex (mPFC) were sufficient and necessary to mediate reduced food intake induced by forced immobilization, also called the restraint stress. The period of reduced food intake (hypophagia) is prolonged (anorexia) when the 5-HT4Rs are overexpressed in the mPFC; this involves modified control of goal-directed behavior (decision), curbing food intake regardless of energy demand. This led to the hypothesis that implementation of the voluntary control processes (underlying decision, motivation) over time during development are modified to prevail over cerebral autonomic control of hunger (i.e. the physiological need for food that contributes to maintain energy balance), compromising survival.
We therefore thought that long-term structural changes could mediate the persistence of anorexia. This is possible because cAMP signaling, downstream of the Gs-coupled 5-HT4Rs in the NAc, modulates spine growth and stabilizes synapses in the brain. To address this possibility, we tested whether the 5-HT4Rs, in the NAc, control cocaine-induced adaptive changes in specific transcription factors in the NAc [i.e. increases in the phosphorylation of CREB (cAMP-response element binding protein), FosB/∆FosB]. Indeed, the cAMP resultant phosphorylation of CREB dampens the rewarding effects of cocaine but the sensitivity to subsequent drug exposures decreases (tolerance) with increased activity of reward pathways (FosB/∆FosB), mediating dependence. An increase number of dendritic spines (may be synapses) due to an up-regulation of ∆FosB and a down-regulation of the histone methyltransferase G9a were proposed to mediate the persistence of cocaine addiction. Here, we found that the absence of 5-HT4Rs mediates an elevated motivation for food but a reduced motivation for cocaine in mice. We show that the ability of cocaine to increase the levels of pCREB is absent in the NAc of the 5-HT4R KO mice. Additionally, the increased levels of FosB and ∆FosB mRNA induced by cocaine were reduced in the NAc of the 5-HT4R KO mice. The levels of G9a mRNA, in the NAc, were elevated, in both saline- and cocaine-treated 5-HT4R KO mice. These mutant mice further display a lower number of dendritic spines in the NAc compared with wild-type animals. In this context, the analogy between overeating and addiction remains intriguing. It appears conceivable that long-term adaptive morphological changes in neurons mediate the persistence of eating disorders, and could compromise adaptive and dynamic aspects of decision-making to eat in the face of environmental changes.
Development & Degeneration of Spinal Motor Neurons
Neuroscience Paris Seine
CNRS UMR 8246/INSERM UMR-S 1130/UPMC UM119
7 Quai St Bernard
Montpellier, France
Invité par Alfonso REPRESA
Salle de conférence INMED ; lundi 5 décembre 2016