When the Brain Coordinates Life-Risk Behavior: A Rewarding Anorexia

All behavior appears to be the result of context-dependent brain functions; neuronal networks implement gradually over development during their interrelationships with environmental factors. This cerebral network likely becomes mature contextdependently and may gradually favor adapted (and adaptive) behavior as adapted decision-making (i.e., goal-directed behavior). Goal-directed behavior expresses motivation. For instance, when individuals feel hungry, they are motivated to obtain food under physiological circumstances. Feeling hungry then translates into the demand for energy. Hunger impels the organism to display goal-directed behavior to seek and consume foods and thus survive. However, individuals do not make the decision to feel hungry, but can decide to satisfy or not satisfy hunger. For some individuals, eating behavior can be chronically disordered and can include persistent food restriction and/or excessive intake despite negative consequences, suggesting disturbances of motivation, and of goal-directed behavior. Food is a basic primary reward, requiring motivation to obtain it (“wanting”) [1]. Some investigators assimilate excessive consumption of foods, regardless of whether it is associated with obesity (Corwin RL, et al.) [2], to addiction [3]. However, whether binge eating represents a kind of addiction remains unclear [2]. Here, we describe common molecular mechanisms between anorexia and addiction.

The rewarding effect of anorexia has been described in humans at the onset of anorexia nervosa symptoms [4]. Is it the result of excess synapses (fixed brain) that maintain food restriction until the point of death? As the prospect of receipt of a positive reward is capable of inducing risky, and potentially lethal behavior, impairments in the neural underpinnings of persistent food restriction until lethal point could be included in those of dependence.

Some investigators examine the activity of neural centers involved in the recognition of rewards and the development of habits [5]. A report described goal-directed decision-making as a complicated process and argued that reward-based decisions depend on the habit and goal-oriented systems [6]. The habit system “stores” stimulus-response associations based on past rewards and the goal-oriented system selects one action by anticipating the positive and negative outcomes [6]. Indeed, “Addiction is a form of learning and relapse is a persistent memory of the drug experience” [7]. As neural bases of learning and memory appears the result of synapse function, as mainly demonstrated by studies of Eric Kandel; Does neural communication, as the serotonin (5-hydroxytryptamine, 5-HT) volume transmission, serve to avoid habits for conferring the most instant flexibility to better adapt to environmental changes [8]?

The existence of the synapse was critically challenged until 1954; and, in 1975, Descarries L, et al. [9], described that 5-HT binds receptors (5-HTRs), more often located at 100 μm than at 20 nm (synaptic transmission), introducing the volume transmission (Descarries L, et al.) [9], from the site of 5-HT release. The preponderant 5-HT volume transmission extends the ubiquitous distribution of the serotonergic system, supporting its multiple functions; all physiologically interrelated, from habituation, memory, moving etc., to protecting survival, likely in order to critically contribute to adaptive and adapted eating responses to stress. The phylogenetically old serotonergic system then appears as a continued red line underlying crucial functions, which appear sophisticated to the point of a 5-HT-independent action of some 5-HTRs to evoke constitutive activity, such as the 5-Ht₄ receptors (5-Ht₄Rs), in eating behavior [10].

In mammals, the serotonergic neuronal cell bodies assemble in the raphe nuclei (reviewed in [11]). Among nine nuclei, the dorsal and median raphe nuclei (DR, MR) send axons to the whole forebrain [11]. In particular, the serotonergic axons in the cerebral cortex mainly arise from the DR (Figure 1a). 5-HT binds 18 G-protein coupled receptors (5-HTRs) and commonly mediates reduction in food intake [8].

Hoebel and Leibowitz’s groups in 1976 and 1986 reported, in series of studies, that 5-HT volume transmission commonly serves to reduce food intake, i.e. hypophagia, and to enhance satiety, in the hypothalamus. Following up these findings, decades of reports have described hypophagia following stimulation of 5-HT_1B and 5-HT_1C receptors (5-HT_1BR, 5-HT_1CR), whereas 5-HT_1AR and 5-HT2BR can exceptionally serve to enhance feeding [12]. In 2004, 5-HT volume transmission has also been reported to favor less motivation for food in food-deprived mice, mediating anorexialike behavior through the activation of addictive signaling (cAMP: cyclic adenosine monophosphate / PKA: protein kinase A / CART: cocaine- and amphetamine-regulated transcript), in the NAc [13,14]. In 2017, causal relationships between the activity of the serotonergic system and hypophagia in response to external stress were identified in a network governing goal-directed behavior [15]. This network consists of the ascending serotonergic inputs from the DR to the mPFC and is controlled by 5-Ht₄Rs [15].

In sum (reviewed in Compan V. [8]), under basal conditions, specific 5-HTRs located in an automatic executive system (the hypothalamus) serve to stabilize usual food intake, whereas in response to external stressors, other 5-HTRs; 5-Ht₄Rs located in a more adaptive-decisive system, including the mPFC and the NAc, favor rewarding effects of food restriction [14-19]. Such dual organization of 5-HTRs could promote decisional processing and dampen autonomic input, resulting in dysfunctional eating irrespective to requirements for energy. When food intake varies temporarily to the baseline, survival is not compromised, and restrictive food intake may well be adapted (and adaptive with beneficial effects on longevity), but when eating response to stress persists, as seen in anorexia nervosa, survival is compromised [20]. The predominance of cortical control could reflect adaptive processes to prevent “negative emotions” as neural commonalities exist between anorexia and antidepressant effect (Jean A, et al.) [15], (Figure 1); while, hypothalamic events could represent an executive system, which became autonomous as learned during long conserved evolutionary processes. It results the hypothesis formulated above: The low number of 5-HT cortical synapses (30%) could serve to prevent habits (do not have to be memorized) for conferring the most instant flexibility to better adapt to environmental changes [8].

The cerebral distribution of 5-Ht₄Rs is conserved from rodents to humans, with one of the highest levels in the NAc [21,22]. Four 5-Ht₄Rs splice variants were described in mice (10 in humans) called 5-Ht_4(a)R, 5-Ht_4(b)R, 5-Ht_4(e)R, 5-Ht_4(f)R [23]. Stimulation of 5-Ht₄Rs reduces deficits of associative learning in olfactory discrimination task (Bockaert J, et al. [24]), and, 5-Ht₄Rs favor longterm (but not short-term) memory [25]. In humans, stimulation of 5-Ht₄Rs also favors memory [26]. The 5-Ht₄Rs may therefore have conserved functions such as feeding from mice to humans. Indeed, stimulation of 5-Ht₄Rs reduces food intake in rodents [14-16,19]. And, the concentration of 5-Ht₄Rs is low when patients with Alzheimer’s disease overeat, but not in individuals with Alzheimer who did not display hyperphagia [27]. Importantly, 5-Ht₄Rs (and apparently not the other 5-HTRs) in the NAc serve to a rewarding effect of restrictive food intake, as stimulation of 5-Ht₄Rs mediates anorexia-like behavior through activation of an addictive signaling pathway [cAMP/PKA/CART] [14,19], (Figure 1). Indeed, in neurons of the NAc, activation of a cAMP signaling is a means of transforming an immediate reduction of drugs’ rewarding effect into a durable dependence [28]. Cocaine triggers counteracted adaptive responses as an increased activity of cAMP/PKA signaling in the NAc [28]. The resultant phosphorylation of the cAMP-responsive element binding (pCREB) dampens rewarding effects [29]. The sensitivity to subsequent drug exposures then decreases (tolerance) with increased activity of reward pathways (dependence) to the point that drugs removal triggers declines in motivation, mimicking depression, leading to maladaptive decision [28]. Considering the involvement of CART in motivational properties of cocaine (Rogge G, et al.) [30], these findings evidence commonalities between addiction and anorexia, consistent with the rewarding effect of anorexia seen at the onset of symptoms. Food restriction is initially highly rewarding because the individual feels to cope with difficultto- manage stressors during adolescence and adulthood [31]. Indeed, the brain can implement food restriction until death, as the result of maladaptive decision-making. As deep brain stimulation in the NAc or the anterior cingulate cortex (that is homologous to the rodent mPFC) in patients with anorexia nervosa led to an overall improvement, our studies conducted in animal models may have critical clinical significance [32]. Accordingly, mPFC-5-Ht₄Rs serve to prevent persistent food restriction by controlling the ascending 5-HT inputs from the DR to the mPFC under stressful conditions [15], (Figure 1). We predict that deregulation of 5-Ht₄Rs could play a vital role in pathological appetitive decision as NAc-5-Ht₄R levels are abnormal in overweight humans, which could be related to the capacity of 5-Ht₄Rs to reshapes excitatory synaptic connections (Evgeni Ponimaskin, submitted), consistent with less dendritic spines in the NAc in 5-Ht₄R knockout (KO) mice [8].

The neuronal network underlying eating behaviors is part of a larger network implicating reward and decision-making systems that react to environmental cues. Accordingly, environmental changes (i.e., stressors) associated with biological predisposition could alter motivation and adaptive decision-making, including persistent food restriction. Adaptive responses to stress depend on the serotonergic system – and, here, adaptive feeding response to stress depends on 5-Ht₄Rs - eating disorders could emerge when serotonergic neurons reach the limit of their adaptive capacities. We suggest that a predominance of a cortical control reflects an adaptive process to prevent depressive-like behavior when facing an acute stress at the onset of anorexia nervosa (Figure 1). Numerous studies have to be conducted to test whether in the face of chronic stress, limits of this adaptive process could “submerge” cortical control and “release the influence of the subcortical areas” such as the NAc (autonomous control without adaptive decisional control), in which uncontrolled oscillating changes in common molecule levels (cAMP, CREB: all controlled by G-protein coupled receptors, here by 5-Ht₄Rs) could lead to an anarchic consumption of foods (from anorexia to bulimia and/or binge eating).

The Agence Nationale de la Recherche (ANR-09-MNPS-024-01: SERFEED), ADOR Foundation (Anorexia, Dependence, Obesity, Receptors University Foundation, Nîmes University) and NIMES University supported this study. We are grateful to S. MENNECHET and A. PULLIDO for mouse breeding.

Author declare no conflict of interest.

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