At its simplest description the neural control of feeding can be explained as the reciprocal inhibition and opposing effects on appetite of two genetically defined groups of neurons located in the hypothalamic arcuate nucleus. The first group of neurons expresses POMC and its activation suppress appetite, whereas the other cell-type expresses both AGRP/NPY and its activation promote feeding (39). Recently Aponte et. al. 2011 used optogenetic tools and transgenic Cre-mice to definitely confirm that the selective activation of AGRP/NPY neurons and its downstream outputs are sufficient to evoke voracious feeding and without previous training (42). They found that food intake increased as a linear function of the number of AGRP neurons activated by blue light, and the activation of at least 300 AGRP neurons were necessary to increase food intake. Interestingly, continuous photostimulation was required to maintain food intake, since feeding rapidly stopped after photostimulation offset, which indicates that AGRP neurons were not only a trigger of feeding, but their continuous activity was required to sustain consumption. Selective stimulation of POMC neurons gave the opposite behavioral outcome. Photostimulation of POMC neurons inhibited food intake and induced body weight-loss after constant 24 h stimulation. This impressive results convincingly demonstrate that a complex behavior such as feeding can be evoked (or inhibited) by the selective activity of a genetically defined group of neurons and its downstream outputs. Moreover, they also pave the way to potential new therapeutic strategies for obesity (43).
Beyond the ARC feeding network composed by AGRP+ and POMC+ neurons, we note that several, if not all, of the genetically defined neuronal populations described in this manuscript are also recruited during feeding, however, so far no optogenetic studies had directly evaluated their role in feeding behavior. Nevertheless, these neuronal circuits, at least in part, may modulate some attributes of feeding behavior (44). For example, direct infusions of leptin in VTA inhibits the firing rate of DA neurons and decreases food intake, suggesting that VTA DA neurons integrate signals from both metabolic hormones and the reward system (45). Despite that pharmacological manipulations of the dopaminergic activity in the NAc does not alter feeding, lesions of VTA DA neurons dramatically impaired free-feeding (46). In addition, both D1+/D2+ MSNs in NAc shells contain a high concentration of MCHR1 receptor and infusion of MCH promotes feeding. Moreover, an MCH antagonist inhibits feeding (47). More importantly direct infusion of MCH into the NAc Shell increases feeding by globally decreasing the firing rate of both types of MSNs (47). Previous evidences have also found that global inactivation of NAc shell promotes feeding. E.g., recordings in freely moving rats have found that a subpopulation of putative MSNs are inhibited during ingestive behavior (probably D2+MSNs) (48, 49), although we have observed that a similar proportion of putative MSNs are selectively excited during free-feeding (probably D1+MSNs) (50), suggesting that during physiological conditions, feeding behavior induces a balance of excitation and inhibition of putative MSNs. Nevertheless, temporary global inactivation of NAc Shell (e.g., by infusing Muscimol) promotes abnormal over-feeding in sated rats, similar to that induced by exogenous MCH infusions (51). The opposite effect was evoked after electrical activation of NAc shell since it refrained feeding behavior (52). All these evidence have supported the “inhibitory gating hypothesis” that propose that a general pause in the NAc activity is necessary to initiate and maintain feeding behavior (52). We suggest that pharmacological inactivation of the NAc shell produces a non-physiological brain state that promotes over-feeding in sated rats. This mechanism might be relevant to understand the neurobiological basis of obesity, since obesity may induce a hypoactive state or blunted response on the striatum (53). One current theory dictates that obesity arises from alteration of the activity of reward brain areas by down-regulating expression of D2 receptors in striatum (54), which in turn can trigger compulsive eating behavior (55). However, it is currently unknown whether the spiking activity of D1+ or D2+ expressing MSNs in NAc plays a causal or correlative role on feeding behavior (49). We can only speculate that under a diet-induced obesity context, selective silencing of D2+ MSNs by optogenetic tools will result in compulsive overeating and, in the long term, body weight gain, mimicking the behavioural effects induced by downregulating the expression of D2 receptors in striatum (55). Finally, it has been shown that NAc shell can control food intake by direct coordination with LH neurons (51). Both hcrt+ and MCH neurons project to NAc and the interaction between the MSNs and either hcrt+ or MCH+ neurons may be relevant to feeding behavior or to process cues-associated with food intake. For example, muscimol inactivation of NAc shell induces abnormal over-feeding, but also activates hcrt+ neurons in LH (51), however optogenetic activation of hcrt+ neurons by itself was not sufficient to modulate feeding behavior (16). Though, it remains possible that hcrt+ neurons can still be important to induce a stress-like food craving state relevant to compulsive eating.