Decades ago, pioneering studies in cats and rodents identified regions within an ancient part of the brain, the hypothalamus, that are sufficient to increase or reduce appetite. Stimulating lateral parts of the hypothalamus was shown to promote feeding, whereas activating ventromedial regions reduced food consumption; these were described as hunger and satiety centers, respectively. In eLife this week, Caroline Wee and Erin Song (Engert and Kunes labs) report that lateral and medial hypothalamic circuits in the larval zebrafish, while sharing parallel functions with mammals, may in fact have more complex and dynamic roles in the control of energy homeostasis.
Similar to mammals, the larval zebrafish is able to regulate its feeding behavior based on its energy needs, largely due to the presence of conserved hypothalamic circuits. Using brain-wide activity mapping, Wee, Song et al. identified two major hypothalamic loci that were differentially regulated in voraciously-feeding fish (i.e. hungry fish presented with food), as compared to satiated fish. The lateral hypothalamus (LH), which shares homology with its mammalian counterpart, was highly active in voraciously-feeding fish, whereas a more ventromedially-situated region, the caudal hypothalamus (cH), had very low activity.
Notably, in hungry fish that had not yet been given food, the authors observed completely opposite activity patterns, namely the cH, and particularly its serotonergic neurons, was now much more active than the LH. Thus, cH and LH activities were not simply related to the internal states of hunger and satiety, but rather, they had opposing activity patterns during hunger depending on whether food was present or absent. The rapid reversal of cH and LH activities was triggered partially by external food sensory cues, but even more significantly by food consumption. Only as the hungry fish continued to feed and approached satiety did both cH and LH activities finally converge at intermediate activity levels. Thus, a restoration of energy balance is paralleled by the return of the network to an equilibrium state.
The significant negative correlation between the cH and LH that was generally observed over the extended time scales of many minutes suggests a potential mutually inhibitory relationship between those two nuclei. Live calcium imaging, confirmed such anti-correlated activity also on timescales of seconds, and by combining optogenetic stimulation with calcium imaging, the authors showed that the cH is indeed capable of silencing a part of the LH, providing a potential mechanistic explanation for such anti-correlated activities.
Finally, given their opposing activity patterns during food-deprivation and voracious eating, the authors predicted that, depending on the timing of stimulation, activating the cH might have opposite effects on LH activity and feeding behavior. Indeed, optogenetically-stimulating the cH in satiated fish before feeding enhanced subsequent food consumption, whereas the same treatment in the presence of food reduced voracious feeding, likely by suppressing LH activation by food.
Thus, the zebrafish LH and cH are neither “hunger” or “satiety” centers per se. Instead, they represent distinct phases of hunger and have unique functional roles within each phase. In the absence of food, cH activation likely sensitizes the fish to future food cues, and may even drive putative exploratory behavior to relieve the animal from this disadvantageous situation, However, once food is presented, activity in this nucleus is silenced, LH activity now dominates and the animal can focus on consummatory behavior. As Florian Engert describes, the cH and LH might be encoding “hangriness” and “happiness” respectively. These conclusions would have been difficult to achieve without the large-scale hypothalamic mapping and functional imaging afforded by the larval zebrafish model.
These findings may also have broader implications regarding the role of serotonin in hunger. Serotonin & serotonin agonists have been experimentally shown to act as appetite suppressants, but tend to paradoxically stimulate food cravings and weight gain in patients. The authors now report that in zebrafish, the serotonergic cH has divergent roles in appetite control, depending on contextual state of the animal. Thus, a detailed understanding of the mechanisms and evolutionary purpose of hunger circuits using simple model organisms could uncover insights related to the treatment of human disease.