Neural circuits and motivational processes for hunger

Abstract

How does an organism's internal state direct its actions? At one moment an animal forages for food with acrobatic feats such as tree climbing and jumping between branches. At another time, it travels along the ground to find water or a mate, exposing itself to predators along the way. These behaviors are costly in terms of energy or physical risk, and the likelihood of performing one set of actions relative to another is strongly modulated by internal state. For example, an animal in energy deficit searches for food and a dehydrated animal looks for water. The crosstalk between physiological state and motivational processes influences behavioral intensity and intent, but the underlying neural circuits are poorly understood. Molecular genetics along with optogenetic and pharmacogenetic tools for perturbing neuron function have enabled cell type-selective dissection of circuits that mediate behavioral responses to physiological state changes. Here, we review recent progress into neural circuit analysis of hunger in the mouse by focusing on a starvation-sensitive neuron population in the hypothalamus that is sufficient to promote voracious eating. We also consider research into the motivational processes that are thought to underlie hunger in order to outline considerations for bridging the gap between homeostatic and motivational neural circuits.

Figure 1

Node-by-node deconstruction of neural circuits for hunger. (a) AGRP neurons are a molecularly defined, starvation-sensitive circuit entry point for which external activation (e.g. using optogenetics- blue ticks and shading) is sufficient to induce voracious food consumption. Photo from Igor Siwanowicz. (b) The axon projections of AGRP neurons reveal a map of the downstream second-order regions potentially mediating the evoked feeding response. (c) The functional influence of specific AGRP neuron axonal projections can be prioritized by cell type-specific neuron and axon activation or silencing methods. Three AGRP neuron projections to regions previously associated with feeding behavior (POMC, PVH and PBN neurons — a subset of the total) have been examined. Projections to the PVH were sufficient to recapitulate the effect of AGRP neuron somatic activation. (d) Cell type-specific functional circuit mapping revealed the inhibitory interaction of AGRP neurons with PVH neurons (blue ticks are 1-ms light pulses). (e) This inhibitory synaptic operation could be independently recapitulated by neuronal silencing in molecularly defined PVH^SIM1 neurons using neuronal silencers. (f) Circuit analysis indicates that distinct projections of AGRP neurons have different functions. ARC^AGRP→ARC^POMC connections influence long-term regulation of food intake and other aspects of energy homeostasis. ARC^AGRP→PBN connections are involved in suppressing visceral malaise. ARC^AGRP→PVH connections regulate acute food intake. PVH neurons in turn communicate with brainstem regions associated with satiety (NTS: nucleus of the solitary tract, DVC: dorsal vagal complex).

Figure 2

Control processes for food seeking and consumption behaviors that may be modulated by AGRP neurons activated during energy deficit. Sensory information is integrated by multiple brain systems that influence control of motor actions (these systems are represented generically in the diagram as ‘Controller’), including those involved in food seeking or consumption. (a) AGRP neurons, which are activated by energy deficit, could increase the sensitivity to sensory stimuli associated with food. (b) Negative reinforcement. For a food deprived animal, sensory information or actions that lead to nutrient ingestion could be reinforced by suppressing an aversive energy deficit state, possibly mediated by AGRP neurons. Red T-arrows represent a state-dependent aversion signal whose offset increases the propensity to respond to sensory cues that predict food or to select actions that result in nutrient consumption. (c) Positive reinforcement. Nutrients are rewarding, even in the absence of a need state, and energy deficit, possibly acting through AGRP neurons, may increase the reward value of food. Blue arrows represent a signal that reinforces responding to sensory information or action selection that results in nutrient ingestion.

Figure 3

Reversible modulation of consummatory preference for sweet solutions dependent on nutrient content, energy deficit, and leptin. In ad libitum (freely) fed mice, optogenetic co-activation of dopamine neurons with consumption of the non-nutritive sweetener sucralose induced a preference for sucralose solution over a nutritive sucrose solution. Food deprivation (24-hour) reversed this preference, but food-restricted mice given leptin switched their preference back to sucralose. Reproduced from [72•].