Review
Neural Circuit Mechanisms Underlying Emotional Regulation of Homeostatic Feeding

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Distinct ARCAGRP neuron circuits regulate feeding and diverse emotional states. These circuits modulate multiple emotional processes in accordance with changing energy demands and environmental conditions to promote positive energy balance.

LHGABAergic and LHglutamatergic neurons exert opposing effects on feeding behavior and emotional behavior. These neurons control feeding via bidirectional interactions with emotional circuitry including the bed nucleus of the stria terminalis, the septum, the lateral habenula, and the ventral tegmental area.

The hippocampus regulates feeding via neural circuit interactions with the lateral septum and lateral hypothalamus, although additional neural circuit mechanisms remain unknown.

Amygdalar circuits integrate homeostatic inputs from the hypothalamus, cognitive inputs from the prefrontal cortex, and visceral inputs from hindbrain satiety centers to modulate feeding.

The neural circuits controlling feeding and emotional behaviors are intricately and reciprocally connected. Recent technological developments, including cell type-specific optogenetic and chemogenetic approaches, allow functional characterization of genetically defined cell populations and neural circuits in feeding and emotional processes. Here we review recent studies that have utilized circuit-based manipulations to decipher the functional interactions between neural circuits controlling feeding and those controlling emotional processes. Specifically, we highlight newly described neural circuit interactions between classical emotion-related brain regions, such as the hippocampus and amygdala, and homeostatic feeding circuitry in the arcuate nucleus and lateral hypothalamus (LH). Together these circuits will provide a template for future studies to examine functional interactions between feeding and emotion.

Section snippets

Behavioral Interactions between Feeding and Emotion

Since feeding is essential for survival, the brain has evolved multiple overlapping mechanisms to assure adequate levels of food intake during changing energy demands 1, 2, 3, 4. Ultimately, the decision to eat is controlled by neuronal activity in distributed feeding centers that primarily reside in the hypothalamus, hindbrain, and limbic brain regions 1, 2, 3, 4. These feeding centers are anatomically connected with broadly distributed brain regions that convey emotional information.

Regulation of Diverse Emotional Behaviors by Arcuate Feeding Neurons

It is well recognized that the arcuate nucleus of the hypothalamus (ARC) has a primary role in feeding 1, 2, 3, 4. For example, chemogenetic (see Glossary) and optogenetic activation of agouti-related protein-expressing ARC (ARCAGRP) neurons increases feeding in sated mice 9, 10. Selective activation of ARCAGRP neuronal projections to the paraventricular hypothalamus (PVH), the LH, or the anterior bed nucleus of the stria terminalis (aBNST) was sufficient to rapidly increase food intake in

LH Modulates the Mesolimbic Reward Circuitry

Along with the ARC, the LH is well recognized as a ‘feeding center’ in the brain. Much of the LH’s effect on feeding has been attributed to the close association between the LH and the ventral tegmental area (VTA) of the mesolimbic reward system [22]. Of particular importance to emotion and feeding, disruption in the mesolimbic dopamine system comprising the nucleus accumbens (NAc) and the VTA is linked to changes in mood and emotions 23, 24, 25. However, the functional interactions between

LH GABAergic Neurons Receive Inputs from Emotional Circuitry

Given that LH GABAergic neurons potently regulate feeding and emotional processes, synaptic inputs to these neurons are also likely to regulate feeding and emotional behavior since integrated synaptic strength controls neural activity. LH GABAergic neurons receive synaptic inputs from brain regions classically involved in emotion-related behaviors including the lateral septum (LS) [31] and NAc [23] and manipulation of these inputs to the LH regulates feeding. For example, a recent study

LH Glutamatergic Neurons Reduce Feeding via Connections with Emotional Circuitry

In contrast to the orexigenic role of LH GABAergic neurons, glutamatergic neurons in the LH exert negative effects on feeding 42, 43. For instance, optogenetic stimulation of LH glutamatergic neurons reduced feeding and was aversive while selective ablation of LH glutamatergic neurons increased food intake 42, 43. The acute appetite-reducing effect of LH glutamatergic neurons appears to be independent of projections to the VTA as selective optogenetic stimulation or inhibition of LH

Newly Identified Hippocampal and Amygdalar Feeding Circuits

As discussed above, primary feeding centers localized in the ARC and LH, in addition to regulating feeding, also modulate emotional processes. However, emotion-related brain regions including the hippocampus and amygdala modulate feeding behavior [5]. For instance, the hippocampal formation (HPC) has been classically implicated in emotional behaviors including anxiety and depressive behavior 52, 53, 54, 55. In addition to the hippocampus’ role in emotion, numerous lines of evidence support a

Concluding Remarks and Future Perspectives

It has been proposed that emotions evolved to reinforce behaviors that promote survival [82]. Since feeding is essential for survival, neural circuit overlap between brain regions controlling feeding and emotions is hardly surprising. At the neural circuit level, key hypothalamic feeding centers (such as the ARC and LH) are bidirectionally connected to brain regions that convey emotional information, including the vHPC, amygdala, VTA, NAc, LS, and BNST (Table 1). These bidirectional connections

Acknowledgments

The authors apologize to all colleagues whose studies were not discussed or cited in this review because of space limitations. Y.Y. is funded by the State University of New York and National Institute of Mental Health (R01MH10944A).

Glossary

Chemogenetics
a behavioral neuroscience approach utilizing designer receptors exclusively activated by designer drugs (DREADDs) that couple to intracellular signaling pathways to selectively activate or inhibit defined neuronal cell types. Targeted neurons are activated or inhibited via injection of a blood–brain barrier-permeable ligand that selectively binds to these receptors to activate intracellular signaling pathways.
Chronic restraint stress
animal model of stress-induced behavior

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