Dynamic Control Of Behavior By Hypothalamic Hunger Neurons

Survival requires neural circuits regulating behavior to rapidly adapt to an animal’s needs. Energy homeostasis is a basic need that drives feeding behavior. The ability to manipulate access to food in the laboratory allows us to assess how the brain responds to dynamic environmental challenges. The brain must properly gauge energy needs and coordinate behavior to find and consume food. There are three main components to this process that are addressed in this dissertation. First, circuits in the brain that coordinate feeding behavior must be well tuned to both external and internal cues signaling energy need and food availability. Second, when hunger circuits are active and food is not available, competing needs that impair food seeking are devalued. Third, hunger circuits promote food consumption by modulating motivation and reward. Hypothalamic agouti-related protein (AgRP)-expressing neurons are active during food deprivation and their activity drives food seeking and consumption. Precisely how AgRP neuron activity is regulated, however, is not completely understood. We used in vivo calcium imaging and gut-brain manipulations to identify multiple pathways that are utilized by nutrients along the gastrointestinal tract to inhibit AgRP neuron activity. When AgRP neurons are active in the absence of food, they suppress persistent inflammatory pain to promote feeding. We show here, using neural activity recordings, that peptidergic signaling blunts the activation of a population of glutamatergic neurons in a hindbrain hub that is a critical relay point for pain information. This work significantly advances our understanding of a relatively unexplored endogenous analgesic circuit. Finally, we demonstrate that AgRP neuron activity is sufficient to increase dopamine release in the striatum following food intake and that tonic elevations of striatal dopamine by drugs or input from a novel satiation center in the cerebellum suppress food intake by attenuating further release in response to food. Together, our findings reveal that hypothalamic neurons are regulated by rapid neural signals from the gut in order to properly enhance reward circuit activation and suppress activity in pain-responsive neurons to ensure survival

Calcium fluorescence

fluorescence time series of imaged somas and neuropil across 3 epochs: 1 run behavior; 2 sleep box; 3 sleep bo

Position data

position time series across 3 epochs: 1 run behavior; 2 sleep box; 3 sleep bo

LFP data

local field potential data from the pyramidal cell layer and stratum radiatum across 3 epochs: 1 run behavior; 2 sleep box; 3 sleep bo

Anti-inflammatory effects of hunger are transmitted to the periphery via projection-specific AgRP circuits

Summary: Caloric restriction has anti-inflammatory effects. However, the coordinated physiological actions that lead to reduced inflammation in a state of caloric deficit (hunger) are largely unknown. Using a mouse model of injury-induced peripheral inflammation, we find that food deprivation reduces edema, temperature, and cytokine responses that occur after injury. The magnitude of the anti-inflammatory effect that occurs during hunger is more robust than that of non-steroidal anti-inflammatory drugs. The effects of hunger are recapitulated centrally by activity in nutrient-sensing hypothalamic agouti-related protein (AgRP)-expressing neurons. We find that AgRP neurons projecting to the paraventricular nucleus of the hypothalamus rapidly and robustly reduce inflammation and mediate the majority of hunger’s anti-inflammatory effects. Intact vagal efferent signaling is required for the anti-inflammatory action of hunger, revealing a brain-to-periphery pathway for this reduction in inflammation. Taken together, these data begin to unravel a potent anti-inflammatory pathway engaged by hypothalamic AgRP neurons to reduce inflammation

Data from: Cholinergic modulation of hippocampal calcium activity across the sleep-wake cycle

Calcium is a critical second messenger in neurons that contributes to learning and memory, but how the coordination of action potentials of neuronal ensembles with the hippocampal local field potential (LFP) is reflected in dynamic calcium activity remains unclear. Here, we recorded hippocampal calcium activity with endoscopic imaging of the genetically encoded fluorophore GCaMP6 with concomitant LFP in freely behaving mice. Dynamic calcium activity was greater in exploratory behavior and REM sleep than in quiet wakefulness and slow wave sleep, behavioral states that differ with respect to theta and septal cholinergic activity, and modulated at sharp wave ripples (SWRs). Chemogenetic activation of septal cholinergic neurons expressing the excitatory hM3Dq DREADD increased calcium activity and reduced SWRs. Furthermore, inhibition of muscarinic acetylcholine receptors (mAChRs) reduced calcium activity while increasing SWRs. These results demonstrate that hippocampal dynamic calcium activity depends on behavioral and theta state as well as endogenous mAChR activation

A microbiome-dependent gut-brain pathway regulates motivation for exercise.

Exercise exerts a wide range of beneficial effects for healthy physiology. However, the mechanisms regulating an individual’s motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise-induced neurochemical changes in the brain. Here, we report on the discovery of a gut–brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome-dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut-derived signals to the brain may enhance the motivation for exercise