LAB OF NEURAL INTEROCEPTION

INTEROCEPTIVE NUTRIENT SENSING IN FLIES AND MICE

OVERVIEW

Animals in the wild encounter many types of external stimuli such as threat and food,

and must exhibit appropriate responses for survival. How does a brain recognize such

stimuli with sensory systems, create internal representations of these external stimuli,

and then elicit appropriate behavioral responses?

To address this problem, we take systems approach and use the fruit fly, Drosophila melanogaster,

because of a wealth of genetic tools available, a relatively simple brain, and a complex, interesting

behavioral repertoire. Rapidly emerging tools also permit relatively facile identification of neural

substrates. We recently launched studies using mice in addition to fruit flies. Our focus has been to identify neurons that subserve a particular innate behavior, apply functional imaging and electro-

physiology to probe their activity, therefore, define precisely contributions of each set of neurons

to behavior. We are currently interested in identification and characterization of post-ingestive,

internal sensors that detect the nutritional value of carbohydrate, fats and protein (macronutrients),

and micronutrients in Drosophila. We are extending this line of work in mice to elucidate the

identities and characteristics of the mammalian nutrient sensors, and understand the mechanisms

by which these sensors contribute to feeding and metabolism.

Among a number of discoveries that our laboratory has made thus far, we have contributed

significantly to understanding the function of Glucose-sensing neurons in the brain. Glucose-sensing

neurons were identified initially by electrophysiological recordings (Oomura et al., 1964 Science),

but the physiological function mediated by these neurons in animals were unclear until recently.

We have been able to elucidate their function using Drosophila: 1) the nutritional content of sugar,

rather than its palatability, was detected by a discrete population of glucose-excited neurons (termed

DH44 neurons) that promote sugar consumption (Dus et al., 2015 Neuron and 2011 PNAS, Oh et al., 2021 Neuron) and 2) a pair of glucose-excited neurons (termed CN neurons) regulate the two key endocrine axes: insulin and glucagon (Oh et al., 2019 Nature). These are a series of significant discoveries because approximately 10-15% of neurons in our brain are glucose-sensing, but it has taken over 50 years to reveal their physiological function in an animal. Understanding the functions of glucose-sensing in Drosophila would provide a foundation for studying their functions in mice and humans, and developing therapeutic potentials for health issues such as obesity, diabetes, eating disorders. In addition to the studies of glucose-sensing, we have identified and characterized neural circuits mediating the detection and response to the deprivation of amino acids (Kim et al., 2021 Nature), and other macronutrients, as well as essential micronutrients (see a Review by Kim et al, 2021 Cell Metabolism). 

RESEARCH  HIGHLIGHT

Rapid, biphasic CRF neuronal responses 

encode positive and negative valence in mice 

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Abstract

Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the hypothalamic–pituitary–adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli.

A glucose-sensing neuron pair regulates insulin and glucagon in Drosophila

Abstract

Although glucose-sensing neurons were identified more than 50 years ago, the physiological role of glucose sensing in metazoans remains unclear. Here we identify a pair of glucose-sensing neurons with bifurcated axons in the brain of Drosophila. One axon branch projects to insulin-producing cells to trigger the release of Drosophila insulin-like peptide 2 (dilp2) and the other extends to adipokinetic hormone (AKH)–producing cells to inhibit secretion of AKH, the fly analogue of glucagon. These axonal branches undergo synaptic remodelling in response to changes in their internal energy status. Silencing of these glucose-sensing neurons largely disabled the response of insulin-producing cells to glucose and dilp2 secretion, disinhibited AKH secretion in corpora cardiaca and caused hyperglycaemia, a hallmark feature of diabetes mellitus. We propose that these glucose-sensing neurons maintain glucose homeostasis by promoting the secretion of dilp2 and suppressing the release of AKH when haemolymph glucose levels are high.

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