Abstract
The potential to control feeding behavior via hypothalamic AgRP/NPY neurons has led to many approaches to modulate their excitability—particularly by glutamatergic input. In the present study using NPY-hrGFP reporter mice, we visualize AgRP/NPY neuronal metabotropic glutamate receptor 1 (mGluR1) expression and test the effect of fasting on mGluR1 function. Using the pharmacological agonist dihydroxyphenylglycine (DHPG), we demonstrate the enhanced capacity of mGluR1 to drive firing of AgRP/NPY neurons after overnight fasting, while antagonist 3-MATIDA reduces firing. Further, under synaptic blockade we demonstrate that DHPG acts directly on AgRP/NPY neurons to create a slow inward current. Using an in vitro approach, we show that emulation of intracellular signals associated with fasting by forskolin enhances DHPG induced phosphorylation of extracellularly regulated-signal kinase (1/2) in GT1-7 cell culture. We show in vivo that blocking mGluR1 by antagonist 3-MATIDA lowers fasting induced refeeding. In summary, this study identifies a novel layer of regulation on AgRP/NPY neurons integrated with whole body energy balance.
Highlights
AgRP/NPY neurons are potent regulators of food seeking behavior (Krashes et al, 2011) by release of GABA (Wu et al, 2009), AgRP (Nakajima et al, 2016) or NPY (Paez and Myers, 1991)
We searched for the presence of metabotropic glutamate receptor 1 (mGluR1) on AgRP/NPY neurons using NPY-hrGFP mice and tested for the effect of fasting on intensity of immunoreactivity
We tested the effect of fasting on mGluR1a/b expression by AgRP/NPY neurons
Summary
AgRP/NPY neurons are potent regulators of food seeking behavior (Krashes et al, 2011) by release of GABA (Wu et al, 2009), AgRP (Nakajima et al, 2016) or NPY (Paez and Myers, 1991). Many pre-synaptic sources of glutamate contribute to excitatory activation of AgRP/NPY neurons to drive feeding behavior, such as paraventricular hypothalamic Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) neurons and glutamatergic neurons in the dorsomedial hypothalamus (Krashes et al, 2014). Synaptic integration occurs in concert with fasting induced changes to intracellular signals of AgRP/NPY neurons, notably including activation of Protein Kinase A (PKA) in arcuate AgRP/NPY neurons (Shimizu-Albergine et al, 2001; Nakajima et al, 2016). We investigate the interface between intracellular signals of hypothalamic AgRP/NPY neurons and mGluR1 function
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