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Dynamic GABAergic afferent modulation of AgRP neurons

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ABSTRACT

Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues prior to ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the pre-consummatory modulation of ARCAgRP neurons. In a manner reciprocal to ARCAgRP neurons, ARC-projecting leptin receptor (LepR)-expressing GABAergic DMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, DMHLepR neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRP neuron activity and feeding behavior.

No MeSH data available.


DMHLepR neurons are a potent source of GABAergic input to ARCAgRP neurons(a–b), DMHvGAT neurons provide monosynaptic inhibitory input to 100% of ARCAgRP neurons (a) and ARCPOMC neurons recorded (b). (c–d), DMHLepR neurons provide selective monosynaptic input to 100% of ARCAgRP (c) but only 9% of ARCPOMC neurons recorded (d). (e), DMHLepR→ARC neurons provide dense axo-somatic innervation of ARCAgRP neurons. (f), Photostimulation of DMHLepR→ARC terminals is sufficient to inhibit ARCAgRP action potential firing. Abbreviations, 3v, third ventricle; PTX, picrotoxin. Scale bar in panel e, 100 μm and f, 25 μm.
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Figure 1: DMHLepR neurons are a potent source of GABAergic input to ARCAgRP neurons(a–b), DMHvGAT neurons provide monosynaptic inhibitory input to 100% of ARCAgRP neurons (a) and ARCPOMC neurons recorded (b). (c–d), DMHLepR neurons provide selective monosynaptic input to 100% of ARCAgRP (c) but only 9% of ARCPOMC neurons recorded (d). (e), DMHLepR→ARC neurons provide dense axo-somatic innervation of ARCAgRP neurons. (f), Photostimulation of DMHLepR→ARC terminals is sufficient to inhibit ARCAgRP action potential firing. Abbreviations, 3v, third ventricle; PTX, picrotoxin. Scale bar in panel e, 100 μm and f, 25 μm.

Mentions: GABAergic modulation of ARC melanocortin neurons is well established to play a role in the regulation of energy homeostasis10,11. Previous monosynaptic rabies mapping12 from genetically-defined ARCAgRP neurons identified the ARC, DMH and, to a much lesser extent, the lateral hypothalamus (LH) as potential anatomic sources of pre-synaptic input13,14. To validate these observations and determine their valence we employed channelrhodopsin-assisted circuit mapping (CRACM). Using a Slc32a1(vGAT)-ires-Cre mouse to selectively transduce putative pre-synaptic GABAergic neurons, we recorded post-synaptic currents on ARCAgRP neurons (as demarked by an Npy-GFP transgene that labels all ARCAgRP neurons15,16). All recorded ARCAgRP neurons exhibited picrotoxin-sensitive light-evoked inhibitory post-synaptic currents (IPSCs) arising from distal DMHvGAT neurons (25/25; Fig 1a, S1a) and local ARCvGAT neurons (10/10; Supplementary Fig. 1b, d), but not from LHvGAT neurons (0/13; Supplementary Fig. 1c, e). However, ARC-projecting DMHvGAT and ARCvGAT neurons were also synaptically connected to counteracting satiety-promoting ARC pro-opiomelanocortin (POMC) neurons (demarked by a Pomc-hrGFP transgene; Fig 1b, Supplementary Fig. 1f, g), negating the utility of the vGAT-ires-Cre mouse as a selective marker of inhibitory ARCAgRP neuron afferents.


Dynamic GABAergic afferent modulation of AgRP neurons
DMHLepR neurons are a potent source of GABAergic input to ARCAgRP neurons(a–b), DMHvGAT neurons provide monosynaptic inhibitory input to 100% of ARCAgRP neurons (a) and ARCPOMC neurons recorded (b). (c–d), DMHLepR neurons provide selective monosynaptic input to 100% of ARCAgRP (c) but only 9% of ARCPOMC neurons recorded (d). (e), DMHLepR→ARC neurons provide dense axo-somatic innervation of ARCAgRP neurons. (f), Photostimulation of DMHLepR→ARC terminals is sufficient to inhibit ARCAgRP action potential firing. Abbreviations, 3v, third ventricle; PTX, picrotoxin. Scale bar in panel e, 100 μm and f, 25 μm.
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Related In: Results  -  Collection

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Figure 1: DMHLepR neurons are a potent source of GABAergic input to ARCAgRP neurons(a–b), DMHvGAT neurons provide monosynaptic inhibitory input to 100% of ARCAgRP neurons (a) and ARCPOMC neurons recorded (b). (c–d), DMHLepR neurons provide selective monosynaptic input to 100% of ARCAgRP (c) but only 9% of ARCPOMC neurons recorded (d). (e), DMHLepR→ARC neurons provide dense axo-somatic innervation of ARCAgRP neurons. (f), Photostimulation of DMHLepR→ARC terminals is sufficient to inhibit ARCAgRP action potential firing. Abbreviations, 3v, third ventricle; PTX, picrotoxin. Scale bar in panel e, 100 μm and f, 25 μm.
Mentions: GABAergic modulation of ARC melanocortin neurons is well established to play a role in the regulation of energy homeostasis10,11. Previous monosynaptic rabies mapping12 from genetically-defined ARCAgRP neurons identified the ARC, DMH and, to a much lesser extent, the lateral hypothalamus (LH) as potential anatomic sources of pre-synaptic input13,14. To validate these observations and determine their valence we employed channelrhodopsin-assisted circuit mapping (CRACM). Using a Slc32a1(vGAT)-ires-Cre mouse to selectively transduce putative pre-synaptic GABAergic neurons, we recorded post-synaptic currents on ARCAgRP neurons (as demarked by an Npy-GFP transgene that labels all ARCAgRP neurons15,16). All recorded ARCAgRP neurons exhibited picrotoxin-sensitive light-evoked inhibitory post-synaptic currents (IPSCs) arising from distal DMHvGAT neurons (25/25; Fig 1a, S1a) and local ARCvGAT neurons (10/10; Supplementary Fig. 1b, d), but not from LHvGAT neurons (0/13; Supplementary Fig. 1c, e). However, ARC-projecting DMHvGAT and ARCvGAT neurons were also synaptically connected to counteracting satiety-promoting ARC pro-opiomelanocortin (POMC) neurons (demarked by a Pomc-hrGFP transgene; Fig 1b, Supplementary Fig. 1f, g), negating the utility of the vGAT-ires-Cre mouse as a selective marker of inhibitory ARCAgRP neuron afferents.

View Article: PubMed Central - PubMed

ABSTRACT

Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues prior to ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the pre-consummatory modulation of ARCAgRP neurons. In a manner reciprocal to ARCAgRP neurons, ARC-projecting leptin receptor (LepR)-expressing GABAergic DMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, DMHLepR neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRP neuron activity and feeding behavior.

No MeSH data available.