Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area

Justin N Siemian,Alexandre Kisner,Cara B Borja,Sarah Sarsfield,Yeka Aponte

doi:10.1038/s41598-019-48537-y

Abstract

A pivotal role of the lateral hypothalamus (LH) in regulating appetitive and reward-related behaviors has been evident for decades. However, the contributions of LH circuits to other survival behaviors have been less explored. Here we examine how lateral hypothalamic neurons that express the calcium-binding protein parvalbumin (PVALB; LHPV neurons), a small cluster of neurons within the LH glutamatergic circuitry, modulate nociception in mice. We find that photostimulation of LHPV neurons suppresses nociception to an acute, noxious thermal stimulus, whereas photoinhibition potentiates thermal nociception. Moreover, we demonstrate that LHPV axons form functional excitatory synapses on neurons in the ventrolateral periaqueductal gray (vlPAG), and photostimulation of these axons mediates antinociception to both thermal and chemical visceral noxious stimuli. Interestingly, this antinociceptive effect appears to occur independently of opioidergic mechanisms, as antagonism of μ-opioid receptors with systemically-administered naltrexone does not abolish the antinociception evoked by activation of this LHPV→vlPAG pathway. This study directly implicates LHPV neurons in modulating nociception, thus expanding the repertoire of survival behaviors regulated by LH circuits.

Highlights

The diverse collection of genetically-distinct cell types in the lateral hypothalamus (LH) is crucial for orchestrating a variety of motivated behaviors that facilitate survival[1,2]
We first investigated whether LHPV neurons regulate nociceptive behaviors by measuring the latency to paw withdrawal during a hot plate assay (PWLHP) while acutely activating or inhibiting these neurons using optogenetics
We found that optogenetic activation of LHPV neurons evoked a significantly greater increase in PWLHP from baseline compared to LHPV:tdTomato control mice (Fig. 1e; n = 6 LHPV:ChR2, n = 8 LHPV:tdTomato; unpaired Student’s t test, t(12) = 3.25, **p = 0.007)

Summary

Introduction

The diverse collection of genetically-distinct cell types in the lateral hypothalamus (LH) is crucial for orchestrating a variety of motivated behaviors that facilitate survival[1,2]. LH GABAergic and glutamatergic neurons project to the ventral tegmental area (VTA), and activation of these pathways positively and negatively influences feeding behavior, respectively[5], as well as other motivated behaviors such as social interaction[6] While studies such as these have begun to identify LH circuits that regulate food intake and reward-related behaviors, less attention has been given to the contributions of genetically-identified LH circuits in modulating nociceptive behaviors. We combined optogenetics and electrophysiology to demonstrate that LHPV neurons are synaptically connected to cells within the vlPAG and that activation of this LHPV→vlPAG pathway modulates nociceptive responses to both thermal and chemical visceral noxious stimuli. Since the PAG is an important site for opioid-mediated analgesia[20,21,26,27], we investigated whether modulation of nociception by the LHPV→vlPAG pathway involved opioidergic mechanisms

Methods

Results

Conclusion