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An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice

Justin Siemian, Ph.D. and a figure from this study

Justin Siemian, Ph.D. and a figure from this study

Hot Off the Press – June 7, 2021

Published in eLife by  Justin Siemian and Yeka Aponte, et al. in the NIDA IRP Neuronal Circuits and Behavior Unit.

Decades of work have revealed the lateral hypothalamus (LH) as a crucial region for orchestrating appetitive and reward-related behaviors. However, the contributions of genetically-identified lateral hypothalamic neurons to other survival processes such as nociception have not been unraveled.

In this manuscript, Siemian et al. use a combination of approaches to identify, selectively target, monitor, and manipulate the activity of a small population of glutamatergic parvalbumin-positive lateral hypothalamic (LHPV) neurons and their projections to study their involvement in a broad range of pain modalities. Using in vivo functional imaging, they show for the first time that LHPV neurons exhibit an array of time-locked responses to noxious events. Moreover, chemogenetic activation of LHPV neurons not only reduces traditional pain-stimulated behaviors but also restores pain-suppressed behavior and reduces pain-associated negative affect. In models of persistent inflammatory or neuropathic pain, optogenetic activation of LHPV neurons or their axonal projections in the ventrolateral periaqueductal gray area (vlPAG) attenuates nociception, and rabies virus-mediated neuroanatomical tracing reveals that LHPV neurons preferentially target glutamatergic neurons over GABAergic neurons in the vlPAG. By contrast, LHPV axonal projections to the lateral habenula (LHb) regulate aversion but not nociception. Finally, they find that LHPV neuronal activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Their findings identify LHPV neurons as a lateral hypothalamic cell type intricately involved in nociception and demonstrate their potential as a novel target for pain treatment or for use in combination therapies with current analgesics.

Publication Information

Siemian, Justin N; Arenivar, Miguel A; Sarsfield, Sarah; Borja, Cara B; Erbaugh, Lydia J; Eagle, Andrew L; Robison, Alfred J; Leinninger, Gina; Aponte, Yeka

An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice Journal Article

In: eLife, vol. 10, pp. e66446, 2021, ISSN: 2050-084X.

Abstract | Links

@article{10.7554/eLife.66446,
title = {An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice},
author = {Justin N Siemian and Miguel A Arenivar and Sarah Sarsfield and Cara B Borja and Lydia J Erbaugh and Andrew L Eagle and Alfred J Robison and Gina Leinninger and Yeka Aponte},
editor = {Peggy Mason and Michael Taffe and Robert Gereau and Peggy Mason and Alexander C Jackson and Gregory Corder and Asaf Keller},
url = {https://pubmed.ncbi.nlm.nih.gov/34042586/},
doi = {10.7554/eLife.66446},
issn = {2050-084X},
year = {2021},
date = {2021-05-01},
journal = {eLife},
volume = {10},
pages = {e66446},
publisher = {eLife Sciences Publications, Ltd},
abstract = {Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHtextsuperscriptPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHtextsuperscriptPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHtextsuperscriptPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHtextsuperscriptPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHtextsuperscriptPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHtextsuperscriptPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

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Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHtextsuperscriptPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHtextsuperscriptPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHtextsuperscriptPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHtextsuperscriptPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHtextsuperscriptPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHtextsuperscriptPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.

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  • https://pubmed.ncbi.nlm.nih.gov/34042586/
  • doi:10.7554/eLife.66446

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