An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice

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 (LHPV) 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 LHPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.

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Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward

Journal of Neuroscience ◽

10.1523/jneurosci.1202-15.2016 ◽

2016 ◽

Vol 36 (2) ◽

pp. 302-311 ◽

Cited By ~ 122

Author(s):

Alice M. Stamatakis ◽

Maaike Van Swieten ◽

Marcus L. Basiri ◽

Grace A. Blair ◽

Pranish Kantak ◽

...

Keyword(s):

Lateral Hypothalamic Area ◽

Hypothalamic Area ◽

Lateral Habenula ◽

Glutamatergic Neurons ◽

Lateral Hypothalamic

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Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Modulate the Anesthetic Potency of Isoflurane in Mice

Neuroscience Bulletin ◽

10.1007/s12264-021-00674-z ◽

2021 ◽

Author(s):

Shiyi Zhao ◽

Rui Li ◽

Huiming Li ◽

Sa Wang ◽

Xinxin Zhang ◽

...

Keyword(s):

Large Population ◽

Lateral Hypothalamic Area ◽

Hypothalamic Area ◽

Lateral Habenula ◽

Genetic Ablation ◽

Glutamatergic Neurons ◽

Lateral Hypothalamic ◽

Melanin Concentrating Hormone ◽

Anesthetic Potency ◽

Eeg Features

AbstractThe lateral hypothalamic area (LHA) plays a pivotal role in regulating consciousness transition, in which orexinergic neurons, GABAergic neurons, and melanin-concentrating hormone neurons are involved. Glutamatergic neurons have a large population in the LHA, but their anesthesia-related effect has not been explored. Here, we found that genetic ablation of LHA glutamatergic neurons shortened the induction time and prolonged the recovery time of isoflurane anesthesia in mice. In contrast, chemogenetic activation of LHA glutamatergic neurons increased the time to anesthesia and decreased the time to recovery. Optogenetic activation of LHA glutamatergic neurons during the maintenance of anesthesia reduced the burst suppression pattern of the electroencephalogram (EEG) and shifted EEG features to an arousal pattern. Photostimulation of LHA glutamatergic projections to the lateral habenula (LHb) also facilitated the emergence from anesthesia and the transition of anesthesia depth to a lighter level. Collectively, LHA glutamatergic neurons and their projections to the LHb regulate anesthetic potency and EEG features.

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

Scientific Reports ◽

10.1038/s41598-019-48537-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Justin N. Siemian ◽

Cara B. Borja ◽

Sarah Sarsfield ◽

Alexandre Kisner ◽

Yeka Aponte

Keyword(s):

Periaqueductal Gray ◽

Lateral Hypothalamic ◽

Gray Area ◽

Fast Spiking ◽

Parvalbumin Neurons

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Dorso-ventral variation in the attenuating effect of lateral hypothalamic stimulation on the switch-off response elicited from the mesencephalic central gray area

Physiology & Behavior ◽

10.1016/0031-9384(87)90108-9 ◽

1987 ◽

Vol 40 (5) ◽

pp. 625-629 ◽

Cited By ~ 2

Author(s):

Pierre Cazala ◽

Pierre Schmitt

Keyword(s):

Hypothalamic Stimulation ◽

Lateral Hypothalamic ◽

Gray Area ◽

Central Gray

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Obesity remodels activity and transcriptional state of a lateral hypothalamic brake on feeding

Science ◽

10.1126/science.aax1184 ◽

2019 ◽

Vol 364 (6447) ◽

pp. 1271-1274 ◽

Cited By ~ 26

Author(s):

Mark A. Rossi ◽

Marcus L. Basiri ◽

Jenna A. McHenry ◽

Oksana Kosyk ◽

James M. Otis ◽

...

Keyword(s):

Energy Homeostasis ◽

Health Concern ◽

Hypothalamic Area ◽

Obesity Epidemic ◽

Glutamatergic Neurons ◽

Two Photon ◽

Lateral Hypothalamic ◽

The Brain ◽

Transcriptional State

The current obesity epidemic is a major worldwide health concern. Despite the consensus that the brain regulates energy homeostasis, the neural adaptations governing obesity are unknown. Using a combination of high-throughput single-cell RNA sequencing and longitudinal in vivo two-photon calcium imaging, we surveyed functional alterations of the lateral hypothalamic area (LHA)—a highly conserved brain region that orchestrates feeding—in a mouse model of obesity. The transcriptional profile of LHA glutamatergic neurons was affected by obesity, exhibiting changes indicative of altered neuronal activity. Encoding properties of individual LHA glutamatergic neurons were then tracked throughout obesity, revealing greatly attenuated reward responses. These data demonstrate how diet disrupts the function of an endogenous feeding suppression system to promote overeating and obesity.

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Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray

Nature Communications ◽

10.1038/s41467-019-12316-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Vijay K. Samineni ◽

Jose G. Grajales-Reyes ◽

Saranya S. Sundaram ◽

Judy J. Yoo ◽

Robert W. Gereau

Keyword(s):

Neural Circuits ◽

Periaqueductal Gray ◽

Gabaergic Neurons ◽

Cell Type ◽

Glutamatergic Neurons ◽

Neuronal Populations ◽

Chronic Itch ◽

Cell Type Specific ◽

Bidirectional Modulation ◽

Affective Components

Abstract Itch is a distinct aversive sensation that elicits a strong urge to scratch. Despite recent advances in our understanding of the peripheral basis of itch, we know very little regarding how central neural circuits modulate acute and chronic itch processing. Here we establish the causal contributions of defined periaqueductal gray (PAG) neuronal populations in itch modulation in mice. Chemogenetic manipulations demonstrate bidirectional modulation of scratching by neurons in the PAG. Fiber photometry studies show that activity of GABAergic and glutamatergic neurons in the PAG is modulated in an opposing manner during chloroquine-evoked scratching. Furthermore, activation of PAG GABAergic neurons or inhibition of glutamatergic neurons resulted in attenuation of scratching in both acute and chronic pruritis. Surprisingly, PAG GABAergic neurons, but not glutamatergic neurons, may encode the aversive component of itch. Thus, the PAG represents a neuromodulatory hub that regulates both the sensory and affective aspects of acute and chronic itch.

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Lateral hypothalamic ‘command neurons’ with axonal projections to regions involved in both feeding and thermogenesis

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2007.05429.x ◽

2007 ◽

Vol 25 (8) ◽

pp. 2404-2412 ◽

Cited By ~ 35

Author(s):

B. J. Oldfield ◽

A. M. Allen ◽

P. Davern ◽

M. E. Giles ◽

N. C. Owens

Keyword(s):

Command Neurons ◽

Lateral Hypothalamic ◽

Axonal Projections

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Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

10.1101/2020.06.17.157479 ◽

2020 ◽

Author(s):

James T. McKenna ◽

Chun Yang ◽

Thomas Bellio ◽

Marissa B. Anderson-Chernishof ◽

Mackenzie C. Gamble ◽

...

Keyword(s):

Avoidance Behavior ◽

Basal Forebrain ◽

Calcium Binding ◽

Viral Vectors ◽

Fluorescent Protein ◽

Glutamate Transporter ◽

Reward Processing ◽

Lateral Habenula ◽

Glutamatergic Neurons ◽

Green Fluorescent

ABSTRACTThe basal forebrain (BF) is involved in arousal, attention, and reward processing but the role of individual BF subtypes is still being uncovered. Glutamatergic neurons are the least well-understood of the three major BF neurotransmitter phenotypes. Here we analyzed the distribution, size, calcium-binding protein content and projections of the major group of BF glutamate neurons expressing the vesicular glutamate transporter subtype 2 (vGluT2) and tested the functional effect of activating them. Mice expressing Cre recombinase under control of the vGluT2 promoter were crossed with a reporter strain expressing the red fluorescent protein, tdTomato, to generate vGluT2-cre-tdTomato mice. Immunohistochemical staining for choline acetyltransferase and a cross with mice expressing green fluorescent protein selectively in GABAergic neurons confirmed cholinergic, GABAergic and vGluT2+ neurons represent separate BF subpopulations. Subsets of BF vGluT2+ neurons expressed the calcium binding proteins calbindin or calretinin, suggesting that multiple subtypes of BF vGluT2+ neurons exist. Anterograde tracing using adeno-associated viral vectors expressing channelrhodopsin2- enhanced yellow fluorescent fusion proteins revealed major projections of BF vGluT2+ neurons to neighboring BF cholinergic and parvalbumin neurons, as well as to extra-BF areas involved in the control of arousal and regions responding to aversive or rewarding stimuli such as the lateral habenula and ventral tegmental area. Optogenetic activation of BF vGluT2 neurons in a place preference paradigm elicited a striking avoidance of the area where stimulation was given. Together with previous optogenetic findings suggesting an arousal-promoting role, our findings suggest BF vGluT2 neurons play a dual role in promoting wakefulness and avoidance behavior.

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Evolution of circuits regulating pleasure and happiness with the habenula in control

CNS Spectrums ◽

10.1017/s1092852917000748 ◽

2017 ◽

Vol 24 (02) ◽

pp. 233-238 ◽

Cited By ~ 4

Author(s):

Anton J. M. Loonen ◽

Svetlana A. Ivanova

Keyword(s):

Globus Pallidus ◽

Essential Role ◽

Stress Disorders ◽

Lateral Habenula ◽

Glutamatergic Neurons ◽

Nuclear Complex ◽

Reward Seeking ◽

Seeking Behavior ◽

Neuroimaging Techniques

The habenula, which in humans is a small nuclear complex within the epithalamus, plays an essential role in regulating the intensity of reward-seeking and adversity-avoiding behavior in all vertebrate ancestors by regulating the activity of ascending midbrain monoaminergic tracts. In lampreys, considered to possess a brain comparable to humans’ earliest evolutionary vertebrate ancestor, the activity of the lateral habenula is controlled by a subset of glutamatergic neurons of the animal’s pallidum (habenula-projecting globus pallidus) that inhibit reward-seeking behavior when this conduct is not successful enough. The pathophysiological roles of the habenula and habenula-projecting globus pallidus in humans have hardly been studied, which is probably due to insufficient resolution of common neuroimaging techniques. Their dysregulation may, however, play an essential role in the pathogenesis of mood and stress disorders and addiction.

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