An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice

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

doi:10.7554/elife.66446

Cited by 27 publications

(16 citation statements)

References 72 publications

(121 reference statements)

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“…The lateral hypothalamic area (LH) is a vital controller of arousal, feeding, and metabolism, integrating sensory information about the world and the body [8,16]. The LH had been identified as a brain region responsive to pain stimuli and chronic pain-induced maladaptive anxiety that is capable of controlling pain-related behavioral responses by feeding [17,18]. Interestingly, the inhibitory LS to LH circuit can suppress feeding [16].…”

Section: Introductionmentioning

confidence: 99%

Lateral septum-lateral hypothalamus circuit dysfunction in comorbid pain and anxiety

et al. 2023

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Pain and anxiety comorbidities are a common health problem, but the neural mechanisms underlying comorbidity remain unclear. We propose that comorbidity implies that similar brain regions and neural circuits, with the lateral septum (LS) as a major candidate, process pain and anxiety. From results of behavioral and neurophysiological experiments combined with selective LS manipulation in mice, we find that LS GABAergic neurons were critical for both pain and anxiety. Selective activation of LS GABAergic neurons induced hyperalgesia and anxiety-like behaviors. In contrast, selective inhibition of LS GABAergic neurons reduced nocifensive withdrawal responses and anxiety-like behaviors. This was found in two mouse models, one for chronic inflammatory pain (induced by complete Freund’s adjuvant) and one for anxiety (induced by chronic restraint stress). Additionally, using TetTag chemogenetics to functionally mark LS neurons, we found that activation of LS neurons by acute pain stimulation could induce anxiety-like behaviors and vice versa. Furthermore, we show that LS GABAergic projection to the lateral hypothalamus (LH) plays an important role in the regulation of pain and anxiety comorbidities. Our study revealed that LS GABAergic neurons, and especially the LSGABAergic-LH circuit, are a critical to the modulation of pain and anxiety comorbidities.

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Section: Introductionmentioning

confidence: 99%

Lateral septum-lateral hypothalamus circuit dysfunction in comorbid pain and anxiety

et al. 2023

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“…In a study designed to delineate the role of the ACC in nocifensive behaviors in response to noxious heat and cold on the thermal-plate, it was realized that the ACC plays a pro-nociceptive role in noxious cold and not noxious heat-induced behaviors in an opioid-dependent manner [37]. Neural activity in the hypothalamic areas was altered by chemotherapy induced neuropathy [22], and interestingly, activation of distinct hypothalamic nuclei can cause pain modulation and analgesia [3,14,53]. It will curious to test if any or all of these nuclei play an active part in the generation of nocifensive behaviors in response to noxious cold.…”

Section: Discussionmentioning

confidence: 99%

A deep-learning driven investigation of circuit basis for reflexive hypersensitivity to pain

Reddy¹,

Vasudeva²,

Shah³

et al. 2023

Preprint

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Objectively measuring animal behavior is key to understanding the neural circuits underlying pain. Recent progress in machine vision has presented us with unprecedented scope in behavioral analysis. Here, we apply DeeplabCut (DLC) to dissect mouse behavior on the thermal-plate test - a commonly used paradigm to ascertain supraspinal contributions to noxious thermal sensation and pain hypersensitivity. We determine the signature characteristics of the pattern of mouse movement and posture in 3D in response to a range of temperatures from innocuous to noxious on the thermal-plate test. Next, we test how acute chemical and chronic inflammatory injuries sensitize mouse behaviors. Repeated exposure to noxious temperatures on the thermal-plate can induce learning, and in this study, we design a novel assay and formulate an analytical pipeline that will facilitate the dissection of plasticity mechanisms in pain circuits in the brain. Last, we record and test how activating Tacr1 expressing PBN neurons - a population responsive to sustained noxious stimuli- affects mouse behavior on the thermal plate test. Taken together, we demonstrate that by tracking a single body part of a mouse, we can reveal the behavioral signatures of mice exposed to noxious surface temperatures, report the alterations of the same when injured, and determine if a molecularly and anatomically defined pain responsive circuit plays a role in the reflexive hypersensitivity to thermal pain.

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“…However, these neurons produce pathway-specific behavioral effects. So, LH projections to the lateral habenula regulate aversion but not nociception (Siemian et al, 2021). In this respect, it has been shown that the LH-DG neural circuitry participates in pain modulation via the LHs' projections to the DG region in multiple animal models of acute and chronic pain (Brojeni et al, 2019;Khaleghzadeh-Ahangar et al, 2021;Torkamand et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Dopaminergic System in the Dentate Gyrus of the Hippocampus in Modulating the Orofacial Pain-Related Behaviors in the Rats

Haghparast¹,

Yousefpour²,

Rashvand³

et al. 2022

BCN

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Chemical stimulation of the lateral hypothalamus (LH) induces analgesia by formation neural circuitries with multiple brain regions. The involvement of hippocampal dopaminergic receptors in the LH stimulation-induced antinociception in certain animal models of pain has been documented, however, considering the fact that the neural circuitries involved in the mediation of orofacial pain are not the same as those that mediate the other types of pain, the present study aims to detect the role of dopamine receptors within the dentate gyrus (DG) in the antinociceptive responses induced by LH stimulation in an animal model of orofacial pain. Male Wistar rats (220-250 g) were implanted with two separate cannulae into the LH and DG on the same side. D1- or D2-like dopamine receptor antagonist, SCH23390 or Sulpiride (0.25, 1, and 4 μg) were microinjected into the DG, five minutes prior to intra-LH injection of carbachol (250 nM). The animals were then injected with formalin 1% (50 μl; sc) into the upper lip lateral to the nose and subjected to the orofacial formalin test. Intra-DG administration of SCH23390 or Sulpiride attenuated the antinociceptive responses induced by intra-LH microinjection of carbachol during orofacial formalin test. The findings of the current study suggest that chemical stimulation of the LH modulates the orofacial pain possibly through activation of the DG dopaminergic neurons. Due to the high incidence and prevalence of orofacial pain in the general population, understanding how such neuronal circuitry modulates nociceptive processing will advance the search for novel therapeutics.

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An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice

Cited by 27 publications

References 72 publications

Lateral septum-lateral hypothalamus circuit dysfunction in comorbid pain and anxiety

Lateral septum-lateral hypothalamus circuit dysfunction in comorbid pain and anxiety

A deep-learning driven investigation of circuit basis for reflexive hypersensitivity to pain

Involvement of Dopaminergic System in the Dentate Gyrus of the Hippocampus in Modulating the Orofacial Pain-Related Behaviors in the Rats

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