A synaptic temperature sensor for body cooling

Kamm, Gretel B.; Boffi, Juan Carlos; Zuza, Kristina; Nencini, Sara; Campos, Joaquin; Schrenk-Siemens, Katrin; Sonntag, Ivo; Kabaoğlu, Burçe; Hay, Muad Abd El; Schwarz, Yvonne; Tappe‐Theodor, Anke; Bruns, Dieter; Acuña, Claudio; Kuner, Thomas; Siemens, Jan

doi:10.1016/j.neuron.2021.10.001

Cited by 38 publications

(22 citation statements)

References 62 publications

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“…Increasing brain slice temperature from 26 °C to 33, 36, and 39 °C allowed the determination that 20% of cells were WSNs (Fig. 6f, g ), 22.5% were MSNs, 40% were ISNs, and 17.5% were silent cells, confirming a previous report 28 . Silent cells did not respond to increasing temperature (Fig.…”

Section: Resultssupporting

confidence: 88%

“…A minimum TC of at least +0.8 impulses s −1 °C −1 was applied to identify WSNs. Neurones with a TC in between +0.2 and +0.8 were regarded as MSNs and neurones with TC below +0.2 were regarded as ISNs 28 , 44 , 45 . Neurones without spontaneous firing were silent cells.…”

Section: Resultsmentioning

confidence: 99%

“…The in vitro evidence from brain slices also showed that DBS triggered rapid changes in membrane potential of excitatory WSNs with a temperature-dependent increase in AP firing rates and calcium transients, underlying a potential mechanism of DBS-evoked hypothermic response. Synaptic blockers eliminated WSNs’ responses to electrical stimulation, indicating that the WSNs’ modulatory networks are also crucial in DBS-evoked hypothermia 28 . The mechanism of DBS, in general, is complex and unclear but may include the classic rate model, the local adenosine release, and neuroprotection, as shown in Parkinson’s disease 54 – 56 .…”

Section: Discussionmentioning

confidence: 99%

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Hypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia

Zhang

Zhong

et al. 2022

Nat Commun

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Therapeutic hypothermia at 32-34 °C during or after cerebral ischaemia is neuroprotective. However, peripheral cold sensor-triggered hypothermia is ineffective and evokes vigorous counteractive shivering thermogenesis and complications that are difficult to tolerate in awake patients. Here, we show in mice that deep brain stimulation (DBS) of warm-sensitive neurones (WSNs) in the medial preoptic nucleus (MPN) produces tolerable hypothermia. In contrast to surface cooling-evoked hypothermia, DBS mice exhibit a torpor-like state without counteractive shivering. Like hypothermia evoked by chemogenetic activation of WSNs, DBS in free-moving mice elicits a rapid lowering of the core body temperature to 32-34 °C, which confers significant brain protection and motor function reservation. Mechanistically, activation of WSNs contributes to DBS-evoked hypothermia. Inhibition of WSNs prevents DBS-evoked hypothermia. Maintaining the core body temperature at normothermia during DBS abolishes DBS-mediated brain protection. Thus, the MPN is a DBS target to evoke tolerable therapeutic hypothermia for stroke treatment.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia

Zhang

Zhong

et al. 2022

Nat Commun

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“…The POA contains neurons that respond to local warming of the hypothalamus [ 42 ] and are involved in various autonomic thermoregulatory responses [ 3 ]. Neurons expressing TRPM2 channels respond to local heating of the POA [ 43 , 44 ]. Further, the POA contains neurons responsive to skin heating, which are observed even in TRPM2 channel knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Thermoregulatory heat-escape/cold-seeking behavior in mice and the influence of TRPV1 channels

et al. 2022

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The present study assessed heat-escape/cold-seeking behavior during thermoregulation in mice and the influence of TRPV1 channels. Mice received subcutaneous injection of capsaicin (50 mg/kg; CAP group) for desensitization of TRPV1 channels or vehicle (control [CON] group). In Experiment 1, heat-escape/cold-seeking behavior was assessed using a newly developed system comprising five temperature-controlled boards placed in a cross-shape. Each mouse completed three 90-min trials. In the trials, the four boards, including the center board, were set at either 36˚C, 38˚C, or 40˚C, while one corner board was set at 32˚C, which was rotated every 5 min. In Experiment 2, mice were exposed to an ambient temperature of 37˚C for 30 min. cFos expression in the preoptic area of the hypothalamus (POA) was assessed. In Experiment 1, the CON group stayed on the 32˚C board for the longest duration relative to that on other boards, and intra-abdominal temperature (Tabd) was maintained. In the CAP group, no preference for the 32˚C board was observed, and Tabd increased. In Experiment 2, cFos expression in the POA decreased in the CAP group. Capsaicin-induced desensitization of TRPV1 channels suppressed heat-escape/cold-seeking behavior in mice during heat exposure, resulting in hyperthermia. In conclusion, our findings suggest that heat sensation from the body surface may be a key inducer of thermoregulatory behaviors in mice.

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“…As an important non-selective cation channel, transient receptor potential melastatin 2 (TRPM2), has an endogenous expression in many organs, such as brain ( Li and Jiao, 2020 ; Zong et al, 2022 ), heart ( Ji et al, 2021 ), liver ( Feng et al, 2019 ), kidney ( Wang et al, 2019 ), and lung ( Wang et al, 2020 ), and participates in various physiological and pathological processes. For example, TRPM2 channel is involved in temperature sensing ( Song et al, 2016 ; Kamm et al, 2021 ), synaptic plasticity regulation ( Wang et al, 2016 ), and insulin secretion ( Ito et al, 2017 ). Based on its response to oxidative stress, the activation of TRPM2 channel mediates several neurodegenerative diseases, including Alzheimer’s disease ( Aminzadeh et al, 2018 ), Parkinson’s disease ( Ferreira et al, 2022 ), multiple sclerosis ( Shao et al, 2021 ), and stroke ( Zong et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

The identification of the key residues E829 and R845 involved in transient receptor potential melastatin 2 channel gating

Luo

Chen²,

Wu³

et al. 2022

Front. Aging Neurosci.

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Transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel, is involved in many physiological and pathological processes, including temperature sensing, synaptic plasticity regulation, and neurodegenerative diseases. However, the gating mechanism of TRPM2 channel is complex, which hinders its functional research. With the discovery of the Ca2+ binding site in the S2–S3 domain of TRPM2 channel, more and more attention has been drawn to the role of the transmembrane segments in channel gating. In this study, we focused on the D820-F867 segment around the S2 domain, and identified the key residues on it. Functional assays of the deletion mutants displayed that the deletions of D820-W835 and L836-P851 destroyed channel function totally, indicating the importance of these two segments. Sequence alignments on them found three polar and charged residues with high conservation (D820, E829, and R845). D820A, E829A, and R845A which removed the charge and the side chain of the residues were tested by 500 μM adenosine diphosphate-ribose (ADPR) or 50 mM Ca2+. E829A and R845A affected the characteristic of channel currents, while D820A behaved similarly to WT, indicating the participations of E829 and R845 in channel gating. The charge reversing mutants, E829K and R845D were then constructed and the electrophysiological tests showed that E829A and E829K made the channel lose function. Interestingly, R845A and R845D exhibited an inactivation process when using 500 μM ADPR, but activated normally by 50 mM Ca2+. Our data suggested that the negative charge at E829 took a vital part in channel activation, and R845 increased the stability of the Ca2+ combination in S2-S3 domain, thus guaranteeing the opening of TRPM2 channel. In summary, our identification of the key residues E829 and R845 in the transmembrane segments of TRPM2. By exploring the gating process of TRPM2 channel, our work helps us better understand the mechanism of TRPM2 as a potential biomarker in neurodegenerative diseases, and provides a new approach for the prediction, diagnosis, and prognosis of neurodegenerative diseases.

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A synaptic temperature sensor for body cooling

Cited by 38 publications

References 62 publications

Hypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia

Hypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia

Thermoregulatory heat-escape/cold-seeking behavior in mice and the influence of TRPV1 channels

The identification of the key residues E829 and R845 involved in transient receptor potential melastatin 2 channel gating

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