🧠 neuroscience

Thermoregulatory roles of preoptic area histamine H1 receptor-expressing neurons

This study identifies preoptic area histamine H1 receptor-expressing neurons as key regulators that drive increases in body temperature and physical activity while promoting nest-building behavior, thereby contributing to daily thermoregulatory rhythms without significantly influencing fever or acute responses to extreme ambient temperatures.

Original authors: Pinol, R. A., Valeri, A., Xiao, C., Hadley, C., Goldschmidt, A. I., Kerspern, D., Kulkarni, S., Gavrilova, O., Lutas, A., Krashes, M. J., Reitman, M.

Published 2026-09-28

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CC0 1.0

Original authors: Pinol, R. A., Valeri, A., Xiao, C., Hadley, C., Goldschmidt, A. I., Kerspern, D., Kulkarni, S., Gavrilova, O., Lutas, A., Krashes, M. J., Reitman, M.

Original paper dedicated to the public domain under CC0 1.0 (https://creativecommons.org/publicdomain/zero/1.0/). ⚕️ This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer

Every living creature that maintains a constant internal temperature faces a daily balancing act. To stay warm enough to function but cool enough to avoid overheating, the body relies on a sophisticated control center in the brain called the preoptic area. This region acts as a thermostat, constantly comparing the current body temperature against a target set point and issuing commands to either generate heat or release it. These commands trigger both automatic physiological changes, such as shivering or widening blood vessels, and motivated behaviors, like seeking a sunny spot or building a nest. While scientists have long known that the brain chemical histamine plays a role in keeping us awake and alert, its specific function in this temperature-control network has remained a mystery. Understanding how the brain decides when to turn up the heat is crucial, not just for understanding basic biology, but for grasping how the body manages energy and responds to the environment.

A team of researchers at the National Institutes of Health has now identified a specific group of nerve cells in the preoptic area that acts as a dedicated switch for raising body temperature. These cells, which carry receptors for histamine, were found to be distinct from other known temperature-regulating neurons. When the researchers activated these specific cells in mice, the animals' body temperatures rose, and they became more physically active. This increase in heat was not merely a side effect of the mice moving around; the energy expenditure increased even when the mice were resting, suggesting these cells directly command the body to produce warmth. The effect was robust and long-lasting, with body temperatures remaining elevated for hours after the initial stimulation stopped, indicating that these cells trigger a cascade of events that sustains the heat production long after the initial signal fades.

The researchers also discovered that these cells are most active during the night, the time when mice are naturally awake and their body temperatures are highest. By temporarily silencing these cells, the scientists observed that the mice failed to reach their usual nighttime temperature peak, even though their activity levels remained normal. This suggests that these neurons are essential for maintaining the higher body temperature associated with the active phase of the day. Interestingly, the cells did not appear to be required for acute cold defense thermogenesis, nor were they needed for the body's response to fever or the stress of being handled, implying their primary role is in the daily rhythm of temperature regulation rather than emergency defense mechanisms.

Beyond internal heat generation, these neurons also drive a specific survival behavior: nest building. When the cells were activated, mice built nests even in warm environments where they would normally ignore nesting material. Conversely, when the cells were silenced, the mice built significantly fewer nests in cool conditions. This points to a dual role for these cells: they not only turn up the internal furnace but also motivate the animal to create a warm shelter. The study traced the connections of these cells and found they send signals to several other brain regions, including areas that control the brown fat tissue responsible for burning energy to generate heat. This network allows the brain to coordinate both the internal production of heat and the external behavior of seeking or building warmth.

The findings clarify how the brain integrates chemical signals to manage body temperature. While many other temperature-sensitive neurons in the preoptic area work to lower body temperature when it gets too high, these histamine-sensing cells are one of the few populations dedicated to raising it. They appear to function as a key component of the daily cycle, ensuring that the body stays warm during the active hours and encouraging the animal to prepare a warm environment. The research suggests that the brain uses these specific cells to maintain a higher baseline temperature during the day, a state that supports activity and vigilance, while also providing the drive to seek comfort when the environment turns cold.

Problem
The preoptic area (POA) of the hypothalamus is a critical hub for regulating body temperature ( $T_b$ ), orchestrating both behavioral (e.g., nest building, huddling) and physiological (e.g., thermogenesis, vasoconstriction) responses. While many POA neuronal populations have been characterized, most decrease $T_b$ upon activation. Only a few populations increase $T_b$ . Histamine signaling is known to regulate $T_b$ across taxa and correlates with wakefulness, yet the specific role of POA neurons expressing the histamine H1 receptor ($Hrh1$) in thermoregulation and energy metabolism remains undefined. Furthermore, the relationship between circadian rhythms, physical activity, and $T_b$ regulation by specific neuronal subpopulations requires further elucidation.

Methodology
The authors generated a Hrh1-Cre knock-in mouse line to target neurons expressing the histamine H1 receptor. They utilized a combination of techniques to investigate the function of POA $^{Hrh1}$ neurons:

Pharmacology: Systemic administration of the H1R antagonist pyrilamine and the H1R agonist 2-Pyridylethylamine (PEA) in wild-type and Hrh1 knockout mice.
Chemogenetics: Expression of hM3Dq (Gq-coupled, activating) and hM4Di (Gi-coupled, inhibitory) DREADDs in POA $^{Hrh1}$ neurons to modulate activity via CNO injection.
Optogenetics: Expression of ChR2 or ChrimsonR in POA $^{Hrh1}$ neurons (and intersectional subsets using Vgat-FlpO and Vglut2-FlpO lines) for precise temporal control of activity.
Physiological Monitoring: Continuous telemetry for core body temperature ( $T_b$ ) and physical activity; indirect calorimetry for total energy expenditure (TEE), respiratory exchange ratio (RER), and food/water intake.
Connectivity Mapping: Anterograde viral tracing (synaptophysin-mCherry) and monosynaptic retrograde rabies tracing to map inputs and outputs.
Functional Imaging: Fiber photometry (GCaMP8s) to measure calcium activity in freely moving mice; two-photon imaging in brain slices to assess neuronal responses to optogenetic stimulation and pharmacological agonists.
Behavioral Assays: Nest building at varying ambient temperatures and thermal place preference tests.
Intervention: Bilateral denervation of interscapular brown adipose tissue (BAT) to test its necessity in POA $^{Hrh1}$ -mediated thermogenesis.

Key Contributions and Results

Activation Increases $T_b$ , Energy Expenditure, and Activity: Acute chemogenetic or optogenetic activation of POA $^{Hrh1}$ neurons robustly increased $T_b$ , TEE, and physical activity in both sexes. The increase in TEE and $T_b$ persisted longer than the increase in physical activity, and calculations indicated that the TEE increase was largely independent of physical activity (only ~24% explained by activity costs). Activation also led to a delayed reduction in food intake and a shift in RER toward fatty acid usage.
Inhibition Modulates Dark Phase $T_b$ : Chemogenetic inhibition of POA $^{Hrh1}$ neurons specifically reduced the $T_b$ increase observed during the dark (active) phase, primarily by lowering the resting $T_b$ (5th percentile). Inhibition had no effect on $T_b$ during the light phase, nor did it affect $T_b$ responses to acute cold (4°C), heat (32°C), fever (LPS or PolyI:C), or handling stress.
Circadian Activity Patterns: Contrary to the hypothesis that these neurons drive the dark phase $T_b$ rise via increased activity, fiber photometry revealed that POA $^{Hrh1}$ neuronal activity was actually lower at the onset of the dark phase compared to the light phase. Furthermore, neuronal activity was inversely correlated with $T_b$ , suggesting these neurons may be more active during periods of low $T_b$ to help maintain homeostasis.
Inhibitory Subpopulation Mediates Thermogenesis: Single-cell RNA sequencing and intersectional optogenetics revealed that POA $^{Hrh1}$ neurons comprise both excitatory (Vglut2) and inhibitory (Vgat) clusters. Only the activation of the inhibitory (Vgat-expressing) subset increased $T_b$ and physical activity; excitatory activation had no effect.
Circuitry and Projections: POA $^{Hrh1}$ neurons receive inputs from various hypothalamic and extra-hypothalamic regions and project broadly to the dorsomedial hypothalamus (DMH), arcuate nucleus (Arc), ventral tuberomammillary nucleus (VTM), and others. Optogenetic stimulation of axon terminals in the DMH, Arc, or VTM individually increased $T_b$ and activity. A potential feedback loop exists between POA $^{Hrh1}$ neurons and histamine-producing VTM neurons.
Mechanism of Thermogenesis: Optogenetic stimulation of POA $^{Hrh1} \to$ DMH neurons increased interscapular BAT temperature. However, bilateral denervation of BAT did not abolish the $T_b$ increase, indicating that POA $^{Hrh1}$ neurons drive thermogenesis through redundant mechanisms (e.g., BAT, shivering, vasomotion).
Prolonged Effects: The elevation in $T_b$ following stimulation outlasted the stimulation period and the duration of neuronal calcium activity, suggesting downstream circuit plasticity or sustained activation of downstream targets rather than persistent firing of POA $^{Hrh1}$ cell bodies.
Behavioral Regulation: POA $^{Hrh1}$ neurons are cold-sensitive (increased Fos expression at 4°C). Chemogenetic inhibition reduced nest building at 22°C, while activation induced nest building even at warm temperatures (33°C). However, these manipulations did not alter thermal place preference.

Significance
The paper establishes POA $^{Hrh1}$ neurons as a distinct population capable of increasing body temperature, a rare function for POA neurons. The study identifies that the thermogenic effect is mediated specifically by the inhibitory (Vgat) subset of these neurons. The findings suggest that POA $^{Hrh1}$ neurons play a role in maintaining body temperature during periods of low activity or low $T_b$ (such as the dark phase resting state) and are critical for cold-induced nest-building behavior. The data also highlight a dissociation between the acute ability to raise $T_b$ and the modest contribution to the circadian $T_b$ rhythm, implying these neurons may serve a protective or homeostatic role rather than being the primary driver of the daily $T_b$ cycle. The identification of a potential VTM-POA feedback loop offers a new perspective on the integration of histaminergic signaling with thermoregulation.

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