Kazuhiro Nakamura

This study found that age-associated sleep changes are ameliorated by DR in the presence of Prdm13 signaling in the DMH, suggesting Prdm13+ DMH neurons will be of great interest to explore a potential intervention on age-associated sleep changes.

Seeking warmth during infection is a sickness behaviour that contributes to the development of fever and is often accompanied by chills. However, the central mechanism underlying this behaviour remains unknown. We recently reported two ascending thermosensory neuronal pathways from the lateral parabrachial nucleus (LPB) of the pons that drive thermoregulatory behaviours in hot and cold environments: one pathway to the preoptic area (POA), a thermoregulatory centre, mediates heat avoidance, whereas the other to the central amygdaloid nucleus (CeA), a limbic emotion centre, mediates cold avoidance. Here we investigated the role of prostaglandin E ₂ (PGE ₂ ), a pyrogenic mediator produced during infection, in the LPB‐mediated mechanism of thermoregulatory behaviour in rats. Thermal preference tests and in vivo physiological recordings revealed that PGE ₂ acting on the prostaglandin EP3 receptor (EP3R) in the LPB elicits behaviour that prefers warmth to a thermoneutral temperature, thereby contributing to an increase in body core temperature. However, it does not elicit brown adipose tissue thermogenesis, an autonomic febrile response. Notably, we discovered that EP3R‐expressing LPB neurons (LPB ^EP3R neurons) project numerous axons to the CeA, but few to the POA. Functional neuronal tracing combined with immunostaining of Fos, a marker for neuronal activation, revealed that LPB ^EP3R →CeA neurons are activated by cold ambient temperature and constitute the majority of the cold‐transmitting LPB→CeA neuronal population mediating cold avoidance. These results indicate that PGE ₂ action on LPB ^EP3R neurons during infection elicits warmth‐seeking behaviour by augmenting their cold sensory transmission to the CeA, which potentially produces the unpleasant cold sensation of chills. image Key points: Seeking warmth during infection is a commonly observed sickness behaviour that contributes to the development of fever, often accompanied by chills. Prostaglandin E ₂ (PGE ₂ ), a pyrogenic mediator, elicits warmth‐seeking behaviour in rats by acting on prostaglandin EP3 receptor (EP3R)‐expressing neurons in the lateral parabrachial nucleus (LPB) of the pons (LPB ^EP3R neurons). This PGE ₂ action does not elicit thermogenesis in brown adipose tissue, an autonomic febrile response. LPB ^EP3R neurons transmit cutaneous cold sensory signals to the limbic emotion centre, central amygdaloid nucleus (CeA), but scarcely innervate the thermoregulatory centre, preoptic area. These results indicate that PGE ₂ acting on LPB ^EP3R neurons during infection elicits warmth‐seeking behaviour by augmenting cold sensory transmission to the CeA, which is a potential mechanism of chills.

BACKGROUND: The internal milieu of the body is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood. METHODS: Guided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signaling pathways involved in arterial chemosensory function. RESULTS: Here, we report the presence of the MC4R (melanocortin 4 receptor) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 (mammalian achaete-scute homolog 1; Ascl1 ) regulatory network in driving elevated Mc4r expression. CONCLUSIONS: Collectively, our data indicate a primarily pathophysiological role of melanocortin signaling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease.

The melanocortin system centrally regulates energy homeostasis, with key components such as melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3) in neuronal primary cilia. Mutations in MC4R and ADCY3 as well as ciliary dysfunction lead to obesity, but how melanocortin signaling works in cilia remains unclear. Using mouse random germline mutagenesis, we identified two missense mutations in G protein–coupled receptor 45 (Gpr45) that lead to obesity through hyperphagia. GPR45 was expressed in paraventricular nucleus of the hypothalamus (PVH), where it localized to cilia and recruited Gα _s to increase ciliary cyclic adenosine monophosphate (cAMP) via ADCY3. GPR45 colocalized with MC4R in PVH cilia and promoted ciliary MC4R activation. Loss of GPR45 in the PVH or MC4R ⁺ neurons caused obesity. These findings establish GPR45 as a key regulator of the ciliary melanocortin system, bridging MC4R and ADCY3.

Thermoregulation is a fundamental homeostatic function in mammals mediated by the central nervous system. The framework of the central circuitry for thermoregulation lies in the hypothalamus and brainstem. The preoptic area (POA) of the hypothalamus integrates cutaneous and central thermosensory information into efferent control signals that regulate excitatory descending pathways through the dorsomedial hypothalamus (DMH) and rostral medullary raphe region (rMR). The cutaneous thermosensory feedforward signals are delivered to the POA by afferent pathways through the lateral parabrachial nucleus, while the central monitoring of body core temperature is primarily mediated by warm-sensitive neurons in the POA for negative feedback regulation. Prostaglandin E₂, a pyrogenic mediator produced in response to infection, acts on the POA to trigger fever. Recent studies have revealed that this circuitry also functions for physiological responses to psychological stress and starvation. Master psychological stress signaling from the medial prefrontal cortex to the DMH has been discovered to drive a variety of physiological responses for stress coping, including hyperthermia. During starvation, hunger signaling from the hypothalamus was found to activate medullary reticular neurons, which then suppress thermogenic sympathetic outflows from the rMR for energy saving. This thermoregulatory circuit represents a fundamental mechanism of the central regulation for homeostasis.

Background: The body’s internal milieu is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood. Methods: Guided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signalling pathways involved in arterial chemosensory function. Results: Here, we report the presence of the Melanocortin 4 receptor (MC4R) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence both resting and chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 ( Ascl1 ) regulatory network in driving elevated Mc4r expression. Conclusions: Collectively, our data indicate a primarily pathophysiological role of melanocortin signalling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease.