Body temperature regulation is a fundamental homeostatic function that is governed by the central nervous system in homeothermic animals, including humans. The central thermoregulatory system also ...functions for host defense from invading pathogens by elevating body core temperature, a response known as fever. Thermoregulation and fever involve a variety of involuntary effector responses, and this review summarizes the current understandings of the central circuitry mechanisms that underlie nonshivering thermogenesis in brown adipose tissue, shivering thermogenesis in skeletal muscles, thermoregulatory cardiac regulation, heat-loss regulation through cutaneous vasomotion, and ACTH release. To defend thermal homeostasis from environmental thermal challenges, feedforward thermosensory information on environmental temperature sensed by skin thermoreceptors ascends through the spinal cord and lateral parabrachial nucleus to the preoptic area (POA). The POA also receives feedback signals from local thermosensitive neurons, as well as pyrogenic signals of prostaglandin E(2) produced in response to infection. These afferent signals are integrated and affect the activity of GABAergic inhibitory projection neurons descending from the POA to the dorsomedial hypothalamus (DMH) or to the rostral medullary raphe region (rMR). Attenuation of the descending inhibition by cooling or pyrogenic signals leads to disinhibition of thermogenic neurons in the DMH and sympathetic and somatic premotor neurons in the rMR, which then drive spinal motor output mechanisms to elicit thermogenesis, tachycardia, and cutaneous vasoconstriction. Warming signals enhance the descending inhibition from the POA to inhibit the motor outputs, resulting in cutaneous vasodilation and inhibited thermogenesis. This central thermoregulatory mechanism also functions for metabolic regulation and stress-induced hyperthermia.
Various environmental stressors, such as extreme temperatures (hot and cold), pathogens, predators and insufficient food, can threaten life. Remarkable progress has recently been made in ...understanding the central circuit mechanisms of physiological responses to such stressors. A hypothalamomedullary neural pathway from the dorsomedial hypothalamus (DMH) to the rostral medullary raphe region (rMR) regulates sympathetic outflows to effector organs for homeostasis. Thermal and infection stress inputs to the preoptic area dynamically alter the DMH → rMR transmission to elicit thermoregulatory, febrile and cardiovascular responses. Psychological stress signalling from a ventromedial prefrontal cortical area to the DMH drives sympathetic and behavioural responses for stress coping, representing a psychosomatic connection from the corticolimbic emotion circuit to the autonomic and somatic motor systems. Under starvation stress, medullary reticular neurons activated by hunger signalling from the hypothalamus suppress thermogenic drive from the rMR for energy saving and prime mastication to promote food intake. This Perspective presents a combined neural network for environmental stress responses, providing insights into the central circuit mechanism for the integrative regulation of systemic organs.
The mechanism by which psychological stress elicits various physiological responses is unknown. We discovered a central master neural pathway in rats that drives autonomic and behavioral stress ...responses by connecting the corticolimbic stress circuits to the hypothalamus. Psychosocial stress signals from emotion-related forebrain regions activated a VGLUT1-positive glutamatergic pathway from the dorsal peduncular cortex and dorsal tenia tecta (DP/DTT), an unexplored prefrontal cortical area, to the dorsomedial hypothalamus (DMH), a hypothalamic autonomic center. Genetic ablation and optogenetics revealed that the DP/DTT→DMH pathway drives thermogenic, hyperthermic, and cardiovascular sympathetic responses to psychosocial stress without contributing to basal homeostasis. This pathway also mediates avoidance behavior from psychosocial stressors. Given the variety of stress responses driven by the DP/DTT→DMH pathway, the DP/DTT can be a potential target for treating psychosomatic disorders.
Body core temperature of mammals is regulated by the central nervous system, in which the preoptic area (POA) of the hypothalamus plays a pivotal role. The POA receives peripheral and central ...thermosensory neural information and provides command signals to effector organs to elicit involuntary thermoregulatory responses, including shivering thermogenesis, nonshivering brown adipose tissue thermogenesis, and cutaneous vasoconstriction. Cool-sensory and warm-sensory signals from cutaneous thermoreceptors, monitoring environmental temperature, are separately transmitted through the spinal-parabrachial-POA neural pathways, distinct from the spinothalamocortical pathway for perception of skin temperature. These cutaneous thermosensory inputs to the POA likely impinge on warm-sensitive POA neurons, which monitor body core (brain) temperature, to alter thermoregulatory command outflows from the POA. The cutaneous thermosensory afferents elicit rapid thermoregulatory responses to environmental thermal challenges before they impact body core temperature. Peripheral humoral signals also act on neurons in the POA to transmit afferent information of systemic infection and energy storage to induce fever and to regulate energy balance, respectively. This chapter describes the thermoregulatory afferent mechanisms that convey cutaneous thermosensory signals to the POA and that integrate the neural and humoral afferent inputs to the POA to provide descending command signals to thermoregulatory effectors.
The treatment of pharyngeal and laryngeal cancers have special characteristics because the pharynx and larynxare closely related to QOL. The major roles of the pharynx and larynx are breathing, ...speaking, and swallowing.These three roles are important for performing daily living activities and are also important for humans. It isrequired to find a balance between cancer treatment and QOL. If a total laryngectomy is performed, you will beunable to speak after the operation. If a total or partial pharyngectomy is performed, dysphagia will occur; youwill be unable to eat well or speak clearly after the operation. After a total laryngectomy, you will be unable tosmell. If the tracheostomy is unable to be closed after a pharyngectomy, the cannula will remain, and QOL willdecrease. If chemoradiation therapy is performed, you will be unable to eat well, you will need PEG, and you willbe unable to smell or taste. The treatment of head and neck cancers are required to improve QOL and a cure isneeded. Therefore, reduction surgery should be considered without degrading the treatment results.
Thermoregulatory behaviour, such as migration to a comfortable thermal environment, is a representative innate animal behaviour and facilitates effective autonomic regulation of body temperature with ...a reduced cost of resources. Here we determine the central thermosensory ascending pathway that transmits information on environmental temperature from cutaneous thermoreceptors to elicit thermoregulatory behaviour. To examine the contribution of the spinothalamocortical pathway, which is known to mediate thermosensory transmission for perception of skin temperature, we lesioned thalamic regions mediating this pathway in rats. Thalamic-lesioned rats showed compromised electroencephalographic responses in the primary somatosensory cortex to changes in skin temperature, indicating functional ablation of the spinothalamocortical pathway. However, these lesioned rats subjected to a two-floor innocuous thermal plate preference test displayed intact heat- and cold-avoidance thermoregulatory behaviours. We then examined the involvement of the lateral parabrachial nucleus (LPB), which mediates cutaneous thermosensory signaling to the thermoregulatory center for autonomic thermoregulation. Inactivation of neurons in the LPB eliminated both heat- and cold-avoidance thermoregulatory behaviours and ablated heat defense. These results demonstrate that the LPB, but not the thalamus, mediates the cutaneous thermosensory neural signaling required for behavioural thermoregulation, contributing to understanding of the central circuit that generates thermal comfort and discomfort underlying thermoregulatory behaviours.
Energy homeostasis of mammals is maintained by balancing energy expenditure within the body and energy intake through feeding. Several lines of evidence indicate that brown adipose tissue (BAT), a ...sympathetically activated thermogenic organ, turns excess energy into heat to maintain the energy balance in rodents and humans, in addition to its thermoregulatory role for the defense of body core temperature in cold environments. Elucidating the central circuit mechanism controlling BAT thermogenesis dependent on nutritional conditions and food availability in relation to energy homeostasis is essential to understand the etiology of symptoms caused by energy imbalance, such as obesity. The central thermogenic command outflow to BAT descends through an excitatory neural pathway mediated by hypothalamic, medullary and spinal sites. This sympathoexcitatory thermogenic drive is controlled by tonic GABAergic inhibitory signaling from the thermoregulatory center in the preoptic area, whose tone is altered by body core and cutaneous thermosensory inputs. This circuit controlling BAT thermogenesis for cold defense also functions for the development of fever and psychological stress-induced hyperthermia, indicating its important role in the defense from a variety of environmental stressors. When food is unavailable, hunger-driven neural signaling from the hypothalamus activates GABAergic neurons in the medullary reticular formation, which then block the sympathoexcitatory thermogenic outflow to BAT to reduce energy expenditure and simultaneously command the masticatory motor system to promote food intake—effectively commanding responses to survive starvation. This article reviews the central mechanism controlling BAT thermogenesis in relation to the regulation of energy and thermal homeostasis dependent on food availability.
Non‐technical summary Shivering is an involuntary somatic motor response that occurs in skeletal muscles to produce heat during exposure to cold environments or during the development of fever. This ...study describes the brain circuitry mechanism that produces shivering. The reception of either cutaneous cool‐sensory signals or pyrogenic signals by neurons in the preoptic area, a thermoregulatory and febrile centre, leads to activation of descending excitatory signalling through hypothalamic and medullary sites to drive shivering. Intriguingly, this central command pathway for shivering parallels that for sympathetically regulated non‐shivering thermogenesis in brown adipose tissue. The present results promote our understanding of the brain mechanisms for thermal homeostasis that orchestrate the regulation of the somatic and autonomic motor systems to meet the critical demand for regulation of the body and brain temperatures.
Shivering is a remarkable somatomotor thermogenic response that is controlled by brain mechanisms. We recorded EMGs in anaesthetized rats to elucidate the central neural circuitry for shivering and identified several brain regions whose thermoregulatory neurons comprise the efferent pathway driving shivering responses to skin cooling and pyrogenic stimulation. We simultaneously monitored parameters from sympathetic effectors: brown adipose tissue (BAT) temperature for non‐shivering thermogenesis and arterial pressure and heart rate for cardiovascular responses. Acute skin cooling consistently increased EMG, BAT temperature and heart rate and these responses were eliminated by inhibition of neurons in the median preoptic nucleus (MnPO) with nanoinjection of muscimol. Stimulation of the MnPO evoked shivering, BAT thermogenesis and tachycardia, which were all reversed by antagonizing GABAA receptors in the medial preoptic area (MPO). Inhibition of neurons in the dorsomedial hypothalamus (DMH) or rostral raphe pallidus nucleus (rRPa) with muscimol or activation of 5‐HT1A receptors in the rRPa with 8‐OH‐DPAT eliminated the shivering, BAT thermogenic, tachycardic and pressor responses evoked by skin cooling or by nanoinjection of prostaglandin (PG) E2, a pyrogenic mediator, into the MPO. These data are summarized with a schematic model in which the shivering as well as the sympathetic responses for cold defence and fever are driven by descending excitatory signalling through the DMH and the rRPa, which is under a tonic inhibitory control from a local circuit in the preoptic area. These results provide the interesting notion that, under the demand for increasing levels of heat production, parallel central efferent pathways control the somatic and sympathetic motor systems to drive thermogenesis.
The recent discovery of the medullary circuit driving “hunger responses” – reduced thermogenesis and promoted feeding – has greatly expanded our knowledge on the central neural networks for energy ...homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of neurons in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin‐mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding.
Energy homeostasis is maintained by the central neural circuits that consist of the hypothalamic circuits evaluating nutritional status and the medullary motor circuits controlling energy expenditure and intake. Here, two key pathways that transmit hypothalamic hunger and satiety signals to the medullary motor systems to drive appropriate responses for energy homeostasis are proposed.
c-Jun N-terminal kinases (JNKs), also referred to as stress-activated kinases (SAPKs), were initially characterized by their activation in response to cell stress such as UV irradiation. JNK/SAPKs ...have since been characterized to be involved in proliferation, apoptosis, motility, metabolism and DNA repair. Dysregulated JNK signaling is now believed to contribute to many diseases involving neurodegeneration, chronic inflammation, birth defects, cancer and ischemia/reperfusion injury. In this review, we present our current understanding of JNK regulation and their involvement in homeostasis and dysregulation in human disease.
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