Central control of body temperature

Abstract

Central neural circuits orchestrate the behavioral and autonomic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response and behavioral states and in response to declining energy homeostasis. This review summarizes the central nervous system circuit mechanisms controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for thermogenesis. The activation of these thermoeffectors is regulated by parallel but distinct efferent pathways within the central nervous system that share a common peripheral thermal sensory input. The model for the neural circuit mechanism underlying central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation, for elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation, and for the discovery of novel therapeutic approaches to modulating body temperature and energy homeostasis.

Keywords: Brown adipose tissue; cutaneous vasoconstriction; dorsomedial hypothalamus; fever; obesity; preoptic hypothalamus; rostral raphe pallidus; shiver; sympathetic nerve activity; therapeutic hypothermia; thermogenesis.

Figure 1.. Functional neuroanatomical model for the fundamental pathways providing the thermoregulatory control and pyrogenic activation of cutaneous vasoconstriction (CVC) and brown adipose tissue (BAT) and shivering thermogenesis.

Cool and warm cutaneous thermoreceptors transmit signals to respective primary sensory neurons in the dorsal root ganglia (DRG) which relay this information to second-order thermal sensory neurons in the dorsal horn (DH). Cool sensory DH neurons glutamatergically activate third-order sensory neurons in the external lateral subnucleus of the lateral parabrachial nucleus (LPB), while warm sensory DH neurons project to third-order sensory neurons in the dorsal subnucleus of the LPB. Thermosensory signals driving thermoregulatory responses are transmitted from the LPB to the preoptic area (POA), which contains the microcircuitry through which cutaneous and core thermal signals are integrated to regulate the balance of POA outputs that are excitatory (dashed green) and inhibitory (dashed red) to thermogenesis-promoting neurons in the dorsomedial hypothalamus (DMH) and to CVC sympathetic premotor neurons in the rostral raphe pallidus (rRPa). Within the POA, GABAergic interneurons (red) in the median preoptic (MnPO) subnucleus are postulated to receive a glutamatergic input from skin cooling-activated neurons in LPB and inhibit each of the distinct populations of warm-sensitive (W-S) neurons in the medial preoptic area (MPA) that control CVC, BAT, and shivering. In contrast, glutamatergic interneurons (dark green) in the MnPO are postulated to be excited by glutamatergic inputs from skin warming-activated neurons in LPB and, in turn, excite the populations of W-S neurons in MPA. Prostaglandin E ₂ (PGE ₂) binds to EP3 receptors, which are postulated to inhibit the activity of each of the classes of W-S neurons in the POA. Preoptic W-S neurons may provide inhibitory control of CVC by inhibiting CVC sympathetic premotor neurons in the rostral ventromedial medulla, including the rRPa, that project to CVC sympathetic preganglionic neurons (SPNs) in the intermediolateral nucleus (IML). Preoptic W-S neurons may provide inhibitory thermoregulatory control of BAT and shivering thermogenesis by inhibiting BAT sympathoexcitatory neurons and shivering-promoting neurons, respectively, in the DMH, which, when disinhibited during skin and core cooling, provide respective excitatory drives to BAT sympathetic premotor neurons and to skeletal muscle shivering premotor neurons in the rRPa. These, in turn, project, respectively, to BAT SPNs in the IML and to alpha (α) and gamma (γ) motoneurons in the ventral horn (VH) of the spinal cord.