Central neural pathways for thermoregulation

Abstract

Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction.

Figure 1

Block diagram of the functional components of a model for the central neural circuit providing cutaneous thermal afferent and thermally-sensitive neuronal control of thermoregulatory effectors. Thermal sensory signals are conveyed via separate pathways to sites involved in conscious perception and localization of thermal sensation and in the integration of thermal sensory information with other sensory inputs that influence thermoregulatory responses. Thermoregulatory sensory-motor integration: integrated cutaneous and visceral thermal sensory signals influence the discharge of effector-specific populations of hypothalamic, thermally-sensitive neurons with projections to motor regions controlling thermal effectors. Thermal effector motor integration: thermally-modulated inputs are integrated with non-thermal signals that contribute to the regulation of the activity of neurons that provide an excitatory drive to the premotor neurons controlling thermal effectors. Thermal effector premotor neurons: supraspinal neurons with descending inputs to spinal motor networks controlling thermal effectors.

Figure 2

Functional neuroanatomical and neurotransmitter model for the fundamental pathways providing the thermoregulatory control and pyrogenic activation of CVC, BAT and shivering thermogenesis. Cool and warm cutaneous thermal sensory receptors 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 (LPBel), while warm sensory DH neurons project to third-order sensory neurons in the dorsal subnucleus of the lateral parabrachial nucleus (LPBd). Thermosensory signals from DH neurons are also relayed to the thalamus and then to the cortex for conscious thermal perception and localization. Thermosensory signals for thermoregulatory responses are transmitted from the LPB to the preoptic area (POA) where GABAergic interneurons in the median preoptic (MnPO) subnucleus are activated by glutamatergic inputs from cool-activated neurons in LPBel and inhibit the distinct populations of warm-sensitive (W-S) neurons in the medial preoptic (MPO) subnucleus that control cutaneous vasoconstriction (CVC), brown adipose tissue (BAT) and shivering. In contrast, glutamatergic interneurons in the MnPO, postulated to be excited by glutamatergic inputs from warm-activated neurons in LPBd, excite W-S neurons in MPO. Prostaglandin (PG) E₂ binds to EP3 receptors on W-S neurons in the POA to inhibit their activity. Preoptic W-S neurons provide thermoregulatory control of CVC by inhibiting CVC sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe pallidus (rRPa), that project to CVC sympathetic preganglionic neurons in the intermediolateral nucleus (IML). CVC premotor neurons can increase CVC sympathetic tone by release of glutamate and/or serotonin (5-HT) within the IML. Preoptic W-S neurons providing thermoregulatory control of BAT thermogenesis inhibit BAT sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) which, when disinhibited during skin cooling, excite BAT sympathetic premotor neurons in the rRPa that project to BAT sympathetic preganglionic neurons in the IML. Some BAT premotor neurons, containing vesicular glutamate transporter 3 (VGLUT3), can release glutamate to excite BAT sympathetic preganglionic neurons and increase BAT sympathetic nerve activity by release of glutamate, while others can release 5-HT to interact with 5-HT1A receptors, potentially on inhibitory interneurons in the IML, to increase the BAT sympathetic outflow and thermogenesis. Preoptic W-S neurons provide thermoregulatory control of shivering responses by inhibiting shivering-promoting neurons in the DMH which are postulated to provide excitation to medial medullary shivering premotoneurons in the rRPa, that project to the ventral horn to excite alpha and gamma motoneurons during shivering in skeletal muscles.

Figure 3

Changes in BAT sympathetic nerve activity (BAT SNA, red traces), BAT temperature (T_BAT), expired (Exp.) CO₂, heart rate (HR), arterial pressure (AP), rectal temperature (T_rec) and brain temperature (T_brain) in response to cooling the rat trunk skin (T_skin, blue trace). The vertical scale bar for the BAT SNA trace represents 100 microvolts. Note that T_rec and T_brain do not change substantially during the skin cooling and rewarming, indicating that the observed changes in BAT SNA, T_BAT, Exp. CO₂, HR and AP were evoked by changes in skin temperature rather than by changes in body core or in brain temperatures. Reproduced with permission from (1).

Figure 4

POA-projecting LPB neurons are activated in a cold environment. (A–F) Fos expression in LPB neurons retrogradely labeled with the retrograde tracer, cholera toxin b-subunit (CTb), injected into the POA in rats exposed to 24°C (A, C, E) and 4°C (B, D, F). A and B show injection sites of CTb (red). In C–F, CTb (brown) and Fos (blue-black) immunoreactivities in the LPBel of the animals shown in A and B are visualized. In E and F, arrowheads indicate Fos-negative, CTb-labeled neurons and arrows indicate Fos-positive, CTb-labeled neurons. 3V, third ventricle; ac, anterior commissure; IC, inferior colliculus; LPBc, central part of the lateral parabrachial nucleus; MPO, medial preoptic area; ox, optic chiasm; scp, superior cerebellar peduncle. Reproduced with permission from (27).

Figure 5

Skin cooling-evoked response of a single LPB neuron antidromically activated from the POA. A, in vivo extracellular unit recording of the action potentials of an LPB neuron (unit, green traces) and changes in BAT SNA (red traces) in response to trunk skin cooling (T_skin, blue trace). The vertical scale bars for the unit and BAT SNA traces represent 300 microvolts and 100 microvolts, respectively. The unit firing rate increased in response to skin cooling and returned to the baseline level in response to rewarming the skin. The changes in firing rate of this neuron paralleled the changes in BAT SNA. A collision test confirmed that this neuron projected to the POA. B, juxtacellular labeling located this neuron in the LPBel (arrow and magnified in inset). Reproduced with permission from (27).

Figure 6

Inhibition of neuronal activity or blockade of ionotropic glutamate receptors in the LPBel reverses shivering and non-shivering thermogenesis and metabolic and cardiac responses that are evoked by skin cooling. A, skin cooling-evoked changes in BAT SNA, T_BAT, Exp. CO₂ and HR before and after bilateral nanoinjections (green dashed lines) of the GABA_A receptor agonist, muscimol, into the LPBel. The vertical scale bar for the BAT SNA trace represents 100 microvolts. B, skin cooling-evoked changes in nuchal EMG before and after bilateral nanoinjections (green dashed lines) of a mixture of the glutamate receptor antagonists, AP5 and CNQX, into the LPBel. The vertical scale bar for the EMG trace represents 400 microvolts. C, representative view of a nanoinjection site in the LPBel as identified with a cluster of fluorescent beads (arrow). Reproduced with permission from (27).

Figure 7

Glutamatergic stimulation of MnPO neurons, but not MPO or LPO neurons, evokes thermogenic, metabolic and cardiac responses and inhibition of MnPO neurons blocks thermogenic, metabolic and cardiac responses to skin cooling. A, changes in physiological variables evoked by a nanoinjection (green dashed line) of NMDA into the MnPO. The vertical scale bars for the BAT SNA trace represent 50 microvolts. B, representative injection site in the MnPO, identified by a cluster of fluorescent beads (arrow). C, composite drawing of saline or NMDA injections sites in the subregions of the POA, with their stimulatory effects on BAT SNA. No saline injections increased BAT SNA by more than 50 percent of the basal area under the curve (AUC) of the power trace during the 3 minute period after the injection. D, changes in BAT SNA, T_BAT, Exp. CO₂ and HR evoked by repeated skin cooling (T_skin, blue trace). Saline or glycine, an inhibitory neurotransmitter, was nanoinjected into the MnPO at the broken lines. The vertical scale bar for the BAT SNA trace represents 400 microvolts. Reproduced with permission from (37).

Figure 8

Pyrogenic role of prostaglandin EP3 receptors in the preoptic area. A, within the rat POA, prostaglandin EP3 receptor immunoreactivity is distributed in the somatodendritic part of MnPO and MPO neurons (inset, arrowheads) (modified from (71), with permission). B, loss of PGE₂-induced (top) or lipopolysaccharide (LPS)-induced (bottom) febrile response selectively in EP3^-/- mice. Top graph shows changes in body temperatures of EP1^-/- (filled squares), EP2^-/- (open squares), EP3^-/- (filled circles) and EP4^-/- (filled triangles) mice following icv PGE₂ injection. Vehicle was injected icv into EP3^-/- mice (open circles). Asterisk indicates P less than 0.01 for EP3^-/- mice versus wild-type mice injected with PGE₂. Bottom graph shows changes in body temperatures of wild-type (open circles), EP1^-/- (filled circles) and EP3^-/- (filled triangles) mice following iv LPS injection. Vehicle was injected iv into wild-type mice (open triangles). Asterisk indicates P less than 0.01 for EP3^-/- mice versus wild-type mice injected with LPS. Reproduced with permission from (74). C, EP3 receptor-expressing POA neurons directly project to the rRPa. Top panel shows a site of injection of Fluoro-Gold, a retrograde neural tracer, that was centered at the caudal one-third of the rRPa (arrow) and spread into the surrounding raphe magnus nucleus (RMg) (red area); bottom, fluorescence photomicrograph shows POA neuronal cell bodies (arrows) double-labeled with Fluoro-Gold fluorescence (yellow) and EP3 receptor immunoreactivity (red). Reproduced with permission from (63). D, EP3 receptor-expressing POA neurons directly project to the DMH. Top, a CTb injection site (arrow) in the DMH; bottom, fluorescence photomicrograph of POA neuronal cell bodies (arrows) double-labeled with EP3 receptor (red) and CTb (green) immunoreactivities. DH, dorsal hypothalamic area; LH, lateral hypothalamic area; VMH, ventromedial hypothalamic nucleus. Reproduced with permission from (77).

Figure 9

Rostral medullary raphe neurons play a major excitatory role in determining cutaneous vasoconstrictor (CVC) sympathetic outflow and cutaneous blood flow. Inhibition of raphe pallidus neurons with microinjection of muscimol (Musc) or GABA prevents the cold-evoked decrease in rabbit ear pinna blood flow (A, reproduced with permission from (119)) and the cold-evoked increase in rat tail CVC activity (B, reproduced with permission from (117)) and increases rabbit ear pinna blood flow from spontaneous levels at room temperature (C, modified from (118), with permission). Increases in raphe pallidus neuronal activity following microinjection of bicuculline (Bic) prevents the increase in rat tail temperature evoked by hypothalamic warming (D, reproduced with permission from (115)) and decreases rat tail blood flow from spontaneous levels at room temperature (E, Reproduced with permission from (116)).

Figure 10

Warm-sensitive preoptic area (POA) projection neurons provide an inhibitory influence on cutaneous vasoconstrictor (CVC) outflow and neurons in dorsomedial hypothalamus (DMH) are not required for PGE₂-evoked CVC activation. A, transection of the neuraxis caudal to the POA produces an increase in rat tail CVC activity. Reproduced with permission from (93). B, POA warming inhibits rat tail sympathetic nerve activity (TSNA) controlling tail CVC. Reproduced with permission from (205). C, inhibition of neurons in the DMH with microinjections of muscimol (Musc) does not affect the activation of rat tail CVC neurons evoked by microinjection of PGE₂ into the POA, but inhibition of putative CVC sympathetic premotor neurons in the raphe pallidus (rRPa) reverses the febrile-like activation of CVC activity. Reproduced with permission from (93).

Figure 11

A, both NMDA and kainic acid (KA) are highly effective at increasing BAT SNA, BAT temperature, expired (exp.) CO₂ and heart rate (HR) when nanoinjected into the raphe pallidus (RPa). Reproduced with permission from (92). B, disinhibition of local neurons in the RPa elicits large and sustained increases in BAT SNA, BAT temperature, expired CO₂ and HR. Reproduced with permission from (92). C, inhibition of the activity of neurons in the RPa with a local injection of muscimol (MUSC) reverses the increases in BAT SNA, BAT temperature, expired CO₂ and HR evoked by PGE₂ icv. Reproduced with permission from (146). D, histological coronal section through the rat brainstem approximately 12.3 mm caudal to bregma, illustrating a typical nanoinjection site (arrowhead) in the RPa. Reproduced with permission from (146).

Figure 12

Role of dorsomedial hypothalamic neurons in BAT and HR thermoregulatory responses. A, in the conscious rat, disinhibition of neurons in the dorsomedial hypothalamus (DMH) with local injection of bicuculline (BMI) elicits increases in body temperature, heart rate and ACTH secretion. Reproduced with permission from (83). B, confocal image demonstrates immunohistochemically that axon terminals of POA GABAergic neurons double-labeled (yellow) with VGAT-immunoreactivity (red) and EGFP (green, following anterograde transport of Sindbis virus) make close appositions with DMH neurons that project directly to the rRPa (labeled with CTb immunoreactivity (blue)). Reproduced with permission from (77). C, blockade of glutamate receptors in the DMH with a nanoinjection of the glutamate receptor antagonist, kynurenic acid (KYN), reverses the increases in BAT SNA, in BAT temperature (thermogenesis), in expired CO₂ and in heart rate elicited by nanoinjection of the febrile mediator, PGE₂, into the medial preoptic area (MPA). Reproduced with permission from (94). D, inhibition of neuronal activity in the DMH with nanoinjections of muscimol eliminates the increases in BAT SNA, in BAT temperature, in expired CO₂ and in heart rate elicited by nanoinjection of PGE₂ into the POA. Reproduced with permission from (77). E, schematic map of the medial hypothalamus illustrating the concentrated localization within the DMH of sites at which injections of muscimol were efficacious in inhibiting PGE₂-evoked increases in BAT SNA. Reproduced with permission from (77).

Figure 13

Spinal glutamatergic and serotonergic regulation of thermoregulatory effectors. A, blockade of thoracic spinal glutamate receptors significantly reduced the increase in BAT temperature elicited by disinhibition of neurons in the rRPa. Reproduced with permission from (89). B, confocal image demonstrates immunohistochemically that axon terminals of rRPa neurons double-labeled (yellow) with VGLUT3-immunoreactivity (red) and EGFP (green, following anterograde transport of Sindbis virus) make close appositions with sympathetic preganglionic neurons (labeled with ChAT immunoreactivity (blue)). Reproduced with permission from (89). C, upper panel, the increase in brown adipose tissue (BAT) sympathetic nerve activity (SNA) following nanoinjection of NMDA into the IML of the T4 spinal segment is potentiated by similar nanoinjection of serotonin (5-HT) into the T4 IML, which also causes a delayed increase in BAT SNA. C, lower panel, 5-HT-induced potentiation of spinal NMDA-evoked increase in BAT SNA is reversed by nanoinjection of the 5-HT receptor antagonist, methysergide, into the T4 IML. Reproduced with permission from (181). D, nanoinjection of the 5-HT _1A/7 receptor agonist, 8-OH-DPAT, into the IML of the T4 spinal segment potentiates the increase in BAT SNA elicited by NMDA injection into the T4 IML and this potentiation is markedly reduced, but not completely reversed by T4 IML nanoinjection of the selective 5-HT_1A receptor antagonist, WAY 100635. Reproduced with permission from (183). E, increases in rabbit ear pinna cutaneous sympathetic nerve discharge elicited by electrical stimulation of the rRPa were markedly reduced by superfusion of the upper thoracic spinal cord with the 5-HT_2A receptor antagonist, SR 46349B, and completely reversed by further superfusion of the thoracic spinal cord with the non-selective glutamate antagonist, kynurenic acid. Reproduced with permission from (120).