Central efferent pathways for cold‐defensive and febrile shivering

Abstract

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 GABA(A) 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.

Central circuitries for body temperature regulation and fever

“…Briefly cooling the skin of anesthetized rats elicits increases in sympathetic thermogenesis in BAT, shivering thermogenesis in skeletal muscles, and metabolism (measured with expired CO 2 ) without substantially affecting body core or brain temperature (Fig. 3A) (106,107). In addition to the thermogenic and metabolic responses, skin cooling also increases heart rate ( Fig.…”

“…Because similar stimulations in other POA subregions do not elicit such responses (108), and LPBel neurons activated in response to skin cooling predominantly project to the MnPO among POA subregions (105), the MnPO appears to be a major POA site that receives cutaneous cool-sensory inputs from the LPBel. Furthermore, inhibition of MnPO neurons blocks BAT thermogenic, shivering, metabolic, and tachycardic responses evoked by skin cooling (106,108) (Fig. 4, A and B).…”

“…From extensive injection mapping with PGE 1 throughout subcortical brain sites, the POA was identified as the sole region in which the E-series of PGs (PGEs) can act to produce fever (158,183). Fever evoked by injection of PGEs into the POA is associated with involuntary somatic and sympathetic effector responses, such as shivering, BAT thermogenesis, and cutaneous vasoconstriction (3,106,171). PGE 1 injection into the POA also induces warm-seeking behavior (30), which is a voluntary behavior during fever that facilitates elevation of body temperature through selection of a warmer environment.…”

Non-adrenergic control of lipolysis and thermogenesis in adipose tissues

“…However, the physiological range of circulating catecholamine levels are insufficient to activate brown fat metabolism (Girardier and Seydoux, 1986). In response to cold exposure, a wellcharacterized somatosensory reflex relayed in the hypothalamic preoptical area translates cold sensation in the periphery to increased efferent sympathetic drive in BAT and WAT depots (Nakamura and Morrison, 2011). In contrast, fasting decreases sympathetic drive in BAT while increasing sympathetic drive in WAT (Brito et al, 2008).…”

Survey and critical appraisal of pharmacological agents with potential thermo-modulatory properties in the context of artificially induced hypometabolism

“…Readers interested in the neuroanatomical networks that govern mammalian thermoregulation via the POAH are referred to a panel of excellent papers by Morrison and Nakamura on this subject [10][11][12][13].…”