Kazuhiro Nakamura(1) and Shaun F. Morrison(2)

1: Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto, Japan
2: Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA

https://doi.org/10.36866/pn.85.21

Appropriate regulation of body temperature is essential to our life. To survive in cold environments, mammals, including humans, must compensate for lost body heat by activating heat production (thermogenesis) mechanisms within the body. Also to combat infection, heat production is increased to develop fever. Such cold-defense and febrile responses involve two modes of thermogenesis: shivering thermogenesis and non-shivering (metabolic) thermogenesis. Shivering thermogenesis is driven by the somatomotor system and occurs in skeletal muscles. Non-shivering thermogenesis is driven by the sympathetic nervous system and occurs primarily in brown adipose tissue. The somatic and sympathetic motor systems mediating these thermogenic responses are governed by the central nervous system.

The thermoregulatory centre in the brain is located in the preoptic area, the most rostral structure in the hypothalamus. The preoptic area receives information on environmental temperature from cutaneous cool and warm receptors (Nakamura & Morrison, 2008a, 2010) and provides command signals to peripheral effectors to drive thermoregulatory responses (Nagashima et al. 2000; Romanovsky, 2007; Morrison et al. 2008). We have previously reported the descending neural pathway from the preoptic area that drives non-shivering thermogenesis in brown adipose tissue (Nakamura & Morrison, 2007, 2008b). In contrast, the mechanism through which central commands for shivering are transmitted from the preoptic area to skeletal muscle has been uncertain, despite the fact that shivering is a well-noticed cold-defensive response.

In our recent study reported in The Journal of Physiology, we simultaneously recorded electro myogram to measure shivering as well as brown adipose tissue temperature to measure non-shivering thermogenesis in anaesthetized rats (Nakamura & Morrison, 2011). This experiment was to examine whether the brain sites that mediate non-shivering thermo genesis are also involved in shivering. At first, this possibility seemed unlikely, because these two thermo genic responses are mediated by the different motor systems that, under normal circumstances, are controlled independently. However, unexpectedly, nanoinjections of drugs into the brain regions that have been known to mediate brown adipose tissue thermogenesis (Nakamura & Morrison, 2007) exerted parallel effects on both thermo genic responses (Nakamura & Morrison, 2011).

Briefly cooling the trunk skin of the rats consistently evoked both shivering in nuchal (neck) muscles and non-shivering thermogenesis in brown adipose tissue (Nakamura & Morrison, 2011). Inhibition of neurons with nanoinjections of muscimol into the median preoptic nucleus, which is a preoptic subregion that receives thermosensory signals from skin thermoreceptors (Nakamura & Morrison, 2008a, 2010), eliminated both shivering and non-shivering thermogenesis evoked by skin cooling (Fig. 1A) (Nakamura & Morrison, 2011). Furthermore, stimulation of neurons in the same preoptic subregion elicited shivering and non-shivering thermogenesis, mimicking skin cooling (Nakamura & Morrison, 2011). These results indicate that an input of cutaneous cool-sensory signals into the preoptic area is a required cue to elicit shivering and non-shivering thermogenesis for cold defense.

Mimicking fever by application of prosta glandin (PG) E2, a pyrogenic mediator, into the preoptic area also elicits both shivering and non-shivering thermogenesis. Both thermogenic responses evoked either by skin cooling or PGE2 injection were eliminated by inhibition of neurons in the dorsomedial hypothalamus or in the rostral medullary raphe pallidus nucleus (Fig. 1B and C) (Nakamura & Morrison, 2011). Therefore, we concluded that neurons in these brain regions integrate descending command signals from the preoptic area leading to shivering and non-shivering thermogenesis. However, because skin temperature thresholds to elicit these thermogenic responses during cooling were different, separate populations of neurons in these brain regions appear to mediate these responses.

Activation of 5-HT1A receptors in the rostral raphe pallidus nucleus with local nanoinjection of an agonist also eliminated the shivering and non-shivering thermogenesis evoked by skin cooling or PGE2 injection (Nakamura & Morrison, 2011). Although the source of the serotonin that might normally activate these 5-HT1A receptors is unknown, it is clear that ligands binding to 5-HT1A receptors, potentially located on somatic and sympathetic premotor neurons (Helke et al. 1997), in this rostral medullary raphe region, can exert a potent inhibitory effect on cold-defensive thermogenic responses, which probably contributes to the hypothermic effects of anti-depressant drugs that bind to 5-HT1A receptors.

Based on these and earlier findings, we propose a model of the neural pathways for the regulation of shivering and non-shivering thermogenesis. Under warm environments (Fig. 2, left), warm-sensory signals from the skin ascend to the preoptic area and activate inhibitory projection neurons in the medial preoptic area, which tonically inhibit thermogenic signalling outflows. Under cool (or cold) environments (Fig. 2, right), cutaneous cool-sensory signals activate local inhibitory neurons in the median preoptic nucleus, which then reduce the activity of the inhibitory projection neurons in the medial preoptic area. In the case of infection, PGE2, which is produced in response to inflammatory cytokine signals, also inhibits the projection neurons in the medial preoptic area through the EP3 receptor. The cooling- or PGE2-mediated inhibition of these projection neurons leads to disinhibition of neurons in the dorsomedial hypothalamus, which, in turn, activate somatic and sympathetic premotor neurons in the rostral medullary raphe. The activated premotor neurons finally excite spinal somatic and sympathetic motor outputs, driving shivering and non-shivering thermogenesis, respectively.

Our findings establish the interesting concept of parallel central outflow pathways from the thermoregulatory centre that drive thermogenesis mediated by the sympathetic nervous system and the somatic motor system. Normally, the somatic motor system is responsible for establishing and coordinating voluntary movements and is controlled by central mechanisms independent of those controlling the sympathetic nervous system (Fig. 3, top). However, when an enhanced level of heat production is required to maintain thermal homeostasis or to develop fever (Fig. 3, bottom), involuntary commands from the thermo regulatory centre drives the somatic motor system to produce the stereotyped motor pattern of shivering. When this involuntary signalling is intense, it becomes difficult to produce fine motor tasks, such as speaking and writing, a common experience in cold winter weather.

References

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