Skeletal Muscles as Effectors in Thermoregulation
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.
The feedback loop begins when a receptor detects the change in the variable, and this information flows to the control center, where it can be combined with other information. Control centers (integrators) compare the variable in relation to a set point and signal the effectors to generate a response. Methods of communication among the components of a feedback loop are necessary in order for it to function. An initiation event or stimulus causes a change in a variable.
Body Temperature feedback loop. Conditions initiate a decrease in body temperature (variable). Thermoreceptors sense the temperature change, and this information travels by nerve impulses to the hypothalamus, where it is compared against the set point of 98.6 degrees. The hypothalamus then controls numerous effectors that respond to a decrease in body temperature. Thermoreceptors detect changes in body temperature.
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.
Skeletal muscles are also effectors in this feedback loop: they contract rapidly in response to a decrease in body temperature. Shivering is a fundamental physiological response that occurs in skeletal muscles to produce heat when it is cold or during the development of fever. This response is initiated and maintained by the central nervous system.
The Thermoregulatory Center
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 and provides command signals to peripheral effectors to drive thermoregulatory responses.
Image depicting the location of the hypothalamus in the brain.
Neural Pathways and Mechanisms
Briefly cooling the trunk skin of the rats consistently evoked both shivering in nuchal (neck) muscles and non-shivering thermogenesis in brown adipose tissue. We simultaneously recorded electro myogram to measure shivering as well as brown adipose tissue temperature to measure non-shivering thermogenesis in anaesthetized rats. In our recent study reported in The Journal of Physiology, we examined 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.
Inhibition of neurons with nanoinjections of muscimol into the median preoptic nucleus, which is a preoptic subregion that receives thermosensory signals from skin thermoreceptors, eliminated both shivering and non-shivering thermogenesis evoked by skin cooling. Furthermore, stimulation of neurons in the same preoptic subregion elicited shivering and non-shivering thermogenesis, mimicking skin cooling. 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. 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. 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.
Neural pathways involved in thermoregulation.
Therefore, we concluded that neurons in these brain regions integrate descending command signals from the preoptic area leading to shivering and non-shivering thermogenesis.
Model of Neural Pathways
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, 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, 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.
Independent Control and Enhanced Heat Production
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. 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.
However, when an enhanced level of heat production is required to maintain thermal homeostasis or to develop fever, involuntary commands from the thermo regulatory centre drives the somatic motor system to produce the stereotyped motor pattern of shivering.
Scheme of the central regulation of the sympathetic nervous system for BAT thermogenesis and the somatic motor nervous system for voluntary movements and shivering.