The thermogenic activity of interscapular brown adipose tissue (IBAT) in response to physiologic stimuli, such as cold exposure, is controlled by its sympathetic innervation. To determine which brain regions might be involved in the regulation of cold-evoked increases in sympathetic outflow to IBAT, the present study compared central nervous system (CNS) areas activated by cold exposure with brain regions anatomically linked to the sympathetic innervation of IBAT. Immunocytochemical localization of Fos was examined in the brains of rats exposed to 4 degrees C for 4 hours. In a separate group of rats, the neural circuit involved in IBAT control, including the location of sympathetic preganglionic neurons in the spinal cord, was characterized with pseudorabies virus, a retrograde transynaptic tracer. Central noradrenergic and serotonergic groups related to the sympathetic outflow to IBAT also were identified. Localization of viral antigens at different survival times (66-96 hours) revealed infection in circumscribed CNS populations, but only a subset of the regions comprising this circuitry showed cold-evoked Fos expression. The raphe pallidus and the ventromedial parvicellular subdivision of the paraventricular hypothalamic nucleus (PVH), both infected at early survival times, were the main areas containing sympathetic premotor neurons activated by cold exposure. Major cold-sensitive areas projecting to spinal interneurons or to regions containing sympathetic premotor neurons, which became infected at intermediate intervals, included lateral hypothalamic, perifornical, and retrochiasmatic areas, anterior and posterior PVH, ventrolateral periaqueductal gray, and Barrington's nucleus. Areas infected later, most likely related to reception of cold-related signals, comprised the lateral preoptic area, parastrial nucleus, dorsomedial hypothalamic nucleus, lateral parabrachial nucleus, and nucleus of the solitary tract. These interconnected areas, identified by combining functional and retrograde anatomic approaches, likely constitute the central circuitry responsible for the increase in sympathetic outflow to IBAT during cold-evoked thermogenesis.

Sympathetic nerve activity to brown adipose tissue (BAT) regulates adipocyte metabolism of its stored lipid fuel and thus the thermogenesis in BAT. To determine if the discharge of neurons in the rostral raphe pallidus (RPa) can influence BAT thermogenesis, changes in sympathetic nerve activity to BAT were recorded after microinjection (60 nl) of the GABAA receptor antagonist bicuculline (500 μM) into the RPa in chloralose-urethan-anesthetized, ventilated rats. Bicuculline caused a large, rapid rise in the sympathetic nerve activity to BAT (which had also increased during acute hypothermia) from very low, normothermic control levels to maximum values (mean: 1,949 ± 604% control; n = 13) after 4–6 min. The sympathetic nerve discharge to BAT had a mean burst frequency (3.5 ± 0.3 Hz) that was significantly less than the heart rate (7.3 ± 0.2 beats/min), and it was not inhibited during baroreceptor reflex activation. Bicuculline-stimulated increases in the sympathetic nerve activity to BAT and cold-evoked increases in neuronal fos expression were localized to the RPa at the level of the caudal half of the facial nucleus. This dramatic increase in sympathetic nerve activity to BAT after disinhibition of neurons in rostral RPa is consistent with a major role for RPa neurons, perhaps as sympathetic premotoneurons for BAT, in medullary control of BAT thermogenesis.

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These studies examined the hypothesis that serotonergic neurons located in central sites known to be involved with autonomic regulation are activated by cold exposure, a potent stimulator of the sympathetic nervous system. In all experiments, rats were exposed to either 3 degrees C or 22 degrees C for 24 h. Significant increases (p < 0.05) in urinary norepinephrine excretion, depletions of myocardial norepinephrine, and enhanced myocardial L-DOPA accumulation following decarboxylase inhibition provided evidence of sympathoexcitation at 3 degrees C. Accumulations of the serotonin metabolite 5-hydroxyindoleacetic acid, in saline-injected rats, and 5-hydroxytryptophan in decarboxylase-inhibited rats were increased in spinal cord and brainstem regions of cold-exposed rats. Two hours after injection of the serotonin synthesis inhibitor p-chlorophenylalanine, significantly greater depletions of serotonin in spinal cord and 5-hydroxyindoleacetic acid in spinal cord and brainstem of cold-exposed rats were noted; synthesis inhibition also caused a larger drop in body temperature in cold-exposed rats. Microdissections dissections of raphe nuclei and thoracic spinal cord sites indicated that the principal sites of serotonergic activation were the dorsal and intermediate spinal regions, and the raphe magnus. Thus, cold-induced sympathoexcitation was accompanied by activation of serotonergic neurons in spinal cord and brainstem regions known to be involved in autonomic regulation.