Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus
ABSTRACT We sought to determine which medullary sympathetic premotor neurons mediate the cardiovascular and thermogenic effects resulting from activation of neurons in the dorsomedial hypothalamus (DMH) in urethane/chloralose-anesthetized, artificially ventilated rats. Unilateral disinhibition of neurons in the DMH with microinjection of bicuculline (2 mM, 30 nl) caused significant increases in brown adipose tissue sympathetic nerve activity (BAT SNA, +828+/-169% of control, n=16), cardiac SNA (+516+/-82% of control, n=16), renal SNA (RSNA, +203+/-25% of control, n=28) and, accompanied by increases in BAT temperature (+1.6+/-0.3 degrees C, n=11), end-tidal CO(2) (+0.7+/-0.1%, n=15), heart rate (+113+/-7 beats/min, n=32), arterial pressure (+19+/-2 mm Hg, n=32) and plasma epinephrine and norepinephrine concentrations. Inhibition of neurons in the rostral raphe pallidus (RPa) with microinjection of muscimol (6 mM, 60 nl) abolished the increases in BAT SNA and BAT temperature and reduced the tachycardia induced by disinhibition of DMH neurons. Inhibition of neurons in the RVLM with microinjection of muscimol (6 mM, 60 nl) markedly reduced the increase in RSNA, but did not affect the evoked tachycardia or the increase in arterial pressure. Combined glutamic acid decarboxylase (GAD-67) immunocytochemistry and pseudorabies viral retrograde tracing from BAT indicated close appositions between GABAergic terminals and DMH neurons in sympathetic pathways to BAT. In conclusion, these results demonstrate the existence of a tonically active, GABAergic inhibitory input to neurons in the DMH and that blockade of this inhibition increases sympathetic outflow to thermogenic and cardiovascular targets by activating functionally specific populations of sympathetic premotor neurons: the excitation of BAT SNA and BAT thermogenesis is mediated through putative sympathetic premotor neurons in the RPa, while the activation in RSNA is dependent on those in RVLM. These data increase our understanding of the central pathways mediating changes in sympathetically mediated thermogenesis that is activated in thermoregulation, stress responses and energy balance.
- SourceAvailable from: Kazuhiro Nakamura[Show abstract] [Hide abstract]
ABSTRACT: Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature in mammals and birds during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. The primary sources of neurally regulated metabolic heat production are mitochondrial oxidation in brown adipose tissue, increases in heart rate and shivering in skeletal muscle. Thermogenesis is regulated in each of these tissues by parallel networks in the central nervous system, which respond to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate the appropriate sympathetic and somatic efferents. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates thermogenesis and discusses the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E(2), to increase body temperature. The cold thermal afferent circuit from cutaneous thermal receptors ascends via second-order thermosensory neurons in the dorsal horn of the spinal cord to activate neurons in the lateral parabrachial nucleus, which drive GABAergic interneurons in the preoptic area to inhibit warm-sensitive, inhibitory output neurons of the preoptic area. The resulting disinhibition of thermogenesis-promoting neurons in the dorsomedial hypothalamus and possibly of sympathetic and somatic premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, activates excitatory inputs to spinal sympathetic and somatic motor circuits to drive thermogenesis.Experimental Physiology 08/2008; 93(7):773-97. DOI:10.1113/expphysiol.2007.041848 · 2.87 Impact Factor
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ABSTRACT: When given systemically to rats and humans, the drug of abuse 3,4 methylenedioxymethamphetamine (ecstasy, MDMA) elicits hyperthermia, hyperactivity, tachycardia, and hypertension. Chemically stimulating the dorsomedial hypothalamus (DMH), a brain region known to be involved in thermoregulation and in stress responses, causes similar effects. We therefore tested the hypothesis that neuronal activity in the DMH plays a role in MDMA-evoked sympathetic and behavioral responses by microinjecting artificial CSF or muscimol, a neuronal inhibitor, into the DMH prior to intravenous infusion of saline or MDMA in conscious rats. Core temperature, heart rate, mean arterial pressure and locomotor activity were recorded by telemetry every minute for 120 min. In rats previously microinjected with CSF, MDMA elicited significant increases from baseline in core temperature (+1.3+/-0.3 degrees C), locomotion (+50+/-6 counts/min), heart rate (+142+/-16 beats/min), and mean arterial pressure (+26+/-3 mmHg). Microinjecting muscimol into the DMH prior to MDMA prevented increases in core temperature and locomotion and attenuated increases in heart rate and mean arterial pressure. These results indicate that neuronal activity in the DMH is necessary for the sympathetic and behavioral responses evoked by MDMA.Brain Research 07/2008; 1226:116-23. DOI:10.1016/j.brainres.2008.06.011 · 2.83 Impact Factor
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ABSTRACT: Activation of neurons in the dorsomedial hypothalamus (DMH) appears to play an important role in signaling the excitation of brain regions responsible for experimental fever and for many of the physiological and behavioral changes seen in experimental stress or anxiety in rats. Here, we examined the effect of disinhibition of the DMH by unilateral microinjection of bicuculline methiodide (BMI) on Fos expression in selected regions of the brain that have been implicated in anxiety and responses to stress and fever in rats. Disinhibition of the DMH resulted in dramatic increases in local Fos expression and also increased the numbers of Fos-positive neurons in the lateral septal nucleus and in both the parvocellular and magnocellular subdivisions of the paraventricular nucleus, with greater increases ipsilateral to the injection site in the DMH. However, microinjection of BMI had no significant effect on Fos expression in the bed nucleus of the stria terminalis, another forebrain area implicated in stress and anxiety. In the brainstem, disinhibition of the DMH increased Fos expression in the nucleus tractus solitarius and the ventrolateral medulla bilaterally with greater increases again ipsilateral to the site of the microinjection, and also in the midline rostral raphe pallidus. Thus, disinhibition of neurons in the DMH in conscious rats results in increases in Fos expression in selected forebrain and brainstem regions that have been implicated in stress-induced physiological changes, anxiety, and experimental fever.Brain Research 04/2008; 1200:39-50. DOI:10.1016/j.brainres.2008.01.018 · 2.83 Impact Factor