Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus

Neurological Sciences Institute, Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, OR 97006, USA.
Neuroscience (Impact Factor: 3.36). 02/2004; 126(1):229-40. DOI: 10.1016/j.neuroscience.2004.03.013
Source: PubMed


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.

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    • "of metabolic and behavioral function , including body weight regulation ( Bellinger and Bernardis , 2002 ) . Stimulation and disinhibition of DMH neurons , by parenchymal microinjection of respectively glutamate and GABA A receptor antagonist , increases BAT thermogenesis and elevates body core temperature ( Figure 1B ; Zaretskaia et al . , 2002 ; Cao et al . , 2004 ; Dimicco and Zaretsky , 2007 ; Morrison and Nakamura , 2011 ) . A recent study also identified a subset of DMH cholinergic neurons ( Jeong et al . , 2015 ) , whose activity was elevated by warm ambient temperature and associated with a decrease in BAT activity and body temperature ( Jeong et al . , 2015 ) . Importantly , DMH lesion abo"
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    ABSTRACT: It has long been known, in large part from animal studies, that the control of brown adipose tissue (BAT) thermogenesis is insured by the central nervous system, which integrates several stimuli in order to control BAT activation through the sympathetic nervous system (SNS). SNS-mediated BAT activity is governed by diverse neurons found in brain structures involved in homeostatic regulations and whose activity is modulated by various factors including oscillations of energy fluxes. The characterization of these neurons has always represented a challenging issue. The available literature suggests that the neuronal circuits controlling BAT thermogenesis are largely part of an autonomic circuitry involving the hypothalamus, brainstem and the SNS efferent neurons. In the present review, we recapitulate the latest progresses in regards to the hypothalamic regulation of BAT metabolism. We briefly addressed the role of the thermoregulatory pathway and its interactions with the energy balance systems in the control of thermogenesis. We also reviewed the involvement of the brain melanocortin and endocannabinoid systems as well as the emerging role of steroidogenic factor 1 neurons in BAT thermogenesis. Finally, we examined the link existing between these systems and the homeostatic factors that modulate their activities.
    Frontiers in Systems Neuroscience 10/2015; 9. DOI:10.3389/fnsys.2015.00150
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    • "These inhibitory projections feature the sympathetic control in the paraventricular nucleus (PVN) (Martin et al., 1991; Allen, 2002) and dorsomedial hypothalamic region (DMH) (Fontes et al., 2001; Cao et al., 2004), brain regions that surround the third ventricle. Blockade of GABA A receptors in these hypothalamic nuclei results in marked increases in sympathetic activity to the heart and kidney (Zhang et al., 1997; Fontes et al., 2001; Chen and Toney, 2003; Cao et al., 2004) that are accompanied by changes in heart rate and blood pressure. Another possibility is the rostralventrolateral medulla, which is easily accessible from the 4th brain "
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    ABSTRACT: Liposomes are nanosystems that allow a sustained release of entrapped substances. Gamma-aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter of the central nervous system (CNS). We developed a liposomal formulation of GABA for application in long-term CNS functional studies. Two days after liposome-entrapped GABA was injected intracerebroventricularly (ICV), Wistar rats were submitted to the following evaluations: (1) changes in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) to ICV injection of bicuculline methiodide (BMI) in anesthetized rats; (2) changes in cardiovascular reactivity to air jet stress in conscious rats; and (3) anxiety-like behavior in conscious rats. GABA and saline-containing pegylated liposomes were prepared with a mean diameter of 200nm. Rats with implanted cannulas targeted to lateral cerebral ventricle (n=5-8/group) received either GABA solution (GS), empty liposomes (EL) or GABA-containing liposomes (GL). Following (48h) central microinjection (2μL, 0.09M and 22g/L) of liposomes, animals were submitted to the different protocols. Animals that received GL demonstrated attenuated response of RSNA to BMI microinjection (GS 48±9, EL 43±9, GL 11±8%; P<0.05), blunted tachycardia in the stress trial (ΔHR: GS 115±14, EL 117±10, GL 74±9bpm; P<0.05) and spent more time in the open arms of elevated plus maze (EL 6±2 vs. GL 18±5%; P=0.028) compared with GS and EL groups. These results indicate that liposome-entrapped GABA can be a potential tool for exploring the chronic effects of GABA in specific regions and pathways of the central nervous system. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 11/2014; 285. DOI:10.1016/j.neuroscience.2014.10.067 · 3.36 Impact Factor
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    • ") nor in the circuitry that modulates thermal metabolism (Cao et al., 2004). "
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    ABSTRACT: The prelimbic cortex (PL) is involved in the control of behavioral and autonomic responses to stress. The present study aimed to investigate whether opioid neurotransmission in the PL modulates autonomic responses evoked by restraint stress (RS). Bilateral microinjection of 0.03, 0.3 and 3 nmol/100nL of the nonselective opioid antagonist naloxone into the PL reduced pressure and tachycardiac responses evoked by RS. However, no effects were observed after its injection at doses of 0.003 and 30nmol/100nL, thus resulting in an inverted U-shaped dose-inhibition curve. Similar to naloxone, the selective μ-opioid antagonist CTAP, and the selective κ-opioid antagonist nor-BNI, also reduced MAP and HR increases induced by RS when injected into the PL, whereas treatment with the selective δ-opioid antagonist naltrindole did not affect the pressor and tachycardiac response caused by RS. Blockade of opioid neurotransmission in the PL did not affect the fall in tail temperature and increase in body temperature induced by RS. The present results confirm the involvement of PL opioid neurotransmission in the modulation of cardiovascular responses evoked during the exposure to an aversive situation, and suggest that responses observed after the blockade of local opioid receptors is due to alterations in PL neuronal activity. Furthermore, these results suggest that a distinct circuitry is involved in modulation of the sympathetic output to differents vascular territories.
    Neuropharmacology 05/2014; 25:367–374. DOI:10.1016/j.neuropharm.2014.04.019 · 5.11 Impact Factor
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