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.

8 Reads
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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
  • Source
    • ") nor in the circuitry that modulates thermal metabolism (Cao et al., 2004). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Modified from Madden and Morrison (2004). a fever like response is elicited by the bicuculline-evoked disinhibition of DMH neurons (Morrison, 1999; Zaretskaia et al., 2002; Cao et al., 2004). Currently, the febrile response is postulated to arise from PGE 2 binding to EP3-R and inhibiting, via inhibitory GTP-binding proteins (Narumiya et al., 1999), the activity of warm-sensitive neurons in POA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: From mouse to man, brown adipose tissue (BAT) is a significant source of thermogenesis contributing to the maintenance of the body temperature homeostasis during the challenge of low environmental temperature. In rodents, BAT thermogenesis also contributes to the febrile increase in core temperature during the immune response. BAT sympathetic nerve activity controlling BAT thermogenesis is regulated by CNS neural networks which respond reflexively to thermal afferent signals from cutaneous and body core thermoreceptors, as well as to alterations in the discharge of central neurons with intrinsic thermosensitivity. Superimposed on the core thermoregulatory circuit for the activation of BAT thermogenesis, is the permissive, modulatory influence of central neural networks controlling metabolic aspects of energy homeostasis. The recent confirmation of the presence of BAT in human and its function as an energy consuming organ have stimulated interest in the potential for the pharmacological activation of BAT to reduce adiposity in the obese. In contrast, the inhibition of BAT thermogenesis could facilitate the induction of therapeutic hypothermia for fever reduction or to improve outcomes in stroke or cardiac ischemia by reducing infarct size through a lowering of metabolic oxygen demand. This review summarizes the central circuits for the autonomic control of BAT thermogenesis and highlights the potential clinical relevance of the pharmacological inhibition or activation of BAT thermogenesis.
    Frontiers in Neuroscience 02/2014; 8(8):14. DOI:10.3389/fnins.2014.00014 · 3.66 Impact Factor
Show more