Tonic inhibition of brown adipose tissue sympathetic nerve activity via muscarinic acetylcholine receptors in the rostral raphe pallidus - PubMed (original) (raw)

. 2017 Dec 15;595(24):7495-7508.

doi: 10.1113/JP275299. Epub 2017 Nov 21.

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Tonic inhibition of brown adipose tissue sympathetic nerve activity via muscarinic acetylcholine receptors in the rostral raphe pallidus

Ellen Paula Santos Conceição et al. J Physiol. 2017.

Abstract

Key points: A tonically active, muscarinic cholinergic inhibition of rostral raphe pallidus (rRPa) neurons influences thermogenesis of brown adipose tissue (BAT) independent of ambient temperature conditions. The tonically active cholinergic input to rRPa originates caudal to the hypothalamus. Muscarinic acetylcholine receptor (mAChR) activation in rRPa contributes to the inhibition of BAT sympathetic nerve activity (SNA) evoked by activation of neurons in the rostral ventrolateral medulla (RVLM). The RVLM is not the sole source of the muscarinic cholinergic input to rRPa. Activation of GABA receptors in rRPa does not mediate the cholinergic inhibition of BAT SNA.

Abstract: We sought to determine if body temperature and energy expenditure are influenced by a cholinergic input to neurons in the rostral raphe pallidus (rRPa), the site of sympathetic premotor neurons controlling thermogenesis of brown adipose tissue (BAT). Nanoinjections of the muscarinic acetylcholine receptor (mAChR) agonist, oxotremorine, or the cholinesterase inhibitor, neostigmine (NEOS), in the rRPa of anaesthetized rats decreased cold-evoked BAT sympathetic nerve activity (SNA, nadirs: -72 and -95%), BAT temperature (Tbat, -0.5 and -0.6°C), expired CO2 (Exp. CO2 , -0.3 and -0.5%) and heart rate (HR, -22 and -41 bpm). NEOS into rRPa reversed the increase in BAT SNA evoked by blockade of GABA receptors in rRPa. Nanoinjections of the mAChR antagonist, scopolamine (SCOP), in the rRPa of warm rats increased BAT SNA (peak: +1087%), Tbat (+1.8°C), Exp. CO2 (+0.7%), core temperature (Tcore, +0.5°C) and HR (+54 bpm). SCOP nanoinjections in rRPa produced similar activations of BAT during cold exposure, following a brain transection caudal to the hypothalamus, and during the blockade of glutamate receptors in rRPa. We conclude that a tonically active cholinergic input to the rRPa inhibits BAT SNA via activation of local mAChR. The inhibition of BAT SNA mediated by mAChR in rRPa does not depend on activation of GABA receptors in rRPa. The increase in BAT SNA following mAChR blockade in rRPa does not depend on the activity of neurons in the hypothalamus or on glutamate receptor activation in rRPa.

Keywords: neostigmine; oxotremorine; scopolamine; thermoregulation.

© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

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Figures

Figure 1

Figure 1. Effect of nanoinjection of OXO, NEOS or SCOP in rRPa

A, nanoinjection of OXO in rRPa (dashed line) in a cold‐exposed rat decreased brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (T

bat

), core temperature (T

core

), expired CO2 (Exp CO2) and heart rate (HR). Histograms of the levels of BAT SNA, T

bat

, Exp CO2, T

core,

mean arterial pressure (MAP) and HR prior to (open bars) and following (solid bars) OXO nanoinjection into rRPa. *Significant difference (P < 0.05). B, nanoinjection of NEOS in rRPa (dashed line) in a cold‐exposed rat decreased BAT SNA, T

bat

, T

core

, Exp CO2 and HR. Histograms of the levels of BAT SNA, T

bat

, Exp CO2, T

core

, MAP and HR prior to (open bars) and following (solid bars) NEOS nanoinjection into rRPa. *Significant difference (P < 0.05). C, nanoinjection of SCOP in rRPa (dashed line) in a warm‐exposed rat increased BAT SNA, T

bat

and Exp CO2. Histograms of the levels of BAT SNA, T

bat

, Exp CO2, T

core

, MAP and HR prior to (open bars) and following (solid bars) SCOP nanoinjection into rRPa. *Significant difference (P < 0.05). D, nanoinjection of SCOP in rRPa (dashed line) in a cold‐exposed rat increased BAT SNA, T

bat

, T

core

, Exp CO2, MAP and HR. Histograms of the levels of BAT SNA, T

bat

, Exp CO2, T

core

, MAP and HR prior to (open bars) and following (solid bars) SCOP nanoinjection into rRPa. *Significant difference (P < 0.05). E, partial histological coronal section containing blue fluorescent beads marking a representative OXO nanoinjection site in rRPa. Composite maps of the nanoinjection sites of OXO (asterisk, n = 5), NEOS (stars, n = 6), SCOP in warm‐exposed rats (circles, n = 6) and SCOP in cold‐exposed rats (@, n = 6) plotted on a schematic coronal drawing through the rRPa at −11.3 mm caudal to bregma. [Color figure can be viewed at

wileyonlinelibrary.com

]

Figure 2

Figure 2. Nanoinjection of SCOP in rRPa following a brain transection caudal to DMH increased BAT SNA and BAT temperature

A, data traces during bilateral transections of the neuraxis caudal to the DMH (continuous lines; left side, L and right side, R), performed in a rat with a cold‐evoked elevation in BAT SNA. Note that the transections eliminated the cold‐evoked BAT SNA. The grey bar represents an approximately 1.0 h interval between the transection and the SCOP nanoinjection in rRPa. Nanoinjection of SCOP in rRPa (dashed line) increased BAT SNA, T

bat

, Exp CO2, MAP and HR. Histograms of the levels of BAT SNA, T

bat

, Exp CO2, T

core

, MAP and HR prior to (open bars) and following (solid bars) SCOP nanoinjection into rRPa following brain transection. *Significant difference (P < 0.05). B, schematic drawing (top panel) of a sagittal section through the rat brain indicating the DMH (dashed oval) and the approximate level (continuous line) of the transection; also shown is a representative histological section (lower panel) at the level of a transection superimposed on a camera lucida drawing of a coronal brain section at −5.0 mm caudal to bregma. C, a composite map of the sites (circles, n = 4) of SCOP nanoinjections plotted on a schematic coronal drawing through the rRPa at −11.3 mm caudal to bregma. [Color figure can be viewed at

wileyonlinelibrary.com

]

Figure 3

Figure 3. Nanoinjection of SCOP in rRPa attenuated the inhibition of BAT SNA evoked by activation of neurons in RVLM, but inhibition of neurons in RVLM did not block the sympathoinhibitory response to NEOS nanoinjection in rRPa

A, nanoinjection of NMDA in RVLM (1st continuous line) inhibits the cold‐evoked activation of BAT SNA and reduces T

bat

, T

core

, Exp CO2 and HR. SCOP nanoinjection in rRPa (dashed line) increased BAT SNA, T

bat

, T

core

, Exp CO2, MAP and HR. Nanoinjection of NMDA (2nd continuous line) in RVLM after the SCOP nanoinjection in rRPa modestly decreased BAT SNA and T

bat

. The effect of NMDA nanoinjection in the naïve RVLM recovered ∼35 min (3rd continuous line) after the SCOP nanoinjection. Histograms illustrating the levels of BAT SNA, T

bat

, Exp CO2 and HR prior to (open bars) and following (solid bars) each of the three nanoinjections of NMDA into RVLM. *Significant difference (P < 0.05). B, bilateral nanoinjections of muscimol in RVLM (continuous lines; L, left side and R, right side) did not block the inhibitory effect of nanoinjection of NEOS in rRPa (dashed line) on BAT SNA and T

bat

, T

core

, Exp CO2, MAP or HR. Histograms showing the levels of BAT SNA, T

bat

, Exp CO2 and HR prior to (open bars) and following (solid bars) NEOS nanoinjection into rRPa. *Significant difference (P < 0.05). Composite maps of the nanoinjection sites of NMDA in RVLM (C, circles, n = 5), SCOP in rRPa (D, circles, n = 5), bilateral nanoinjections of muscimol (E, circles, n = 5) in RVLM, and NEOS (F, circles, n = 5) in rRPa plotted on schematic drawings through the rRPa at −11.3 mm caudal to bregma and the RVLM at −12.2 mm caudal to bregma.

Figure 4

Figure 4. NEOS nanoinjection in rRPa inhibits the increased BAT SNA evoked by local nanoinjection of BIC or saclofen

A, nanoinjection of saline vehicle (dotted line) in rRPa did not affect the increases in BAT SNA, T

bat

or Exp CO2 evoked by BIC nanoinjection in rRPa (continuous line). B, example of a nanoinjection of NEOS (short‐dashed line) in rRPa inhibiting the BIC‐evoked activation of BAT SNA and reduced T

bat

and Exp CO2. Composite map of the nanoinjection sites for saline after BIC (asterisk, n = 4) and for NEOS after BIC (circles, n = 5) plotted on a schematic drawing through the rRPa at −11.30 mm caudal to bregma. Histograms of the levels of BAT SNA, T

bat

and Exp CO2 prior to (open bars) and following (solid bars) NEOS nanoinjection into rRPa. *Significant difference (P < 0.05). C, nanoinjection of saline vehicle (dotted line) in rRPa did not affect the activation of BAT SNA or the increases in T

bat

and Exp CO2 evoked by saclofen nanoinjection in rRPa (long‐dashed line). D, example of a nanoinjection of NEOS (short‐dashed line) in rRPa, which decreased the saclofen‐evoked (long‐dashed line) increase in BAT SNA and reduced T

bat

and Exp CO2. Composite map of the nanoinjection sites for saline after saclofen (asterisk, n = 5) and for NEOS after saclofen (circles, n = 4) plotted on schematic drawing through the rRPa at −11.30 mm caudal to bregma. Histograms of the levels of BAT SNA, T

bat

and Exp CO2 prior to (open bars) and following (solid bars) NEOS nanoinjection into rRPa. *Significant difference (P < 0.05).

Figure 5

Figure 5. SCOP‐evoked increase in BAT SNA does not require glutamate receptor activation in rRPa

A, typical data traces showing that nanoinjection of the ionotropic glutamate receptor antagonists, AP5 and CNQX, in rRPa (continuous line) does not reverse the increases in BAT SNA, T

bat

and Exp CO2 evoked by prior nanoinjection of SCOP in rRPa (dashed line). Composite map of the nanoinjection sites of AP5 and CNQX after SCOP (circles, n = 5), plotted on a schematic drawing through the rRPa at −11.30 mm caudal to bregma. Histograms of the levels of BAT SNA, T

bat

and Exp CO2 prior to (open bars) and following (solid bars) AP5/CNQX nanoinjection into rRPa. *Significant difference (P < 0.05). B, example data traces showing that nanoinjection of the metabotropic glutamate receptor antagonist,

dl

‐AP3, in rRPa (short‐dashed line) does not reverse the increases in BAT SNA, T

bat

and Exp CO2 evoked by prior nanoinjection of SCOP into rRPa (long‐dashed line). Composite map of the nanoinjection sites of

dl

‐AP3 after SCOP (circles, n = 5) plotted on schematic drawings through the rRPa at −11.30 mm caudal to bregma.

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