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Themed Issue Papers |
1 Department of Biomedical Science, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211, USA
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-aminobutyric acid (GABA) inhibitory neurotransmission within the NTS play a fundamental role in this process. The hypothesis will be presented that baroreflex resetting by somatosensory input is mediated by: (1) selective inhibition of barosensitive NTS neurones; and (2) excitation of sympathoexcitatory neurones in the rostral ventrolateral medulla. Current research findings will be discussed that support an interaction between GABA and substance P (SP) signalling mechanisms in the NTS. An understanding of these mechanisms may prove to be essential for future detailed analysis of the cellular and molecular mechanisms underlying sensory integration in the NTS.
(Received 14 September 2005;
accepted after revision 5 October 2005; first published online 20 October 2005)
Corresponding author J. T. Potts: Department of Biomedical Science, College of Veterinary Medicine, Dalton Cardiovascular Research Center, University of Missouri, 134 Research Park Drive, Columbia, MO 65211, USA. Email: pottsjt{at}missouri.edu
To reset or not to reset... ?
The role of the arterial baroreceptor reflex in regulating, and possibly establishing, the level of arterial pressure during exercise has been a topic of consideration and debate for decades. This debate was initiated in the early 1970s by a series of studies by Sleight and colleagues showing that a reflex change in heart period in response to a pharmacologically induced change in blood pressure was substantially blunted during exercise (Bristow et al. 1969; Cunningham et al. 1970, 1972; Pickering et al. 1972). These data were used to support the concept that the arterial baroreflex was less functional during exercise and thus did not play an important role in establishing or regulating arterial pressure. However, other data at the time conflicted with this conclusion (Bevegard & Shepherd, 1966; Melcher & Donald, 1981). These investigators held that the arterial baroreceptor reflex, specifically carotid sinus baroreflex control of heart rate and blood pressure, was reset, supporting the concept that baroreflex function was preserved during exercise. DiCarlo and Bishop went on to show that intravenous infusion of nitroglycerin, used to limit the rise in arterial pressure produced by exercise, augmented the increase in both heart rate and renal sympathetic nerve activity during volitional exercise in chronically instrumented conscious rabbits (DiCarlo & Bishop, 1992). These data are consistent with the view that the arterial baroreflex is acutely and rapidly reset following the onset of exercise.
It was not until 1993 that Potts and colleagues successfully demonstrated that the operational properties for carotid baroreflex control of heart rate and blood pressure were reset during volitional exercise in humans, which aided in retaining overall reflex sensitivity (Potts et al. 1993). In agreement with this observation, other investigators have reported similar findings over the ensuing years (Papelier et al. 1994; Raven et al. 1997; Burger et al. 1998; Norton et al. 1999; Fadel et al. 2001). Therefore, these observations, in conjunction with knowledege that the arterial baroreflex resets during sustained changes in arterial pressure (Sagawa, 1983; Andresen & Yang, 1989), led to the concept that the baroreflex is indeed capable of continuous regulation of arterial pressure during exercise through the process of resetting.
Over the past 14 years, many laboratories set out to identify the neural mechanism(s) responsible for exercise-induced resetting of the baroreflex. In all of these studies, it was shown that either descending neural input from locomotor centres (a.k.a. central command) or ascending neural feedback from skeletal muscle receptors was capable of modifying arterial baroreflex function in a manner similar to the changes reported during exercise (McWilliam et al. 1991; Iellamo et al. 1997; Potts & Mitchell, 1998; Potts, 2001, 2002; Gallagher et al. 2001; McIlveen et al. 2001; Fadel et al. 2001; Potts et al. 2003). These findings strongly suggest that a central alteration(s) in the neurotransmission of arterial baroreceptor signals may be responsible for mediating rapid and reversible resetting of the baroreflex. However, the precise site(s) within the central baroreflex circuitry, as well as the cellular mechanism(s), remain unknown.
If central resetting of the baroreceptor reflex occurs during exercise, it remains unresolved which component(s) of the central baroreflex arc (i.e. nucleus tractus solitarii (NTS), caudal or rostral ventrolateral medulla) is involved in this process. Clearly, an alteration of synaptic transmission in one or more of these central sites within the baroreflex arc could reset the reflex, but the individual contributions of each region still remain unclear. This review will critically evaluate the role for neural feedback from skeletal muscle receptors in resetting the arterial baroreflex, with the emphasis being placed on the potential contribution of inhibitory neurotransmission within the NTS to this process. The NTS was chosen for several reasons. First, the NTS is the first medullary region where a potential central interaction between baroreceptor and somatosensory receptor inputs could occur. As will be discussed, both primary baroreceptor afferents, as well as spinal dorsal horn neurones which transmit somatosensory input, project to and synapse within the NTS. Second, if an interaction between these sensory pathways occurred in the NTS, it would set the level of central baroreceptor activity that would then be transmitted to other central nuclei involved in baroreceptor transmission. Third, the NTS possesses an array of synaptic machinery, such as a complex network of synaptically connected excitatory and inhibitory interneurones, as well as a host of neurotransmitters and excitatory, inhibitory and peptidergic receptor subtypes, which makes it well suited to modulate incoming sensory signals. Finally, the NTS is known to play a pivotal role in the integration of many other viscerosensory systems (Barraco, 1994). Therefore, there is compelling evidence to think that the NTS is involved in mediating the central interaction between baroreceptor and somatosensory receptor inputs. Despite these arguments, other medullary regions, such as the rostral ventrolateral medulla (VLM), may also participate in this central interaction. Therefore, I have included a discussion of the effect of neurogenic feedback from skeletal muscle on sympathoexcitiatory pathways in the rostral VLM in terms of its role in baroreflex resetting.
Thorough analysis of studies to date will suggest that neural feedback from skeletal muscle receptors activates a GABAergic circuit in the NTS which reduces the excitability of barosensitive NTS neurones. The hypothesis that depression of NTS neuronal excitability, coupled with direct excitation of sympathetic premotor neurones in the rostral VLMs by somatosensory feedback will be proposed as a possible central mechanism for resetting of the arterial baroreceptor reflex during exercise.
Teleological argument that inhibition of NTS signalling resets the baroreflex
A model based on the argument that inhibition of baroreceptor signalling at the level of the NTS is required to reset the arterial baroreflex during exercise will be tested. The primary purpose for inhibition of the NTS is to necessitate a greater degree of baroreceptor input to evoke a reflex response, in this case bradycardia and hypotension, during exercise. In the absence of NTS inhibition, increases in baroreceptor activity may severely limit the degree of vagal withdrawal and sympathoexcitatory responses evoked by exercise.
Figure 1A illustrates the central hypothesis and the basic features of the model. Resting heart rate (HR) and sympathetic nerve activity (SNA) is under the tonic control of cardiac vagal motoneurones (CVM) located in the nucleus ambiguus (NA) and inhibitory GABA neurones in the caudal VLM that inhibit sympathetic premotor neurones in the rostral VLM. The level of neural activity through these central pathways is modulated by the degree of excitatory drive from barosensitive NTS neurones that are dynamically controlled by input from aortic and carotid sinus baroreceptors which continuously respond to beat-to-beat changes in arterial pressure (Sagawa, 1983). This negative feedback control system results in the classic baroreflex function curve, in which the operating point determines the steady-state relationship between baroreceptor input and basal cardiovascular variables (i.e. HR and SNA).
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In this model, it is hypothesized that somatosensory input mediates exercise tachycardia and sympathoexcitation by two central effects: (1) limiting the degree of excitation of barosensitive NTS neurones via activation of an intrinsic inhibitory GABA mechanism; and (2) directly exciting sympathetic premotor neurones in the rVLM. This is illustrated in Fig. 1C. It is proposed that excitation of GABA neurones in the NTS resets the classic baroreflex input–output relation which normalizes the level of NTS activity to aid in preserving reflex sensitivity. However, this model predicts that lateral resetting alone would not increase HR and SNA (see (i) in Fig. 1C). Therefore, it is also proposed that somatosensory input directly excites sympathetic premotor neurones in the rostral VLM (see (ii) in Fig. 1C). In this manner, somatic input would limit baroinhibition of the heart and vasculature at the level of the NTS and promote sympathoexcitation at the level of the rostral VLM. In the remainder of this review, I will present evidence from our laboratory and from others that supports the idea that neurogenic feedback from skeletal muscle receptors excites GABAergic circuits in the NTS, as well as exciting sympathetic premotor neurones in the rostral VLM.
Neural feedback from skeletal muscle modulates arterial baroreflex function
The concept that neural feedback from skeletal muscle modulates arterial baroreflex function is well established in both human and animal models of exercise (McWilliam & Yang, 1991; McWilliam et al. 1991; McMahon & McWilliam, 1992; Iellamo et al. 1997; Potts & Mitchell, 1998; Potts & Li, 1998; Potts et al. 1998, 2003; Gallagher et al. 2001; Smith et al. 2003). McWilliam and colleagues used decerebrate and anaesthetized cats to investigate the effect of somatsensory feedback on carotid baroreflex function. Using an isolated carotid sinus preparation, they reported that a step increase in carotid sinus pressure evoked rapid reflex bradycardia that was substantially attenuated during periods of brief muscle contraction elicited by ventral root stimulation (McWilliam et al. 1991; McMahon & McWilliam, 1992). They used this finding to suggest that neural feedback from somatic afferents attenuated the sensitivity, or gain, of the baroreflex. However, owing to the non-linear nature of baroreflex function (Heyman & Neil, 1958; Sagawa, 1983), this could equally have been explained by rapid resetting of the baroreflex. This concept is illustrated in Fig. 2. If this rationale was correct, then somatosensory activation should shift threshold pressure for the baroreflex function curve (i.e. minimal baroreceptor pressure required to evoke reflex bradycardia and sympathoinhibition) to higher systemic pressure. We directly tested this hypothesis using anaesthetized dogs and showed that activation of somatic afferents, by electrically induced muscle contraction and passive muscle stretch, increased the minimal threshold pressure of the carotid sinus baroreflex for inhibition of renal sympathetic nerve activity (RSNA), hypotension and bradycardia (Potts & Mitchell, 1998). Taken together, these findings provide compelling evidence that neural feedback from mechanically sensitive skeletal muscle receptors rapidly resets carotid baroreflex function to the prevailing level of systemic pressure in the absence of central command motor signals. Consistent with this view, a recent study in humans (Smith et al. 2003) found that reducing sensory feedback from skeletal muscle with epidural anaesthesia during static leg exercise resulted in a lateral shift in the carotid baroreflex function curve to lower systemic pressure while retaining overall reflex gain. This finding further supports the idea that neurogenic input from skeletal muscle is tonically active during exercise and that tonic afferent somatosensory feedback is necessary to completely reset the carotid baroreflex. In decerebrate cats it has also been shown that electrically induced muscle contraction and mechanical stretch of the hindlimb reset carotid baroreflex function curves upwards for heart rate and aortic pressure (McIlveen et al. 2001). However, the reflex curves were not reset laterally to higher systemic pressure. A possible explanation for this discrepancy may have been the absence of a definable threshold pressure, which probably made it difficult to quantify lateral resetting of the baroreflex. Nevertheless, these findings collectively support the concept that sensory feedback from active skeletal muscle resets the operational properties of the arterial baroreflex to the prevailing level of systemic pressure during exercise.
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and C fibre somatic afferents were primarily responsible for mediating the cardiorespiratory effects by showing that anodal stimulation of, and lidocaine application to, the dorsal roots blocked all responses to electrically evoked muscle contraction (McCloskey & Mitchell, 1972). Further insight into the specific afferent population may be gained by considering the different sensory modalities (mechanical versus chemical) and temporal activation patterns (immediate versus delayed) of A and C fibre afferents. Although it is difficult to ascribe a single sensory modality to A and C fibres because they are polymodal afferents, an obvious difference lies in their firing patterns to a given stimulus. For example, mechanosensitive fibres discharge immediately in response to an applied stimulus, whereas purely chemosensitive fibres respond with a latency of 15–30 s (Mense & Stahnke, 1983; Kaufman et al. 2002). Therefore, the rate at which the arterial baroreflex resets may be the key to identifying the specific afferent population involved in this process. Perhaps the most convincing evidence for involvement of mechanosensitive afferents was reported by McWilliam and colleagues (McWilliam & Woolley, 1988; McWilliam et al. 1991; McMahon & McWilliam, 1992). They found that very brief somatic stimulation (2–4 s) was sufficient to alter baroreflex function. Taken together, these findings suggest that resetting of the arterial baroreflex immediately following the onset of muscle contraction is most likely to be mediated by mechanical feedback from A and C fibre somatic afferents. Furthermore, during prolonged muscle activity, especially under high loading conditions, somatosensory signals from chemically sensitive afferents, those responding to local metabolic changes within active skeletal muscle, may also contribute to resetting. The contribution of chemically sensitive somatic afferents to baroreflex resetting has previously been shown (Papelier et al. 1997). Therefore, in this manner the brain would receive constant feedback from skeletal muscle that could be used for continuous resetting of the baroreflex to optimize systemic pressure and perfusion of active skeletal muscle. This led us to ask the following question: which medullary site(s) activated by neural feedback from skeletal muscle are involved in baroreflex resetting? Spinal dorsal horn neurones project to specific regions of the NTS
What is the evidence that the NTS and rVLM may be medullary sites for central interaction between arterial baroreceptor and skeletal muscle receptor signals? Anatomically, the NTS is the first medullary site where a central interaction between these two sensory pathways could occur, since it receives axons from both primary baroreceptor afferents and spinal dorsal horn neurones that transmit sensory input from A and C fibre somatic afferents. However, there is also physiological evidence supporting the notion that both the NTS and rVLM are ‘supraspinal sites’ for integration of these sensory signals. Previous neuronal tracing studies have shown that somatic afferent neurones project primarily to laminae I–IV of the spinal dorsal horn, where they synapse onto second order neurones that project to supraspinal medullary sites, including the NTS and rVLM (Kalia et al. 1981; Menetrey & Basbaum, 1987; Gamboa-Esteves et al. 2001; Potts et al. 2002). Interestingly, the distribution pattern of superficial and deep dorsal horn neurones projecting to the NTS is quite heterogeneous (Gamboa-Esteves et al. 2001; Potts et al. 2002). These studies reported that the densest innervation of spinal dorsal horn projections occurred in regions of the NTS that extend caudal to the obex, while there was sparse innervation in intermediate and rostral NTS regions. Therefore, caudal regions of the NTS appear to be the most likely site for a central interaction. Although these studies provide an anatomical basis for a central interaction between baroreceptor and somatosensory receptor afferents, the precise location and relationship between these projections and NTS neurones remain poorly understood.
Electrophysiological studies have also clearly demonstrated that somatosensory feedback excites both NTS and rVLM neurones (Person, 1989; Bauer et al. 1990, 1992; Toney & Mifflin, 1994, 2000; Boscan et al. 2002a; Potts & Waldrop, 2005). Within the rVLM, it has been shown that antidromically activated reticulospinal neurones are excited by muscle contraction (Bauer et al. 1990, 1992). Interestingly, in these studies roughly 50% of rVLM neurones excited by somatosensory input displayed cardiac rhythmicity. This suggests that only half of this rVLM population was modulated by baroreceptor input. The potential implication of this finding to baroreflex resetting will be discussed later.
Within the NTS, rhythmic muscle contraction in anaesthetized cats also increases the discharge rate of NTS neurones (see Fig. 3). In this study (Potts & Waldrop, 2005), we found that not only were these cells excited by somatic input, but their excitation pattern was tightly coupled to the frequency of somatic activation. In addition, although these neurones clearly responded to neural feedback from skeletal muscle, they failed to respond to baroreceptor stimuli, suggesting that they did not receive converging input from arterial baroreceptors. This finding has been reported previously (Toney & Mifflin, 1994). Therefore, these data, together with the above-mentioned anatomical evidence, clearly support the notion that neurogenic feedback from skeletal muscle alters the activity of a baroreceptor-insensitive population of NTS neurones and reticulospinal sympathetic neurones in the rVLM. Regarding the NTS, this raises the question of what the functional role for this neuronal population might be.
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Although the focus of this article is on the central interaction between baroreceptor and skeletal muscle afferents in the NTS, it is equally likely that other neural inputs, such as descending input from the hypothalamus and/or other locomotor-related centres within the brain, may modulate baroreflex function via a similar mechanism. Indeed, recent studies using animals and humans have provided compelling evidence that descending input related to the degree of voluntary muscle contraction, or motor unit recruitment, resets arterial baroreflex function and alters the activity of NTS neurones (Iellamo et al. 1997; Querry et al. 2001; McIlveen et al. 2001; Ogoh et al. 2002; Williamson et al. 2002; Raven et al. 2002; Komine et al. 2003; Murata et al. 2004; Matsukawa et al. 2005; Degtyarenko & Kaufman, 2005). Therefore, it appears that both central command signals and neurogenic feedback from skeletal muscle are involved in resetting the arterial baroreflex during exercise. Future research endeavours will be needed to determine whether the GABAergic NTS mechanism discussed here is also activated by descending central command signals.
If neural feedback from skeletal muscle resets the baroreflex by activating an inhibitory NTS circuit, then it follows that blocking inhibitory neurotransmission should prevent resetting. Recent evidence has shown that depression of baroreflex function produced by activation of somatic afferents is prevented by blockade of GABAergic transmission in the NTS (Boscan & Paton, 2001; Boscan et al. 2002b; Potts et al. 2003). As shown in Fig. 4A, we recently investigated the central interaction between contraction-sensitive somatic afferents and arterial baroreceptors using an arterially perfused, decerebrated preparation. The reader is directed to previous reports that highlight the advantages and disadvantages of this model (Paton, 1996, 1999), as well as a recent modification that facilitates electrically induced muscle contraction (Potts et al. 2000). Using this preparation, we found that baroreflex-evoked bradycardia was substantially blunted when somatosensory afferents were activated by muscle contraction. In support of our hypothesis, baroreflex bradycardia was restored to control levels when GABAergic transmission was blocked by pretreatment with bicuculline, a selective GABAA receptor antagonist, which was microinjected into the NTS. Although these data support the notion that somatosensory feedback inhibits baroreflex function by promoting GABA release, they do not provide direct evidence for resetting. This issue must be addressed by future research.
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and C fibre afferents that typically possess activation thresholds that are lower then classical nociceptive afferents (Mense & Stahnke, 1983; Kaufman & Rybicki, 1987; Kaufman et al. 2002). Thus, it seems likely that the populations of somatic afferents activated in these studies may have differed. Interestingly, despite this difference both studies found that the arterial–cardiac baroreflex was depressed by a GABAergic mechanism activated by somatosensory input. This observation could be used to suggest that this GABA mechanism in the NTS may be a common inhibitory circuit involved in the processing of viscerosensory inputs. In other words, it may be possible that different sensory inputs to the NTS may be inhibited by somatosensory activation, since they converge onto a common GABA circuit. However, this may not always be the case. While Boscan reported that somatosensory input depressed both arterial baroreflex and peripheral chemoreflex function (Boscan & Paton, 2002a), we failed to observe depression of peripheral chemoreflex function (see Fig. 4B). This finding instead suggests that activation of this GABA circuit may depend upon the modality of somatosensory input. However, without a detailed understanding of the organization and connectivity between viscerosensory inputs and this GABAergic circuit, a definite answer awaits future research. Somatosensory-evoked GABAergic inhibition of baroreflex function requires NK1 receptor activation
There is a large body of evidence showing that the tachykinin substance P (SP) is involved in cardiorespiratory regulation. It has been suggested that SP probably functions as a fast neurotransmitter or a neuromodulator of glutamatergic transmission (Helke et al. 1980; Gillis et al. 1980; Gatti et al. 1995; Maley, 1996; Helke & Seagard, 2004). It has also been reported that cardiorespiratory regions in the medulla, including the NTS, nucleus ambiguus (NA), hypoglossal motor nucleus (XII) and the ventral respiratory group (VRG), express NK1 receptors (NK1-Rs; Lawrence & Jarrott, 1996; Dixon et al. 1998; Gray et al. 1999; Wang et al. 2001; Guyenet et al. 2002). Furthermore, activation of somatic and arterial baroreceptor afferents evokes local release of SP in the NTS (Williams & Fowler, 1997; Potts et al. 1999; Potts & Fuchs, 2001; Williams et al. 2002). Although it is known that SP potentiates inward ionic currents in sensory neurones mediating excitatory signalling in the spinal cord (Lepre et al. 1993; Kato et al. 2002), it is not known whether SP release in the NTS can modulate inhibitory signalling.
Recent studies have shown that NK1-Rs can, in fact, promote inhibitory neurotransmission in several regions of the brain, including the NTS (Olpe et al. 1987; Perez et al. 1992; Sloviter et al. 2001; Sekizawa et al. 2003; Bailey et al. 2004). In addition, it has been shown that SP evokes cardiovascular responses that may be dependent upon changes in baroreflex function, although there are discrepancies between these studies (Talman & Reis, 1981; Carter & Lightman, 1985; Kubo & Kihara, 1987; Chan et al. 1990; Barnes et al. 1991; Feldman, 1995; Seagard et al. 2000; Bauman et al. 2002; Boscan et al. 2002a; Pickering et al. 2003; Abdala et al. 2003; Bailey et al. 2004). Importantly, Boscan and colleagues showed that somatosensory-evoked depression of baroreflex function could be reversed by pharmacological blockade of either NK1 or GABAA receptors in the NTS (Boscan et al. 2002b), suggesting that activation of NK1-Rs indeed modulates GABAergic signalling in medullary autonomic circuits.
As discussed above, there is evidence that neural feedback from skeletal muscle promotes SP release which, in turn, depresses baroreflex function by activating GABA circuits in the NTS. However, it is currently unknown whether somatosensory input evokes GABA release directly or indirectly. In terms of an indirect mechanism, NK1-Rs expressed on excitatory NTS neurones may make synaptic contact with GABAergic interneurones. In this manner activation of excitatory NTS neurones, presumably by glutamate, would depolarize inhibitory GABA neurones and release GABA. In partial support of this idea, both anatomical and functional evidence has reported that excitatory NTS neurones express NK1-Rs (Lawrence & Jarrott, 1996; Maley, 1996; Riley et al. 2002). Furthermore, the NTS contains a synaptically connected network of both excitatory and inhibitory interneurones (Kawai & Senba, 1996, 1999). Taken together, this suggests that the necessary ‘neural substrates’ are in place for such a mechanism. The other possibility is that somatosensory-evoked GABA release may result from direct synaptic input onto inhibitory GABA interneurones. Although there is currently no direct evidence to support this mechanism, we have been actively pursuing this possibility.
Recently, we have developed an immunohistochemical approach using a monoclonal antibody against glutamic acid decarboxylase (GAD67), the rate-limiting enzyme for GABA synthesis and a known marker of GABA neurones (Stornetta et al. 2002), to directly visualize GABA-containing cell bodies in the brainstem (Fong et al. 2005). As shown in Fig. 5, we have modified this approach so that we can determine whether NK1-R protein is colocalized with GABA neurones in the NTS. Although this work is on-going, we are finding that colocalization of NK1-R and GABA neurones is restricted to the caudal NTS in a pattern that is similar to the pattern of axonal labelling in the NTS by spinal dorsal horn neurones that we and others have previously reported (Gamboa-Esteves et al. 2002; Potts et al. 2002). In addition, using in situ hybridization of GAD67 mRNA we have found that some spinal dorsal horn processes are in close apposition with GAD67-expressing NTS neurones (see Fig. 5B). Taken together, these intriguing preliminary data suggest that neural feedback from skeletal muscle may directly stimulate GABA release in the NTS.
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Neural cardiovascular regulation and baroreflex resetting during exercise is extremely complex, involving changes in neurotransmission that effect both central and peripheral neurones. In the present paper, a central interaction model has been developed in which neural feedback from somatic afferents, stimulated by muscle contraction, project to and activate a cascade of events in the NTS that ultimately result in local release of GABA that selectively inhibits barosensitive neurones. This model in presented in Fig. 6. In terms of baroreceptor signalling within the NTS, it is proposed that primary baroreceptor afferents corelease glutamate and SP, which activate postsynaptic glutamate receptors and NK1-Rs expressed on second order barosensitive glutamatergic interneurones (Talman et al. 1980; Gordon, 1995; Andresen et al. 2004). This information is then transmitted through the NTS network and ultimately activates NTS output neurones that project to and excite CVM in the NA and inhibit sympathetic premotor neurones in the rVLM. We propose that feedback from skeletal muscle receptors directly activates a population of GABA neurones in the NTS that express NK1-Rs. Depolarization of these neurones releases GABA in a manner that selectively targets and inhibits barosensitive NTS neurones. It is our contention that, owing to the confined expression of this ‘somato-GABAergic’ mechanism to the caudal NTS the resulting degree of NTS inhibition is sufficient to shunt barosensitive neurones, resulting in ‘functional resetting’ of the arterial baroreflex while retaining overall sensitivity.
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