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Review
, 305 (3), R187-204

C1 Neurons: The Body's EMTs

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Review

C1 Neurons: The Body's EMTs

Patrice G Guyenet et al. Am J Physiol Regul Integr Comp Physiol.

Abstract

The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension.

Keywords: C1 neurons; blood pressure; brain stem.

Figures

Fig. 1.
Fig. 1.
Location and principal axonal projections of the C1 neurons. A: schematic representation of the location and main axonal projections of the C1 neurons (parasagittal view). B: higher resolution view of the pontomedullary region outlined in A showing the location of the C1 cells in relation to nearby anatomical structures. The location of the other groups of central nervous system (CNS) adrenergic neurons (C2 and C3) is also represented. The C1 neurons (in green) reside in the ventrolateral medulla (green oval in B) from the retrotrapezoid nucleus rostrally (RTN, putative central respiratory chemoreceptors) to the rostral one third of the lateral reticular nucleus (LRt, a precerebellar nucleus). The C1 neurons are located slightly ventral to the ventral respiratory group (VRG). The main projections of the C1 cells include lower brain stem noradrenergic neurons (A1, 2, 5, 6, 7, in blue), selected serotonergic neuron-rich regions (raphe pallidus RPa, dorsal raphe), the dorsal vagal complex (nucleus of the solitary tract and dorsal motor nucleus of the vagus, NTS/DMV), the intermediolateral cell column (IML) and numerous brain nuclei involved in the regulation of the sympathetic nervous system (SNS), parasympathetic nervous system (PNS) and the pituitary. The main rostral targets are the lateral parabrachial nuclei (PBN), the periacqueductal grey matter (PAG), and, in the hypothalamus, the paraventricular nucleus (PVH), the dorsomedial nucleus (DMH) and the perifornical area (PfA; the orexin neuron-rich area) and others (median preoptic area and medial preoptic nucleus, MPA, MPo). The C1 neurons also innervate the paraventricular nucleus of the thalamus (PVT), noted for its role in stress responses. FN, facial motor nucleus; Mo5 trigeminal motor nucleus; NA, nucleus ambiguus; tpz, trapezoid body. The axonal projections of the C1 neurons are based primarily on the result of virus-based tracing methods in rat and mouse (1, 30). Subsets of C1 neurons have more limited axonal projections. In general, most presympathetic C1 neurons do not innervate the hypothalamus. C: rostrocaudal distribution of the C1 cells (bulbospinal and other) and GABAergic interneurons that relay the baroreflex. The ordinate represents the number of neurons per transverse section (normalized to maximum) and the abscissa the Bregma level of the sections as per an atlas (138). The primary data are from Refs. and 157. For comparison, the location of the three overlapping segments of the ventral respiratory column (BotC, Bötzinger complex; PreBotC, pre-Bötzinger complex; rVRG, rostral ventral respiratory group) are also represented (166). AP midpoint, midpoint of area postrema; CVLM, caudal VLM; IVLM, intermediate VLM; RVLM, rostral VLM; NAc, compact portion of nucleus ambiguus. The rostral end of the LRt (arrow) refers to the anterior tip of the bilobated portion of the nucleus according to (138).
Fig. 2.
Fig. 2.
Contribution of the C1 cells to the autonomic responses to hypotension. This and the following three figures are color-coded as follows: C1 neurons in pale blue, autonomic neurons and hormone releasing PVH neurons in orange, excitatory glutamatergic neurons (except C1 cells) in green, inhibitory presumably GABAergic neurons in magenta. Hypotension disinhibits (activates) many C1 cells via a pathway that consists minimally of three neurons: baroreceptor afferent neurons (baroreceptor), glutamatergic neurons located in the NTS and projecting to the ventrolateral medulla and, finally, IVLM GABAergic interneurons innervating the C1 cells (158). Barosensitive C1 neurons located in the rostral ventrolateral medulla (RVLM) are predominantly bulbospinal. Barosensitive C1 neurons located in the IVLM innervate the hypothalamus among other places. The spinally projecting C1 cells innervate preganglionic sympathetic neurons located in the intermediolateral cell column (IML) that control a variety of vascular beds and the heart plus the norepinephrine (NE)-releasing chromaffin cells of the adrenal medulla (Adr). Hypotension also activates breathing by stimulating the central respiratory pattern generator (CRG). There is no direct evidence that this effect is mediated by axonal collaterals of presympathetic barosensitive C1 neurons as depicted. Hypotension also triggers the CRH/ACTH/corticosterone cascade, presumably through direct projections from IVLM C1 neurons to the paraventricular nucleus of the hypothalamus (PVH). Direct projections of barosensitive C1 cells to the PVH may also activate magnocellular vasopressin (VP)-releasing neurons and preautonomic PVH neurons that control renal sodium excretion. C1 cells, directly and/or indirectly (i.e., via A1 noradrenergic neurons) also activate the release of oxytocin (OT) from the supraoptic nucleus (SO). Barosensitive C1 cells also activate subsets of CNS noradrenergic neurons (not illustrated, see Fig. 5).
Fig. 3.
Fig. 3.
Contribution of the C1 cells to the autonomic responses to hypoxia. Hypoxia activates the C1 cells via a minimally disynaptic pathway that consists of carotid body (CB) afferents activated by a reduction in Po2 and a projection from the caudal portion of the NTS to the VLM. CNS hypoxia may also directly or indirectly (via the glia) activate the C1 cells, an effect that may contribute to the Cushing reflex. Three classes of hypoxia-activated C1 cells are represented. RVLM C1 cells innervate preganglionic sympathetic neurons that regulate several vascular beds, the myocardium, and the adrenal medulla, including noepinephrine and epinephrine (E)-releasing cells. This projection likely consists of several subsets of C1 cells (see Fig. 6). Activation of the C1 cells by hypoxia may also increase breathing via stimulation of the CRG. Hypoxia also probably activates the cardiovagal outflow via direct inputs from IVLM C1 neurons to cardiovagal neurons located in the DMV. Activation by hypoxia of IVLM C1 neurons increases CRH release and reduces the activity of presympathetic neurons in the raphe pallidus (RPa) that regulate sympathetic efferent activity to brown adipose tissue (BAT). This inhibition probably operates via projections from IVLM C1 cells to both to the RPa and to the PVH. For color coding, see Fig. 1.
Fig. 4.
Fig. 4.
Contribution of the C1 cells to the glucoprivic responses. Hypoglycemia activates a subset of presympathetic C1 cells that regulate the epinephrine-releasing chromaffin cells. Hypoglycemia-responsive C1 cells may stimulate gastrointestinal (GI) activity via a direct input to the DMV. C1 cells with projections to the PVH activate the CRH/ACTH/corticosterone cascade and stimulate appetite for carbohydrates. Appetite stimulation by the C1 cells may operate via inhibition of a subset of PVH neurons that target the NTS and the parabrachial region (PBN). The C1 neurons may inhibit these PVH neurons by releasing NPY and catecholamines or, since the C1 neurons are glutamatergic, may recruit unspecified inhibitory interneurons represented in magenta. Hypoglycemia also inhibits BAT activity possibly via activation of IVLM C1 neurons innervating the RPa and the PVH. Three subsets of hypoglycemia-responsive C1 cells are represented but the actual number is unknown.
Fig. 5.
Fig. 5.
C1 cells activate central and peripheral noradrenergic neurons. C1 cells innervate and activate the locus coeruleus (A6) and other pontine noradrenergic neurons (A5). Evidence that the C1 neurons activate A1 and A2 neurons is based on unpublished evidence from our laboratory and is consistent with the sensitivity of these noradrenergic neurons to hypotension (inhibition) and hypoxia (activation). Given the ubiquitous nature of noradrenergic terminals in the forebrain and the prominent effect of norepinephrine (NE) on glial cells, activation of the LC by the C1 cells may be beneficial to neuronal function in the face of a reduction of AP, partial pressure of oxygen or glucose. Strictly by analogy, one function of the A5 projection to the IML could be to stimulate glial metabolism when the activity of sympathetic preganglionic neurons, hence their metabolic demand, is highest (e.g., hypotension, hypoxia, hemorrhage, and hypoglycemia). A1 and A2 neurons may have more specialized functions (neuroendocrine regulation, control of VP/OT release).
Fig. 6.
Fig. 6.
C1 cells as “emergency medical technicians.” Differential recruitment of subsets of C1 cells for different emergency responses. Hypothetical scheme that illustrates how the differential recruitment of 12 subsets of C1 cells by hypotension, hypoxia, diving, or hypoglycemia might produce a response pattern adapted to each situation. The anatomical target of each type of C1 cells and the postulated physiological effect produced by their activation are also indicated. Green: responses mediated by C1 cells that innervate parasympathetic preganglionic neurons. Black: responses mediated by C1 cells that innervate sympathetic preganglionic neurons. White: responses mediated by C1 cells that innervate the PVH and other forebrain regions. Gray: responses mediated via activation of the CNS noradrenergic system (locus coeruleus, etc.). Orange: response mediated by activation of the respiratory pattern generator. The number of C1 cell subsets could be smaller if some of the responses listed are produced by axonal collaterals. For example the CNS noradrenergic neurons could be activated by collaterals of the presympathetic neurons that regulate the circulation and by collaterals of glucose-sensitive cells (presympathetic or others).

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