Monica M. Caverson

Function of the ventrolateral medulla in the control of the circulation

The CNS control of the cardiovascular system involves the coordination of a series of complex neural mechanisms which integrate afferent information from a variety of peripheral receptors and produce control signals to effector organs for appropriate physiological responses. Although it is generally thought that these control signals are generated by a network of neural circuits that are widely distributed in the CNS, over the last two decades a considerable body of experimental evidence has accumulated suggesting that several of these circuits involve neurons found on or near the ventral surface of the medulla oblongata. Neurons in the VLM have been shown to be involved in the maintenance of vasomotor tone, in baroreceptor and chemoreceptor (central and peripheral) reflex mechanisms, in mediating the CIR and somatosympathetic reflexes and in the control of the secretion of vasopressin. These physiological functions of VLM neurons have been supported by neuroanatomical and electrophysiological studies demonstrating direct connections with a number of central structures previously implicated in the control of the circulation, including the IML, the site of origin of sympathetic preganglionic axons, and the SON and PVH, the site of origin of neurohypophyseal projecting axons containing AVP. Considerable suggestive evidence has also been obtained regarding the chemical messengers involved in transmitting information from VLM neurons to other central structures. There have been developments suggesting a role for monoamines and neuropeptides in mediating the neural and humoral control of SAP by neurons in the VLM. This review presents a synthesis of the literature suggesting a main role for VLM neurons in the control of the circulation.

Direct pathway from cardiovascular neurons in the ventrolateral medulla to the region of the intermediolateral nucleus of the upper thoracic cord: an anatomical and electrophysiological investigation in the cat.

Horseradish peroxidase (HRP) and single unit recording experiments were done in cats to identify neurons in the ventrolateral medulla (VLM) projecting directly to the intermediolateral nucleus (IML) of the thoracic cord and relaying cardiovascular afferent information from the buffer nerves and hypothalamus. In the first series, HRP was allowed to diffuse from a micropipette into the region of the IML at the level of T2. After a survival period of 30-138 h, transverse and horizontal sections of the brainstem were processed according to the tetramethyl benzidine method. Labeled neurons were found in the VLM 1-5 mm rostral to the obex, bilaterally, but with an ipsilateral predominance. The majority were observed in sections 2-4 mm rostral to the obex, clustered in an area lateral to the inferior olivary nucleus around the intramedullary rootlets of the hypoglossal nerve. Additional labeled neurons were found scattered along the ventral surface of the medulla; most of these neurons were oval in shape, 15-30 micron in diameter, and had dendritic processes which lay parallel to the ventral surface. In the second series, the region of the VLM shown to contain labeled neurons was systematically explored for single units antidromically activated by electrical stimulation of the IML in chloralosed, paralyzed and artificially ventilated animals. These antidromically identified units were then tested for their responses to electrical stimulation of the carotid sinus (CSN) and aortic depressor (ADN) nerves, and the paraventricular nucleus (PVH). Ninety-four single units in the VLM were antidromically activated with latencies corresponding to a mean conduction velocity of 19.1 +/- 1.5 m/s. Of these units 52% (49/94) were orthodromically excited by stimulation of buffer nerves; 12 by stimulation of the CSN only (mean latency, 16.0 +/- 3.6 ms), 5 by stimulation of the ADN only (mean latency, 9.5 +/- 2.0 ms), 7 by both buffer nerves, and the remaining 25 units responded to at least one of the buffer nerves and to PVH. Stimulation of PVH excited orthodromically 42 of the 94 units (45%), of which 17 responded only to stimulation of PVH (mean latency, 17.9 +/- 3.5 ms). These experiments provide anatomical and electrophysiological evidence for the existence of a direct cardiovascular pathway from the VLM to the region of the IML and suggest that neurons in the VLM are involved in the integration of cardiovascular afferent inputs from buffer nerves and the hypothalamus to provide an excitatory input to vasoconstrictor neurons in the IML.

Lesions of the paraventricular nucleus alter the development of spontaneous hypertension in the rat.

The role of the paraventricular nucleus of the hypothalamus (PVH) in the development of hypertension was determined after bilateral electrolytic or sham lesions of this structure in 4-5-week-old male spontaneously hypertensive rats (SHR). The average arterial pressure in the PVH-lesioned group was significantly lower compared to sham-lesioned animals during the first 3 weeks after the PVH lesions. At 9 weeks of age the arterial pressures of the PVH-lesioned animals increased, but remained significantly lower than those of the sham-operated animals of the same age. This difference in arterial pressures was observed to 16 weeks of age. Heart rate was significantly reduced by PVH lesions up to 5 weeks after the lesions, at which point the heart rate tended towards the control values of the sham-lesioned animals. These data have demonstrated that the region of the PVH is important in the initial phase of the development of hypertension and in the full expression of the hypertension in the SHR, and provide evidence of a central mechanism in the hypertensive process in the SHR.

Bidirectional cardiovascular connections between ventrolateral medulla and nucleus of the solitary tract

Single-unit recording experiments were done in chloralose-anesthetized, paralyzed and artificially ventilated cats to identify neurons in ventrolateral medulla (VLM) that send efferent axons directly to the region of the nucleus of the solitary tract (NTS) and receive cardiovascular afferent inputs from the carotid sinus (CSN) and aortic depressor (ADN) nerves and the NTS. Units in VLM were identified by antidromic excitation to stimulation of functionally and histologically verified sites in the NTS complex. Antidromic potentials were recorded from 34 units in VLM. Units responded with a mean antidromic latency of 4.37 +/- 0.32 ms corresponding to a mean conduction velocity of 0.93 +/- 0.07 m/s. Of these 34 units, 18 were excited orthodromically by stimulation of the CSN and/or ADN. Furthermore, 10 of the 18 units responding to stimulation of the buffer nerves were also orthodromically excited by stimulation of NTS. An additional 76 units were identified in VLM that only responded orthodromically to stimulation of NTS with a mean latency of 9.75 +/- 2.93 ms, of which 33 also responded orthodromically to stimulation of the buffer nerves. These data provide electrophysiological evidence of a bidirectional connection between neurons in VLM that receive and integrate peripheral cardiovascular afferent inputs and send efferent axons directly back to the region of NTS. These results suggest that neurons in the VLM may be part of a medullary feedback reflex loop through which afferent information from cardiovascular receptors exerts an influence on NTS neurons involved in the control of the circulation.

Cardiovascular afferent inputs to neurons in the ventrolateral medulla projecting directly to the central autonomic area of the thoracic cord in the cat

Experiments were done in chloralosed, paralyzed and artificially ventilated cats to identify single units in the ventrolateral medulla (VLM) projecting directly to the central autonomic area of the thoracic cord (CA) and responding to peripheral and central inputs carrying cardiovascular information. Forty-three single units were antidromically activated in the VLM to stimulation of either ipsilateral or contralateral CA with latencies corresponding to conduction velocities of 27.5 +/- 2.0 m/s. Of these 43 units, only 14 (33%) responded orthodromically to stimulation of either the carotid sinus nerve (CSN) or of pressor sites in the paraventricular nucleus of the hypothalamus (PVH) or both. These experiments have demonstrated a bilateral projection of VLM neurons to the CA and have provided evidence for their role in integrating and mediating cardiovascular information from the CSN and PVH directly to spinal sympathetic centers.

Neuropeptide and serotonin immunoreactive neurons in the cat ventrolateral medulla

The distribution of cell bodies containing serotonin (5-HT)-, substance-P (SP)-, neurotensin (NT)-, and somatostatin (SS)-like immunoreactivity (IR) in ventrolateral medulla (VLM) of the cat was studied immunohistochemically after administration of colchicine into the cisterna magna. Perikarya containing 5-HT-, SP-, NT- or SS-IR were found throughout the rostrocaudal extent of the VLM. Although neurons containing the different neuroactive substances appeared to have an overlapping distribution in VLM, some distinct differences were observed. In the caudal VLM most of the immunoreactive cell bodies observed contained 5-HT-IR. These neurons were found primarily in the region medial to lateral reticular nucleus (LRN) around the exiting intramedullary rootlets of the hypoglossal nerve (12N). In the intermediate region of VLM, perikarya containing 5-HT- and SP-IR were observed primarily near the ventrolateral surface of the medulla in the region around the exiting rootlets of the 12N. In contrast, most of the cells containing NT- and SS-IR were consistently observed to occupy a region in the medullary reticular formation immediately dorsal to that where 5-HT- and SP-IR perikarya were found. Finally, most of the immunoreactive perikarya were found in the rostral VLM; perikarya containing 5-HT- and SP-IR were observed throughout the nucleus paragigantocellularis lateralis (PGL) near the ventrolateral surface of the medulla. These data indicate that neurons immunoreactive to either 5-HT or several different neuropeptides were located in regions of VLM which have previously been implicated in the control of arterial pressure. As regions of VLM containing these neuroactive substances in neuronal perikarya have been shown to have direct connections with spinal sympathetic areas it is likely that these VLM cells are components of neuronal circuits involved in homeostatic mechanisms controlling the circulation.

Direct pathway from neurons in the ventrolateral medulla relaying cardiovascular afferent information to the supraoptic nucleus in the cat

In chloralose anesthetized cats experiments were done to electrophysiologically identify neurons in the ventrolateral medulla (VLM) which relay cardiovascular afferent information directly to the supraoptic nucleus (SON). Action potentials elicited antidromically by electrical stimulation of the SON were recorded from 69 histologically verified single units in the VLM. Single units responded with latencies corresponding to conduction velocities of 7.8 +/- 0.6 m/s. Of these units 26 were excited orthodromically by stimulation of the buffer nerves; 12 responded to stimulation of only the carotid sinus nerve, 7 responded to stimulation of only the aortic depressor nerve, and 7 responded to both buffer nerves. The axons of VLM units that responded to buffer nerves conducted at a significantly slower velocity than those of non-responsive units (5.7 +/- 0.4 and 9.1 +/- 0.8 m/s, respectively). These data provide electrophysiological evidence of two different populations of VLM neurons which project directly to the SON, and suggest that the direct pathway from the VLM to the SON is involved in the release of vasopressin by SON neurons during activation of baroreceptor and chemoreceptor afferent fibers.

Lateral hypothalamic and peripheral cardiovascular afferent inputs to ventrolateral medullary neurons

Experiments were done in chloralose anesthetized, paralyzed and artificially ventilated cats to identify single units in ventrolateral medulla (VLM) projecting directly to the intermediate gray (IG) region of the upper thoracic cord and responding to inputs from pressor sites in the anterior lateral hypothalamus (Hla) and carotid sinus (CSN) and aortic depressor (ADN) nerves. Forty-eight units were antidromically activated in VLM to stimulation of the IG at the level of T2. Of these 48 units, 15 (31%) were orthodromically excited by stimulation of the Hla with a mean latency of 15.8 +/- 2.1 ms. In addition, 8 of the 15 units responding to Hla stimulation were also excited orthodromically by stimulation of either the CSN or ADN or both. Of the remaining 33 units, 15 responded to stimulation of only the buffer nerves and 18 were unresponsive to the tested inputs. These results provide electrophysiological evidence for the existence of neurons in VLM which receive hypothalamic and buffer nerve inputs and suggest that the VLM plays a role in integrating and relaying cardiovascular afferent information from peripheral baroreceptors and chemoreceptors and from supramedullary centers to provide effector signals to spinal autonomic neurons involved in the control of the circulation.

Electrophysiological identification of neurons in ventrolateral medulla sending collateral axons to paraventricular and supraoptic nuclei in the cat

Experiments were done in chloralosed, paralyzed and artificially ventilated cats to identify single units in the ventrolateral medulla (VLM) that send collateral axons directly to the region of the paraventricular (PVH) and supraoptic (SON) nuclei, and responding to peripheral inputs carrying cardiovascular afferent information. Twenty-six single units were antidromically activated in the VLM to stimulation of both the PVH and SON, and in each case the antidromic potential evoked by stimulation of one site was cancelled by stimulation of the other site. These units responded with latencies corresponding to conduction velocities of 5.1 +/- 0.4 m/s. Of these 26 units, 10 responded orthodromically to stimulation of either the carotid sinus or aortic depressor nerves. These data have demonstrated the existence of VLM neurons which send collateral axons to the PVH and SON and have provided evidence for their role in mediating cardiovascular afferent information directly to hypothalamic regions involved in autonomic and neuroendocrine regulation.

Central organization of afferent renal nerve pathways.

Although afferent renal nerves have been studied for over a quarter of a century, their physiological role remains unclear. There is considerable experimental evidence indicating that afferent renal nerves convey sensory information from renal receptors to integrative circuits in the central nervous system which gives rise to command signals controlling the function of effector organs. In addition, it has been demonstrated that these integrative neural circuits are found at several different levels of the neuraxis; the spinal cord, the medulla and the hypothalamus. In this review, recent neuroanatomical and electrophysiological data on the central pathways of afferent renal nerves is discussed with reference to their possible role in homeostasis.