Function and pharmacology of spinally-projecting sympathetic pre-autonomic neurones in the paraventricular nucleus of the hypothalamus

Abstract

The paraventricular nucleus (PVN) of the hypothalamus has been described as the "autonomic master controller". It co-ordinates critical physiological responses through control of the hypothalamic-pituitary-adrenal (HPA)-axis, and by modulation of the sympathetic and parasympathetic branches of the central nervous system. The PVN comprises several anatomical subdivisions, including the parvocellular/ mediocellular subdivision, which contains neurones projecting to the medulla and spinal cord. Consensus indicates that output from spinally-projecting sympathetic pre-autonomic neurones (SPANs) increases blood pressure and heart rate, and dysfunction of these neurones has been directly linked to elevated sympathetic activity during heart failure. The influence of spinally-projecting SPANs on cardiovascular function high-lights their potential as targets for future therapeutic drug development. Recent studies have demonstrated pharmacological control of these spinally-projecting SPANs with glutamate, GABA, nitric oxide, neuroactive steroids and a number of neuropeptides (including angiotensin, substance P, and corticotrophin-releasing factor). The underlying mechanism of control appears to be a state of tonic inhibition by GABA, which is then strengthened or relieved by the action of other modulators. The physiological function of spinally-projecting SPANs has been subject to some debate, and they may be involved in physiological stress responses, blood volume regulation, glucose regulation, thermoregulation and/or circadian rhythms. This review describes the pharmacology of PVN spinally-projecting SPANs and discusses their likely roles in cardiovascular control.

Keywords: Blood pressure; GABA; PVN; angiotensin; cardiovascular; hypothalamus; neuropeptides; oxytocin; paraventricular nucleus; parvocellular mediocellular; penile erection; pharmacology.; substance P; sympathetic; tachykinin; vasopressin.

Fig. (1)

Spinally-projecting sympathetic pre-autonomic neurones of the paraventricular nucleus of the hypothalamus (PVN). The PVN consists of several sub-populations of neurones some of which project to the spinal cord. There are likely to be each combination indicated in the Venn diagram. This review focuses on the shaded area; spinally-projecting sympathetic pre-autonomic neurones (spinallyprojecting SPANs) of the PVN. Many of these target the cardiovascular system (CVS).

Fig. (2)

Central cardiovascular control in the rat. The cardiovascular system is largely controlled by areas of the brainstem; however, there is also strong evidence that centres in the forebrain, including the PVN, exert “top-level” control via both medulla-projecting and spinally-projecting SPANs. Afferents from carotid baroreceptors ascend via cranial nerve IX (the glossopharangeal nerve), while afferents from the aortic bodies ascend via cranial nerve X (the vagus nerve). These afferents are processed by the nucleus of the solitary tract (NTS). Parasympathetic drive emanates from the nucleus ambiguus, whilst sympathetic drive emanates from a number of locations, in particular the rostroventrolateral medulla. The role of the medulla in cardiovascular control is reviewed by [9].

Fig. (3)

Actions of spinally-projecting SPANs originating in the paraventricular nucleus (PVN) of the hypothalamus. The PVN lies alongside the 3^rd ventricle (3v), and contains a number of neurones which project to the intermediolateralis (IML) of the spinal cord. When stimulated with excitatory neurotransmitters or electrical current, they activate sympathetic pre-ganglionic neurones in the IML which, in turn, increase heart rate and blood pressure and glucose secretion. They may also increase TSH release. These PVN neurones are tonically inhibited by GABA input. Please see main text for references.

Fig. (4)

Methods for patch-clamping retrogradely-labelled neurones. A, the retrograde tracer fluorogold is injected into the rat intermediolateralis (IML) at level T2-T4, it is also possible to use other tracers, such as rhodamine-labelled microspheres (see Fig. 8). The IML is dense with pre-ganglionic neurones that project to the superiocervical (SCG) and stellate (SG) ganglia, and from there to the heart and blood vessels [65, 227]. The appearance of a fluorogold-labelled neurone B, prior to patch clamp recording, C, during patch-clamp, under near infrared differential interference contrast microscopy, and D, when patched with Lucifer yellow (a fluorescent dye) in the patch clamp pipette. The dye fills the neurone, and this gives re-confirmation that recording was from the appropriate cell. Reproduced from [43], with permission.

Fig. (5)

Substance P (SP) increases the rate of action potential discharge of individual neurones in brain slices in the presence of GABA. Brain slices were taken from adult rats, and action potentials recorded from single neurones in the PVN. A, representative results showing SP applied to SPANs under control conditions; B, mean results, showing SP alone has no effect on rate of action potential discharge. C, representative results showing application of GABA; D, mean results showing that GABA inhibits spontaneous action potential frequency. E, representative results showing SP added during GABA inhibition; F, mean results showing that SP increases the rate of action potential discharge against a background of tonic GABA inhibition. G, Representative results showing SP interaction with NK1 antagonism; H, mean results showing the effects of SP are abolished by the selective NK1 antagonist L703606. Cont = control. Reproduced from [54], with permission.

Fig. (6)

Substance P (SP) injected into the PVN elicits a rise in heart rate and blood pressure. Heart rate and blood pressure were recorded in anaesthetised adult rats. Representative records of A, heart rate and B, blood pressure during intra-PVN injection of SP/FITC-SP (solution of SP and FITC-conjugated SP). C, mean data from a number of experiments. D, epifluorescent image of the medial PVN, after SP/FITC-SP intra-PVN injection. “3V” indicates the third ventricle; the white arrow indicates a parvocellular neurone labelled with FITCSP. Scale bar is 50µm. “SP” indicates SP/FITC-SP injection. Reproduced from [54], with permission.

Fig. (7)

Pharmacological control of SPANs within the PVN. Spinally-projecting SPANs are tonically inhibited by GABA input, which is normally enhanced by nitric oxide (NO). However, during chronic heart failure, this potentiation of GABA is lost, leading to an overall increase in sympathetic activity. Substance P (SP) causes indirect activation of spinally-projecting SPANs by inhibition of the inhibitory GABAA receptors, via a protein kinase C (PKC)-dependent pathway.

Fig. (8)

Spinally-projecting SPANs do not co-localise with leptin receptor (OB-R) in rat PVN. Spinally-projecting SPANs were labelled with rhodamine beads (red) using retrograde labelling (see Fig. 2) in an adult rat. A 40µm cryo-slice of the PVN was counter-stained for OB-R (green), using primary goat anti-OB-R IgG, Santa Cruz biotechnology; secondary rabbit anti-goat, Jackson. Scale bar is 10µm. Unpublished data.