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Using a combination of anterograde and retrograde neuronal tract-tracing techniques, the descending projections from the paraventricular nucleus of the hypothalamus (PVN) to the brain/spinal cord and in particular those axonal projections that appear to be contiguous with sympathetic preganglionic neurones (SPN) projecting to the stellate ganglion have been studied. Descending PVN pathways were located by the anterograde transport of biotinylated dextran amine (BDA), whilst SPN were retrogradely labelled with cholera B toxin subunit conjugated to horseradish peroxidase (CB-HRP). BDA-labelled PVN axons terminated in both hypothalamic and extrahypothalamic (including the midbrain, medulla and spinal cord) brain nuclei, with dense terminal labelling observed particularly in the arcuate hypothalamic nucleus and adjacent median eminence, in the solitary tract, vagal nuclei and in the intermediolateral region of the spinal cord (IML). Varicose descending PVN fibres in the IML were often observed to closely appose both the cell soma and dendrites of retrogradely labelled SPN (projecting to the stellate ganglion) in the spinal cord. In addition, it was shown that PVN descending axons crossing to the contralateral side of the spinal cord were closely associated with retrogradely labelled SPN projecting to the superior cervical ganglion. Such findings suggest that descending pathways from the PVN may exhibit a direct influence on cardiac sympathetic outflow and may also influence the behaviour of the contralateral population of SPN projecting to the superior cervical ganglion.

1. The functional role of the paraventricular nucleus (PVN) has been examined by studying its connections with cardiovascular neurons in the medulla and spinal cord and its influence on activity in several sympathetic nerves. 2. Chemical stimulation of neurons within the PVN can elicit pressor responses and can excite reticulo-spinal vasomotor neurons in the rostral ventrolateral medulla (RVLM). 3. The PVN-RVLM excitation is blocked by kynurenic acid applied iontophoretically in the vicinity of RVLM-spinal neurons, suggesting this is a glutamate-dependent pathway. 4. Electrical stimulation of PVN neurons evoked action potentials in RVLM neurons after 27 ms with a small variability. 5. Anterograde and retrograde labelling of PVN and RVLM neurons revealed PVN terminals closely associated with RVLM-spinal neurons and showed that the PVN is connected to the spinal cord via three pathways. 6. Chemical activation of PVN neurons can produce a pattern of activation of cardiovascular neurons similar to that occurring in defence against plasma volume expansion. 7. It is concluded that the PVN connections with the RVLM and spinal cord are important to a role in defending against life-threatening disturbances.

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Highlights► Ascending NTS fibres target PVN-associated neurons. ► Suggest glutamate as the neurotransmitter. ► Anatomical basis for the different functions of cardiovascular receptors.

New Findings r What is the topic of this review?This review gives an update on the cellular and molecular mechanisms within the autonomic nervous system involved in non-pathological and pathological cardiovascular regulation. r What advances does it highlight?For cardiovascular homeostasis in non-pathological conditions to be maintained, discrete neural networks using specified signalling mechanisms at both cellular and molecular levels are required. In heart failure, the cell signalling protein partners CAPON and PIN decrease the bioavailability of nitric oxide by inhibiting neuronal nitric oxide synthase activity, leading to the removal of tonic neuronal inhibition. Following a myocardial infarction, pro-inflammatory cytokines in the paraventricular nucleus and the subsequent generation of reactive oxygen species, via angiotensin II activation of the angiotensin II type 1 receptor, increase neuronal excitability further, leading to sympathetic excitation.A pathological feature of heart failure is abnormal control of the sympathetic nervous system. The paraventricular nucleus of the hypothalamus (PVN) is one of the most important central sites involved in regulating sympathetic tone and is, in part, responsible for the dysregulation of the sympathetic nervous system evident in heart failure. Generation of sympathetic tone in response to fluctuations in cardiovascular regulation uses discrete anatomical pathways and neurochemical modulators. Direct and indirect projections from the PVN pre-autonomic neurons innervate the sympathetic preganglionic neurons in the spinal cord, which in turn innervate sympathetic ganglia that give rise to the sympathetic nerves. Pre-autonomic neurons of the PVN themselves receive an afferent input arising from the nucleus tractus solitarii, and viscerosensory receptors convey cardiovascular fluctuations to the nucleus tractus solitarii. The PVN contains excitatory and inhibitory neurons, whose balance determines the sympathetic tone. In non-pathological conditions, the tonic inhibition of the PVN pre-autonomic neurons is mediated by GABA-and NO-releasing neurons. In heart failure, the pre-autonomic neurons are disinhibited by the actions of the excitatory neurotransmitters glutamate and angiotensin II, leading to increased sympathetic activity. A key feature of the disinhibition is a reduction in the bioavailability of NO as a consequence of disrupted CAPON and PIN signalling mechanisms within the neuron. Another critical feature that contributes to increased neuronal excitation within the PVN is the production of pro-inflammatory cytokines immediately following a myocardial infarction, the activation of the angiotensin II type 1 receptor and the production of reactive oxygen species. By examining the changes associated with the sympathetic nervous system pathway, we will progress our understanding of sympathetic regulation in heart failure, identify gaps in our knowledge and suggest new therapeutic strategies.

The paraventricular nucleus of the hypothalamus plays a pivotol role in the regulation of plasma volume. Part of the response to an increase in volume load is an inhibition of renal sympathetic nerve activity. The present experiments were designed to determine which subnuclei of the paraventricular nucleus are involved in this sympatho-inhibitory response. Experiments were performed on anaesthetised rats. Activated neurones were recognised by the expression of the early gene c-fos, identified by immunohistochemical labelling of its protein product Fos. Plasma volume loading with 4 % Ficoll 70, using an infusion-withdrawal procedure (2 ml over 1 min) repeated 15 times over 1 h revealed a total of 775 ± 101 (n = 6) Fos-positive neurones scattered throughout both the magnocellular and parvocellular subnuclei. In comparison, sustained hypertension resulted in 452 ± 56 (n = 3) Fos-positive neurones similarly distributed, whereas a normotensive control group (n = 3) displayed 115 ± 18 Fos-positive neurones. Because of this lack of a specific effect we used a more selective stimulation of right atrial receptors via a balloon placed at the junction of the superior vena cava and the right atrium so it did not impede venous return. Inflation of the balloon inhibited renal sympathetic nerve activity (36 ± 5 %, n = 7) and repetitive inflation over 1 h resulted in c-fos activation of a small number of neurones (54 ± 14) located only in the parvocellular subnuclei. Whether these are inhibitory interneurones acting within the paraventricular nucleus, or spinally projecting neurones which inhibit or excite renal sympathetic activity by an action in the spinal cord remains to be determined. Experimental Physiology (2002) 87.1, 25-32.