Alastair V. Ferguson

The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function.

The hypocretins/orexins are hypothalamic peptides most recognized for their significant effects on feeding and arousal. Indeed, loss of the peptides results in a cataplexy quite similar to that observed canine models of human narcolepsy. However, neurons producing these peptides project to numerous brain sites known to be important in neuroendocrine regulation of pituitary function and autonomic centers as well. Results from numerous laboratories have suggested broad physiological roles for the hypocretins/orexins in neuroendocrine and autonomic regulation as a consequence of actions in the dorsal vagal complex, paraventricular nucleus, and pituitary. This review focuses upon evidence for potential physiologic roles for the peptides in these sites.

Sensory circumventricular organs: central roles in integrated autonomic regulation

Circumventricular organs (CVO) play a critical role as transducers of information between the blood, neurons and the cerebral spinal fluid (CSF). They permit both the release and sensing of hormones without disrupting the blood-brain barrier (BBB) and as a consequence of such abilities the CVOs are now well established to have essential regulatory actions in diverse physiological functions. The sensory CVOs are essential signal transducers located at the blood-brain interface regulating autonomic function. They have a proven role in the control of cardiovascular function and body fluid regulation, and have significant involvement in central immune response, feeding behavior and reproduction, the extent of which is still to be determined. This review will attempt to summarize the research on these topics to date. The complexities associated with sensory CVO exploration are intense, but should continue to result in valuable contributions to our understanding of brain function.

Nitric oxide regulates NMDA-driven GABAergic inputs to type I neurones of the rat paraventricular nucleus.

1. Whole‐cell recordings were obtained from type I paraventricular nucleus (PVN) neurones in coronal slices of rat hypothalamus to study the involvement of nitric oxide (NO) in the modulation of inhibitory transmission resulting from the activation of N‐methyl‐D‐aspartate (NMDA) receptors by the high affinity receptor agonist D,L‐tetrazol‐5‐ylglycine. 2. A brief pulse of NMDA agonist (0.1‐10 microM) faithfully elicited increases in action potential firing frequency in all type I cells tested (n = 55). In cells with membrane potentials positive to ‐75 mV, this excitation was accompanied by an underlying depolarization (> 2 mV) in the majority of cases (n = 45). At membrane potentials negative to ‐75 mV, NMDA agonist application elicited an initial monotonie depolarization, which was auxiliary to profound, rhythmic oscillations of the membrane potential, resulting in the emergence of burst‐like activity in these cells (n = 8). 3. In addition to depolarizing the neurones, the NMDA agonist also elicited inhibitory postsynaptic potentials (IPSPs) in 40% (n = 22) of the cells tested. The IPSPs were inhibited by the GABAA receptor antagonist bicuculline methiodide (BMI). 4. Microdialysis of NO into the PVN has been shown to increase local levels of inhibitory neurotransmitters, including GABA. The possibility that NO‐induced increases in GABA lead to an increase in inhibitory synaptic activity in PVN was investigated by administering NO by three different methods. Bath application of the donor compound, S‐nitroso‐N‐acetyl‐penicillamine (SNAP; n = 7), bubbled NO solution (n = 5), or the NO precursor L‐arginine (n = 6) all elicited increases in IPSP frequency. 5. Production of NO in other brain centres has been linked to the activation of the NMDA receptor. In order to determine whether the increase in IPSPs following NMDA was the result of activation of NO, the production of NO was blocked with the NO synthase inhibitor N omega‐nitro‐L‐arginine methylester (L‐NAME). Subsequent NMDA receptor activation elicited more pronounced depolarizations, but there was no accompanying increase in IPSP frequency (n = 5). 6. This study demonstrates that GABAergic inhibition resulting from NMDA receptor activation can be regulated profoundly by NO. By increasing inhibitory transmission within a nucleus, NO may serve as an important intermediary in the regulation of neuronal excitability in the central nervous system.

Angiotensin II:A peptidergic neurotransmitter in central autonomic pathways

Over the past 20 years a growing body of evidence has been directed to establishing the roles of angiotensin II (ANG) within the central nervous system. When this work began in the late 1970s the concept that this circulating hormone may also act as a neurotransmitter within the brain was contrary to the established dogma regarding synaptic transmission. There is now substantial anatomical data describing the distribution of ANG receptors, and the biochemical machinery for the production of this peptide, within the CNS. In addition many studies have described physiological and cellular consequences of activation of these receptors by both exogenous administration and endogenous release of ANG. Data from single cell studies are now also beginning to elucidate both signal transduction pathways and ion channels, influenced as a consequence of peptide actions at these receptors. These observations effectively establish the status of ANG as a chemical messenger (neurotransmitter) used for synaptic communication by specific populations of CNS neurons.

The Paraventricular Nucleus of the Hypothalamus A Potential Target for Integrative Treatment of Autonomic Dysfunction

Background: The paraventricular nucleus of the hypothalamus (PVN) has emerged as one of the most important autonomic control centers in the brain, with neurons playing essential roles in controlling stress, metabolism, growth, reproduction, immune and other more traditional autonomic functions (gastrointestinal, renal and cardiovascular). Objectives: Traditionally the PVN was viewed as a nucleus in which afferent inputs from other regions were faithfully translated into changes in single specific outputs, whether neuroendocrine or autonomic. Here we present data which suggest that the PVN plays significant and essential roles in integrating multiple sources of afferent input and sculpting an integrated autonomic output by concurrently modifying the excitability of multiple output pathways. In addition, we highlight recent work that suggests that dysfunction of such intranuclear integrative circuitry contributes to the pathology of conditions such as hypertension and congestive heart failure. Conclusions: This review highlights data showing that individual afferent inputs (subfornical organ), signaling molecules (orexins, adiponectin), and interneurons (glutamate/GABA), all have the potential to influence (and thus coordinate) multiple PVN output pathways. We also highlight recent studies showing that modifications in this integrated circuitry may play significant roles in the pathology of diseases such as congestive heart failure and hypertension.

Orexin actions in hypothalamic paraventricular nucleus: physiological consequences and cellular correlates

Orexinergic neurons originating in the perifornical, lateral hypothalamus project to numerous brain sites including neuroendocrine centers known to be important in the physiologic response to stress. Those projections suggest an action of endogenous orexin on adrenocorticotropin (ACTH) release, either by neuromodulatory effects in the paraventricular nucleus (PVN), or by neuroendocrine actions in the pituitary gland following release into the median eminence. We sought to determine if exogenously applied orexin A might act in the brain to alter ACTH release and to determine if a site of action in the hypothalamic paraventricular nucleus could be identified. Cerebroventricular administration of orexin A in conscious male rats resulted in a dose-related elevation in circulating ACTH levels. At 30 min post-infusion, ACTH levels were elevated 2.5-fold by the low dose of orexin A (0.3 nmol), 5.7-fold by the middle dose tested (1.0 nmol), and 7.5-fold by the highest dose tested (3.0 nmol). Pretreatment with a CRH-antagonist (i.v.) blocked the ability of i.c.v. administered orexin A to activate the hypothalamo-pituitary-adrenal (HPA) axis. Bath application of orexin A in hypothalamic slice preparations resulted in depolarizations (8.0+/-0.6 mV), accompanied by increases in spike frequency in identified magno- and parvocellular neurons in the PVN. Our data suggest a potential role for endogenous orexin in the hypothalamic regulation of stress hormone secretion.

The Area Postrema: A Brain Monitor and Integrator of Systemic Autonomic State

The area postrema is a medullary structure lying at the base of the fourth ventricle. The area postremas privileged location outside of the blood-brain barrier make this sensory circumventricular organ a vital player in the control of autonomic functions by the central nervous system. By virtue of its lack of tight junctions between endothelial cells in this densely vascularized structure and the presence of fenestrated capillaries, peptide and other physiological signals borne in the blood have direct access to neurons that project to brain areas with important roles in the autonomic control of many physiological systems, including the cardiovascular system and systems controlling feeding and metabolism. However, the area postrema is not simply a conduit through which signals flow into the brain, but it is now being recognized as the initial site of integration for these signals as they enter the circuitry of the central nervous system. NEUROSCIENTIST 14(2):182—194, 2008. DOI: 10.1177/1073858407311100

ACTIONS OF ANGIOTENSIN IN THE SUBFORNICAL ORGAN AND AREA POSTREMA: IMPLICATIONS FOR LONG TERM CONTROL OF AUTONOMIC OUTPUT

1. Considerable physiological and anatomical evidence indicates that circulating angiotensin II (AngII), plays important roles in the long‐term regulation of autonomic output as a result of actions in two circumventricular structures, the subfornical organ (SFO) and area postrema (AP).

Hormonal and Neurotransmitter Roles for Angiotensin in the Regulation of Central Autonomic Function

In this review we present the case for both hormonal and neurotransmitter actions of angiotensin II (ANG) in the control of neuronal excitability in a simple neural pathway involved in central autonomic regulation. We will present both single-cell and whole-animal data highlighting hormonal roles for ANG in controlling the excitability of subfornical organ (SFO) neurons. More controversially we will also present the case for a neurotransmitter role for ANG in SFO neurons in controlling the excitability of identified neurons in the paraventricular nucleus (PVN) of the hypothalamus. In this review we highlight the similarities between the actions of ANG on these two populations of neurons in an attempt to emphasize that whether we call such actions “hormonal” or “neurotransmitter” is largely semantic. In fact such definitions only refer to the method of delivery of the chemical messenger, in this case ANG, to its cellular site of action, in this case the AT1 receptor. We also described in this review some novel concepts that may underlie synthesis, metabolic processing, and co-transmitter actions of ANG in this pathway. We hope that such suggestions may lead ultimately to the development of broader guiding principles to enhance our understanding of the multiplicity of physiological uses for single chemical messengers.

Angiotensin II actions in paraventricular nucleus: functional evidence for neurotransmitter role in efferents originating in subfornical organ

Angiotensin II (ANG) has been suggested to be the neurotransmitter utilised by subfornical organ (SFO) efferents projecting to the paraventricular nucleus (PVN). The PVN has been shown to be involved in mediating the cardiovascular response elicited by electrical stimulation of SFO. The possible role of ANG as a neurotransmitter in these pathways has been examined in the present study. The cardiovascular effects of ANG microinjection into the PVN were examined in urethane anaesthetized, male Sprague-Dawley rats. Microinjection of 20 ng or 50 ng ANG into PVN resulted in mean increases in blood pressure of 12.8 +/- 0.6 mmHg (P < 0.0005), and 16.2 +/- 1.4 mmHg (P < 0.0001) respectively, without effect on heart rate. These responses were significantly attenuated following systemic administration of losartan, an ANG type 1 receptor (AT1) antagonist (Control, +12.8 +/- 0.6 mmHg; post-losartan, +5.6 +/- 1.7 mmHg), but were unaffected by the AT2 receptor antagonist, PD123319 (Control, +10.8 +/- 1.6 mmHg; post-PD123319, +11.6 +/- 2.4 mmHg). Initial and later components of the biphasic pressor response elicited by electrical stimulation of SFO (200 microA, 10 Hz, 1 ms pulse width, 10 s) were also significantly attenuated by losartan, but unaffected by PD123319. The short latency increase in mean arterial pressure was 16.6 +/- 2.3 mmHg in comparison to a post-losartan increase of 9.3 +/- 1.6 mmHg (P < 0.001). Similarly, the secondary response consisted of a control increase of 9.6 +/- 1.3 mmHg and a post-losartan increase of 3.4 +/- 0.9 mmHg (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)