Central Regulation Of Autonomic Functions Research Articles

Cardiac vagal tone: a neurophysiological mechanism that evolved in mammals to dampen threat reactions and promote sociality.

Cardiac vagal tone: a neurophysiological mechanism that evolved in mammals to dampen threat reactions and promote sociality.

AJP-Regulatory, Integrative and Comparative Physiology: Looking Toward the Future

<i>AJP-Regulatory, Integrative and Comparative Physiology</i>: Looking Toward the Future

Oxytocinergic Neurons in the Hypothalamic Paraventricular Nucleus Stimulate Brown Adipose Tissue Thermogenesis through Rostral Medullary Raphe

Hypothalamic neurons in the paraventricular nucleus (PVN) produce several neuropeptides, including oxytocin and vasopressin, and send their axons to various brain regions. These PVN neurons have been considered to serve neuroendocrine and autonomic functions, and many studies have demonstrated the involvement of oxytocin in social and emotional behaviors (e.g. maternal and sexual behaviors, and stress responses). Although these behaviors are accompanied with autonomic responses, it is unclear how oxytocin modulates the activities of the autonomic nervous system. To investigate the roles of PVN oxytocinergic neurons in the central regulation of autonomic function, in this study, we first performed neural tract tracing in rats from PVN oxytocinergic neurons to the rostral medullary raphe region (rMR), which contains sympathetic premotor neurons controlling brown adipose tissue (BAT) thermogenesis. In the rMR, oxytocin‐immunoreactive fibers, but not vasopressin‐immunoreactive fibers, were distributed, and oxytocin‐containing terminals were apposed to tryptophan hydroxylase‐expressing (i.e., serotonergic) neurons, potentially BAT sympathetic premotor neurons. Retrograde tracing from the rMR with cholera toxin b‐subunit (CTb) labeled a portion of oxytocinergic neurons in the caudal PVN, but not in the supraoptic nucleus, suggesting that the PVN is a major source of oxytocinergic fibers in the rMR. Then, we performed in vivo BAT sympathetic nerve recording combining optogenetic stimulation of the PVN‐derived oxytocinergic axon terminals in the rMR. Recombinant adeno‐associated viral vectors were injected into the PVN to express the engineered channel rhodopsin variant, ChIEF, under the oxytocin promoter. We confirmed that most of PVN neurons expressing ChIEF‐mCherry contained oxytocin and that their axon fibers were densely distributed in the rMR. Optogenetic stimulation of these fibers evoked BAT sympathetic nerve activities as well as increased expired CO2 and heart rate. Similar thermogenic and cardiac responses were elicited by nanoinjection of oxytocin into the rMR, and these responses were blocked by prior injection of the oxytocin receptor antagonist, L‐368,899 into the rMR. In addition, oxytocin injection into the rMR also potentiated NMDA‐evoked BAT sympathetic nerve activities. These findings indicate that PVN oxytocinergic neurons stimulate thermogenic sympathetic outflow to BAT through activation of rMR neurons. This oxytocinergic pathway may play an important role in emotion‐related autonomic responses.Support or Funding InformationThis work was supported by JSPS KAKENHI Grant Numbers JP16H05128, JP15H05932, JP26118508 (KN) and by AMED under Grant Number JP18gm5010002 (KN)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Strategy of neuropharmacotherapy of autonomic nervous system’s dysfunction

In the present paper the modern sights on the problem of autonomic nervous system’s dysfunction in clinical practice and, particularly, on the peculiarities of natural history and treatment of neurocirculatory distonia have been analyzed. Therapeutic use of drugs – psychoemotional correctors and central adaptogens in this form of pathology has been grounded. A main attention paid to drug Adaptol as adaptogen with central mechanisms of action with properties of anxiolytics and nootropics. Mechanisms of action and clinico-pharmacological effects of Adaptol as harmonizator of central regulation of autonomic functions in CNS, and expediency of its use in the autonomic nervous system dysfunction with the point of view of its efficacy and safety have been looked.

Cognitive Status, Gray Matter Atrophy, and Lower Orthostatic Blood Pressure in Older Adults.

Associations between orthostatic blood pressure and cognitive status (CS) have been described with conflicting results. We hypothesize that long-term exposure to lower orthostatic blood pressure is related to having worse CS later in life and that atrophy of regions involved in central regulation of autonomic function mediate these associations. Three-to-four measures of orthostatic blood pressure were obtained from 1997-2003 in a longitudinal cohort of aging, and average systolic orthostatic blood pressure response (ASOBPR) was computed as % change in systolic blood pressure from sit-to-stand measured at one minute post stand. CS was determined in 2010-2012 by clinician-adjudication (n = 240; age = 87.1±2.6; 59% women; 37% black) with a subsample also undergoing concurrent structural neuroimaging (n = 129). Gray matter volume of regions related to autonomic function was measured. Multinomial regression was used to compare ASOBPR in those who were cognitively intact versus those with a diagnosis of mild cognitive impairment or dementia, controlling for demographics, trajectories of seated blood pressure, incident cardiovascular risk/events and medications measured from 1997 to 2012. Models were repeated in the subsample with neuroimaging, before and after adjustment for regional gray matter volume. There was an inverse association between ASOBPR and probability of dementia diagnosis (9% lower probability for each % point higher ASOBPR: OR 0.91, CI95% = 0.85-0.98; p = 0.01). Associations were similar in the subgroup with neuroimaging before and after adjustment for regional gray matter volume. ASOBPR may be an early marker of risk of dementia in older adults living in the community.

Brain-Selective Overexpression of Angiotensin-Converting Enzyme 2 Attenuates Sympathetic Nerve Activity and Enhances Baroreflex Function in Chronic Heart Failure

Angiotensin-converting enzyme 2 (ACE2) has been suggested to be involved in the central regulation of autonomic function. During chronic heart failure (CHF), elevated central angiotensin II signaling contributes to the sustained increase of sympathetic outflow. This is accompanied by a downregulation of ACE2 in the brain. We hypothesized that central overexpression of ACE2 decreases sympathetic outflow and enhances baroreflex function in CHF. Transgenic mice overexpressing human ACE2 selectively in the brain (SYN-hACE2 [SA]) and wild-type littermates (WT) were used. CHF was induced by permanent coronary artery ligation. Four weeks after coronary artery ligation, both WT and SA mice exhibited a significant decrease in left ventricular ejection fraction (<40%). A slight decrease in mean arterial pressure was found only in SA mice. Compared with WT mice with CHF, brain-selective ACE2 overexpression attenuated left ventricular end-diastolic pressure; decreased urinary norepinephrine excretion; baseline renal sympathetic nerve activity (WT CHF: 71.6±7.6% max versus SA CHF: 49.3±6.1% max); and enhanced baroreflex sensitivity (maximum slope: WT sham: 1.61±0.16%/mm Hg versus SA CHF: 1.51±0.17%/mm Hg). Chronic subcutaneous blockade of mas receptor increased renal sympathetic nerve activity in SA mice with CHF (A779: 67.3±5.8% versus vehicle: 46.4±3.6% of max). An upregulation in angiotensin II type 1 receptor expression was detected in medullary nuclei in WT CHF mice, which was significantly attenuated in SA mice with CHF. These data suggest that central ACE2 overexpression exerts a potential protective effect in CHF through attenuating sympathetic outflow. The mechanism for this effect involves angiotensin (1-7) mas signaling, as well as a decrease in angiotensin II type 1 receptor signaling in the medulla.

ACE2 Inhibits Angiotensin‐II Mediated NADPH Oxidase Activation In The Central Nervous System

ACE2 plays a protective role in the central regulation of autonomic function by reducing oxidative stress. To assess the mechanisms involved, ACE2 KO and non transgenic (NT) mice (n=6) were infused with AngII (osmotic pump: 600 ng/kg/min sc) and infected with a hACE2 or control (eGFP) adenovirus (2×106 pfu, 200 nL) in the PVN 3d post infusion. After 10d of infusion, NADPH oxidase (NOX) and superoxide dismutase (SOD) activity (U/mg), and SOD 1 and 2 protein expression (Immunofluorescence, arbitrary units) were assessed in the brainstem. NOX (2.8 ±0.1 vs. 1.0 ±0.02) and SOD activities (1.4 ±0.1 vs. 1.0 ±0.05; P&lt;0.05) were significantly increased in KO mice (P&lt;0.05 vs. NT), as well as SOD1 (2.5 ±0.6 vs. 1.0 ±0.04) and SOD2 (1.7 ±0.1 vs. 1.0 ±0.05) expression (P&lt;0.05 vs. NT). Post AngII, NOX activity was increased in both KO (3.1 ±0.2) and NT (2.1 ±0.2) and remained higher in the KO (P&lt;0.05 vs. NT), while SOD1 and 2 expression and activity were only increased in the NT (2.3±0.6; 1.6±0.1; 1.2±0.1; respectively, P&lt;0.05 vs. baseline). ACE2 over‐expression reduced NOX activity in the KO without changing SOD expression or activity. These data suggest that ACE2 gene deletion promotes AngII‐mediated oxidative stress, and ACE2 compensation in the PVN decreases oxidative stress in the brainstem by inhibiting NOX activation, thus contributing to the improvement of autonomic function in this model. (HL093178 and APS Postdoctoral Fellowship)

ACE2 prevention of oxidative stress in the brain is associated with a reduction in Angiotensin II‐induced sympathetic vasomodulation

We previously reported the presence of Angiotensin Converting Enzyme type 2 (ACE2) in brain regions involved in cardiovascular regulation. Here we test the role of central ACE2 on oxidative stress and autonomic function. ACE2 knockout (KO) mice (n=3/group) were infected with a hACE2 or control (eGFP) adenovirus (2×10e6 pfu, 200 nL) in the paraventricular nucleus (PVN) 3d before AngII infusion (osmotic pump: 600 ng/kg/min sc). After 4d infusion, mice were injected with dihydroethidium (DHE) intracardially and staining measured in brain regions (Image J, arbitrary units). Baseline blood pressure (BP) (telemetry: 112±7 vs. 111±3 mmHg) and DHE staining in the brain were not different between ACE2 KO and wildtypes. Post infusion, AngII levels in the hypothalamus were significantly higher in KO vs. wildtype mice (RIA: 2.9±0.3 vs. 2.0±0.2 fmol/mg, n=5, P&lt;0.05) and DHE fluorescence in KO (eGFP‐infected) dramatically increased (P&lt;0.01) vs. baseline in the PVN (194±12 vs. 101±3), NTS (52±2 vs. 20±2) and RVLM (207±22 vs. 77±12). This increase was prevented in Ad‐hACE2‐infected KO in the PVN (114±8, P&lt;0.01) as well as in the NTS (22±2, P&lt;0.01) and RVLM (88±8, P&lt;0.01). Moreover, ACE2 gene therapy decreased the LF/HF ratio (BP variability) in AngII‐infused KO (5±1 vs. 9±3). These data support the protective role of ACE2 in the central regulation of autonomic function by reducing oxidative stress. (NIH NS052479 and P20RR018766)

Nitric oxide synthase inhibition in rostral ventrolateral medulla attenuates pressor response to psychological stress in rabbits

Nitric oxide (NO) has been critically implicated in the central regulation of autonomic function. We recently found, however, that acute (up to 30min) blockade of NO synthase (NOS) in the rostral ventrolateral medulla (RVLM) inhibited sympathetic baroreflex transmission, without altering the cardiovascular response to psychological (air-jet) stress in rabbits. In the present study, we examined the effect of the later phase (1-3h) of NOS inhibition in the RVLM on the pressor and sympathetic responses to air-jet stress in conscious rabbits. Air-jet evoked a sustained increase in blood pressure (+14+/-2mmHg), heart rate (+37+/-9beats/min) and renal sympathetic nerve activity (+52+/-8%). Bilateral microinjection of a NOS inhibitor l-NAME (10nmol) into RVLM did not affect resting parameters or stress responses during the first 30min after injection. Conversely, in the later phase of NOS inhibition, the pressor, tachycardic and renal sympathetic responses to air-jet stress were reversibly attenuated by 48-72%. Microinjection of l-NAME outside the RVLM did not change stress responses. Microinjection of glutamate (3nmol) into the RVLM induced similar pressor effects before and after l-NAME (+30+/-6mmHg and +26+/-6mmHg, respectively). Microinjection of d-NAME altered neither stress responses nor pressor response to glutamate. These results suggest that NOS inhibition in the RVLM has a dual effect on the autonomic response to psychological stress. In the early phase, NOS inhibition has little impact on this response. However, in the later phase, NOS inhibition attenuates the stress response, perhaps via indirect mechanisms such as altering the local redox state.

Tonic glutamatergic drive of RVLM vasomotor neurons?

the rostral ventrolateral medulla (RVLM) plays a critical role in the maintenance of baseline arterial pressure (AP) in all species in which it has been examined, and it appears to be the primary site responsible for the tonic supraspinal drive of sympathetic vasomotor outflow and AP, at least in

Secretin depolarizes nucleus tractus solitarius neurons through activation of a nonselective cationic conductance.

The recent suggestion that secretin may be useful in treating autism and schizophrenia has begun to focus attention on the mechanisms underlying this gut-brain peptide's actions in the central nervous system (CNS). In vitro autoradiographic localization of (125)I-secretin binding sites in rat brain shows the highest binding density in the nucleus tractus solitarius (NTS). Recent evidence suggests that intravenous infusion of secretin causes fos activation in NTS, a relay station playing important roles in the central regulation of autonomic functions. In this study, whole cell patch-clamp recordings were obtained from 127 NTS neurons in rat medullary slices. The mean resting membrane potential of these neurons was -54.7 +/- 0.3 mV, the mean input resistance was 3.7 +/- 0.2 GOmega, and the action potential amplitude of these neurons was always >70 mV. Current-clamp studies showed that bath application of secretin depolarized the majority (80.8%; 42/52) of NTS neurons tested, whereas the remaining cells were either unaffected (17.3%; 9/52) or hyperpolarized (1.9%; 1/52). These depolarizing effects were maintained in the presence of 5 microM TTX and found to be concentration dependent from 10(-12) to 10(-7) M. Using voltage-clamp techniques, we also identified modulatory actions of secretin on specific ion channels. Our results demonstrate that while secretin is without effect on net whole cell potassium currents, it activates a nonselective cationic conductance (NSCC). These results show that NTS neurons are activated by secretin as a consequence of activation of a NSCC and support the emerging view that secretin can act as a neuropeptide within the CNS.

Nitric oxide inhibits the firing activity of hypothalamic paraventricular neurons that innervate the medulla oblongata: role of GABA

Nitric oxide (NO) has been shown to modulate autonomic function by acting both peripherally and centrally. A growing body of evidence indicates that the paraventricular nucleus of the hypothalamus (PVN), an important site for autonomic and endocrine homeostasis, constitutes an important locus mediating central NO actions. However, the cellular targets and mechanisms mediating NO actions within the PVN are not completely understood. Here, we examined whether NO influences the firing activity of identified PVN neurons that innervate two functionally different autonomic centers, the dorsal vagal complex (DVC) and the rostral ventrolateral medulla (RVLM). Perforated patch-clamp recordings were performed in hypothalamic slices containing retrogradely labeled PVN neurons innervating the DVC or the RVLM. Application of the NO donors dyethylamine- or 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) NONOate inhibited the firing activity of both DVC- and RVLM-projecting PVN neurons. Furthermore, application of 2-(4-carboxypheny)-4,4,5,5,-tetramethilimidazoline-1-oxyl-3-oxide (carboxy-PTIO), or the relatively selective neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole alone, increased their basal firing activity, suggesting the presence of an endogenous NO inhibitory tone. GABAergic synaptic activity in PVN neurons was potentiated by NO donors, an action that involved a presynaptic mechanism. Furthermore, the NO-mediated inhibition of firing activity was blocked by the GABA A receptor antagonist bicuculline, suggesting that NO-inhibitory actions involved potentiation of local GABAergic synaptic activity. Immunohistochemical studies showed that approximately 25% of DVC- and RVLM-projecting PVN neurons express nNOS, suggesting that a proportion of these medullary-projecting PVN neurons contribute to the cellular source of NO within the PVN. In summary, NO has been identified as an important molecule controlling autonomic function under physiological and pathological conditions. Here, we provide information on the cellular mechanisms mediating central NO actions. Our results demonstrate for the first time that NO modulates the activity of identified populations of PVN neurons that innervate the medulla oblongata, an action that is likely mediated by enhancing synaptic GABAergic function. This work suggests that NO–GABA interaction in PVN neurons that innervate the medulla constitutes an efficient cellular mechanism mediating NO central regulation of autonomic function.

Evidence of oesophageal stimulus dependant response in the human anterior cingulate and primary somatosensory cortex

S. J. Coen, L. J. Gregory, L. Yaguez, D. Hall, E. Amaro, S. Smale, S. C. Williams, D. G. Thompson, Q. Aziz Institute of Psychiatry, London, United Kingdom, University of Manchester, Manchester, United Kingdom, Kings College Hospital, London, United Kingdom Synopsis Studies investigating the neural correlates of non-painful and painful oesophageal stimulation have produced variable results. Furthermore, regions involved in the encoding of stimulation intensity are not fully understood. Using a standardised method for establishing quantifiable intensities of oesophageal stimulation, the neural correlates of four levels of oesophageal stimulation were investigated. Stimulation resulted in a complex pattern of cerebral activation that was similar across different levels of stimulation intensity. The anterior cingulate gyrus (ACG) and primary somatosensory cortex (SI), both showed evidence of stimulus dependent response, which may be a result of encoding of intensity and unpleasantness or levels of attention. Introduction Although the functional correlates of non-painful and painful visceral stimulation have previously been investigated (1), the results have been variable. Furthermore, despite the fact that functional Magnetic Resonance Imaging (fMRI) can be used to objectively quantify perception of visceral sensation, regions involved in the encoding of stimulation intensity are not fully understood. By using a standardised method for determining varying intensities of oesophageal stimulation, the neural correlates of four levels of stimulation and the regions involved in encoding of intensity can be investigated. Aims: The purpose of this study was to determine the neural correlates of four intensities of oesophageal stimulation as well as investigating regions involved in the encoding of stimulation intensity, using fMRI. Methods Subjects: 7 healthy volunteers (5 male, mean age 22 years, +7 months) participated in the study. All subjects gave informed, written consent prior to intubation and scanning. The study was approved by our local ethics committee for research. Oesophageal stimulation: a standard manometry catheter with a silicone balloon attached was passed trans-nasally into the lower oesophagus (35cm from the nostril). The catheter was attached to a pump that inflated the balloon with air at regular intervals. The experiment examined four conditions. During each condition one of four balloon distension intensities, obtained by dividing the difference between sensory (the point at which volunteers first perceived a sensation) and pain thresholds (100%) into 4 levels at 25% increments (i.e. 25%, 50%, 75% and 100%), was used to stimulate the distal oesophagus. A modified block design was employed for each intensity, where each “active” and “rest” phase was repeated five times. Behavioural data measuring the subjective perception of the stimulus (0 = non-painful, 5 = discomfort, 10 = extreme pain) was acquired after each active epoch, using visual analogue scales (VAS). fMRI acquisition: Functional Magnetic Resonance Imaging was performed using a GE Neuro-optimised 1.5 Tesla system (General Electric, Milwaukee WI, USA), based at the Maudsley Hospital, London. Sixteen 7mm slices (0.7 mm gap) parallel to the bicomissural plane were acquired, with a repetition time (TR) of 3 seconds and an echo time (TE) of 40ms, flip angle 90o. A total of 122 T2* weighted images per slice, depicting BOLD contrast (Ogawa et al, 1990) were collected over a six minute and six second period of continuous acquisition during which, subjects received localised phasic distensions to the oesophagus. This procedure was performed on four occasions to collect data for four levels of intensity of oesophageal distension. Image Analysis: Spatially realigned BOLD responses were modelled as the weighted sum of the input function convolved with two Poisson functions. A goodness of fit statistic was computed and a voxel-wise inference was carried out non-parametrically. At the group level, individual statistic maps were transformed into standard stereotactic space and median activation images constructed. Results Mean VAS scores increased progressively with increasing stimulation intensities (χ2 = 10.9, df 3, P=0.001), (mean VAS (+SEM); 25% = 3+0.80, 50% = 3.68+0.91, 75% = 5.67+0.79, 100% = 7.34+0.48). In response to 100% and 75% stimulation intensity, activation was seen in the anterior cingulate gyrus (ACG) (BA 24, 32), bilateral insula, supplementary motor area (SMA), thalamus, bilateral primary and secondary sensory cortices (SIS 114: 559-578 2. Lowy AD. Central Autonomic Pathways. In: Lowey AD, Spyer KM eds. Central regulation of autonomic function (1990). New York: Oxford University Press, 4:88-103. 3. Porro CA, Cettolo V, Pia Francescato M, Baraldi P. Temporal and intensity coding in of pain in the human cortex. Journal neurophysiology 1998;80:3312-3320. 4. Tolle TR, Kaufmann T, Siessmeier T, Lautenbacher S, Berthele A, Munz F, Zieglgeansberger W, Willoch F, Schwaiger M, Conrad B, Bartenstien P. Region specific encoding of sensory and affective components of pain in the human brain: a positron emission tomography correlation analysis. Ann Neurol 1999;45: 4047. 5. Vogt BA, Watanabe H, Grootoonk S, Jones AKP. Topography of diprenorphine binding in human cingulate gyrus and adjacent cortex derived from co-registered PET and MR images. Human Brain Mapping 1995; 3:1-12.

Role of neuronal nicotinic receptors in the transmission and processing of information in neurons of the central nervous system

The properties of nicotinic acetylcholine receptors (nAChRs) were studied following exogenous expression in a host system or using whole-cell recordings in brain slices, autoradiography and immunohistochemistry. When expressed in HEK-293 cells, α4β2 nAChRs displayed both a high and a low affinity component. The ratio of these two states was modified by chronic nicotine exposure, resulting in an enhanced sensitivity and a marked reduction in desensitization. Mutations in the gene coding for the α4 subunit are responsible for a particular form of nocturnal epilepsy. When expressed in Xenopus oocytes, α4β2 nAChRs containing these mutations displayed distinct alterations in agonist affinity, desensitization and calcium permeability. Magnocellular endocrine neurons in the supraoptic (SO) nucleus of the hypothalamus were found to express functional α7-containing nAChRs, which could play a role in regulating neurohypophysial peptide secretion. Facial (VII), hypoglossal (XII) and vagal (X) motoneurons of young rats responded to ACh by a fast inward current. The nAChRs present in VII and XII nuclei were of the non-α7-containing type, whereas those present in the X nucleus contained the α7 subunit. In Bcl-2 transgenic mice, facial nerve axotomy caused nAChRs downregulation by interfering negatively with the expression of the α4 subunit. Binding sites corresponding to α7-containing nAChRs were also detected in spinal motor nuclei and axotomy provoked a reduction of the binding. Together, these data indicate that long-term exposure to nicotine can promote neuroadaptive changes in nAChRs and that genetic alterations of neuronal nAChRs can result in transmissible neurological diseases. They also suggest that these receptors probably play a role in the central regulation of autonomic functions, as well as in motor control.

CNS innervation of vagal preganglionic neurons controlling peripheral airways: a transneuronal labeling study using pseudorabies virus

The CNS cell groups that project to vagal preganglionic neurons which innervate the most distal part of the airways were identified by the viral retrograde transneuronal labeling method. Pseudorabies virus (PRV) was injected into the lung parenchyma of C8 spinal rats and after 5 days survival, brain tissue sections from these animals were processed for immunohistochemical detection of PRV. Retrogradely labeled parasympathetic preganglionic cells (first-order neurons) were seen mainly in the ventral medulla oblongata: the compact portion of the nucleus ambiguus and the area ventral to it. Occasionally, a few labeled cells were seen within the rostral part of the dorsal vagal nucleus. This labeling pattern correlated well with the retrograde cell body labeling seen following cholera toxin β-subunit (CT-b) injections in the lung parenchyma. PRV transneuronally labeled neurons (second-order and/or presumed third-order neurons) were found throughout the CNS with the characteristic labeling in the brainstem. Labeled neurons were identified along and just beneath the ventral medullary surface, and in nearby areas: the parapyramidal, retrotrapezoid, gigantocellular and lateral paragigantocellular reticular nuclei, as well as the caudal raphe nuclei (raphe pallidus, obscurus, and magnus). Several nucleus tractus solitarius (nTS) regions contained labeled cells including the commissural, medial, and ventrolateral nTS subnuclei. The A5 cell group and a small number of locus coeruleus neurons were also labeled. PRV-infected neurons were present in the Kölliker–Fuse and Barrington's nuclei. In the mesencephalon, neurons within the ventral periventricular gray matter were labeled. Labeling was present in the dorsal, lateral and paraventricular hypothalamic nuclei, and within the amygdaloid complex. In summary, the parasympathetic preganglionic neurons that innervate the peripheral airways are controlled by networks of lower brainstem and suprapontine neurons that lie in the same regions known to be involved in central regulation of autonomic functions.

Central regulation of autonomic function: no brakes?

1. Nitric oxide (NO) is formed by neuronal NO synthase (nNOS) and acts as a non-conventional neurotransmitter in the brain. A growing body of evidence supports the hypothesis that NO acts to decrease sympathetic output to the periphery; these effects may occur at several autonomic sites. The present review describes studies from our laboratory that address this hypothesis. 2. Restraint stress activates putative NO-producing neurons in many autonomic centres: preoptic area, medial septum, amygdala, hypothalamus, including the paraventricular nucleus (PVN), raphe nuclei, nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM). These results suggest that NO is directly or indirectly involved in regulating sympathetic output to the periphery. 3. Systemic angiotensin II (AngII) activates putative NO-producing neurons in the PVN. These neurons may be activated either by the increases in arterial pressure that accompany AngII injections or due to activation of AngII-containing neural pathways. 4. Hypotension is associated with the activation of putative NO-producing PVN neurons, small numbers of which also project to the NTS or VLM. As the majority of activated neurons is in the magnocellular division, NO production may be related to the production of vasopressin. 5. Adult spontaneously hypertensive rats (SHR) show increased gene expression of nNOS in the hypothalamus, dorsal medulla and caudal VLM. These differences are not present in young prehypertensive SHR, suggesting that the changes in gene expression in adult rats are associated with the increased sympathetic nerve activity found in these rats. 6. Gene expression of nNOS is altered in the hypothalamus and caudal VLM of renal hypertensive rats at 3 and 6 weeks after surgical induction of hypertension. Contrasting results at the two time points may be due to differing underlying physiological processes that characterize the two stages of renal hypertension. 7. Nitric oxide may affect sympathetic output through several possible mechanisms. These include affecting production of the second messenger cGMP and interactions with more classical neurotransmitters or with neurohormonal systems in the brain.

Postnatal ontogeny of glutamate receptors in the rat nucleus tractus solitarii and ventrolateral medulla

The nucleus tractus solitarii and the ventrolateral medulla are two brainstem regions involved in regulation of autonomic functions. Glutamate (Glu) receptors localized within these two regions play a key role in neural control of swallowing and breathing and in blood pressure regulation. In the present study, postnatal changes in global [ 3 H ]Glu binding and in [ 3 H ]Glu binding to N-methyl- d-aspartate (NMDA) receptors were analyzed in the nucleus tractus solitarii and the ventrolateral medulla using in vitro receptor autoradiography. Similar results were obtained in both regions. When expressed as density values (fmol/mg tissue), both global and NMDA-sensitive Glu binding increased by approximately 50–70% between birth and postnatal day 9 (P9) and then decreased until P30. When expressed as binding per nucleus (i.e., after correction for tissue growth), global Glu binding still increased between birth and P9 and decreased between P9 and P30 whereas NMDA-sensitive binding increased until P9 and remained stable thereafter. Saturation studies showed a postnatal increase in Glu receptor number per nucleus, which occurred mainly between birth and P9, and a decrease in Glu receptor affinity between P9 and adulthood. These results indicate that dramatic changes in glutamatergic neurotransmission occur in the nucleus tractus solitarii and the ventrolateral medulla during the first month of postnatal life. They suggest that both neonates and young animals may not be fully mature as regard to central regulation of autonomic functions.

Insulin in the brain: a hormonal regulator of energy balance.

EARLY studies of brain glucose metabolism established the axiom that insulin is not required for utilization of glucose by the central nervous system (CNS) (1). A corollary to this concept was the belief that circulating insulin is incapable of crossing the bloodbrain barrier (BBB) and is therefore without effects in the brain. While the first of these tenets remains unchallenged, the second has been subjected to detailed scrutiny for over a decade, following the identification of both insulin (2) and its receptor (3) in the adult mammalian brain. Early reports of relatively high concentrations of insulin in brain extracts raised the possibility that insulin is synthesized and released locally in the CNS, as had been established for several other peptide hormones (2). Recent investigations, however, indicate that “brain insulin” is derived largely from the circulation (4), and a growing body of evidence suggests that its delivery into the neuropil may be facilitated by a specialized BBB transport system (5, 6). Moreover, insulin produces marked effects on food intake behavior and is implicated in the central regulation of autonomic function. Thus, although our current understanding of the roles played by insulin in the brain is far from complete, the early perception of the brain as an insulin-insensitive tissue can no longer be considered tenable. In this article, we review recent literature related to the hypothesis that insulin is an afferent CNS signal which regulates normal energy balance.

Central Regulation of Autonomic Functions. Edited byArthurD.Loweyand K.MichaelSpyer. Oxford University Press, 1990. £65.00 hardback

<i>Central Regulation of Autonomic Functions</i>. Edited by<scp>Arthur</scp>D.<scp>Lowey</scp>and K.<scp>Michael</scp><scp>Spyer</scp>. Oxford University Press, 1990. £65.00 hardback

BOOK REVIEWS: Central Regulation of Autonomic Functions.

BOOK REVIEWS: Central Regulation of Autonomic Functions.