Autonomic Homeostasis Research Articles

Chemical characterization of leptin-activated neurons in the rat brain

Leptin has profound effects on food intake, body weight, and neuroendocrine status. The lack of leptin results in hormonal and metabolic alterations and a dramatic increase in body weight. Leptin acts in the brain, especially in the hypothalamus; however, the central nervous system sites that respond to leptin have not been examined comprehensively. In this study, we explored systematically the distribution of leptin-activated neurons throughout the rat brain. Furthermore, we investigated the chemical identity of subsets of these leptin-activated cells. Fos-like immunoreactivity (Fos-IR) was investigated in the rat brain after two different doses of leptin (1.0 mg/kg and 5.0 mg/kg) at 2 hours and 6 hours after injections. The induction of Fos-IR was observed in hypothalamic nuclei, including the paraventricular nucleus (PVH), the retrochiasmatic area (RCA), the ventromedial nucleus (VMH), the dorsomedial nucleus (DMH), the arcuate nucleus (Arc), and the ventral premammillary nucleus (PMV). In addition, leptin-induced Fos-IR was found in several nuclei of the brainstem, including the superior lateral and external lateral subdivisions of the parabrachial nucleus (slPB and elPB, respectively), the supragenual nucleus, and the nucleus of the solitary tract (NTS). By using double-labeling immunohistochemistry or immunohistochemistry coupled with in situ hybridization, leptin-activated neurons were found that contained cocaine- and amphetamine-regulated transcript mRNA in several hypothalamic nuclei, including the RCA, Arc, DMH, and PMV. In the Arc and DMH, leptin-induced Fos-IR was observed in neurons that expressed neurotensin mRNA. Dynorphin neurons in the VMH and in the Arc also expressed Fos-IR. In the brainstem, we found that cholecystokinin neurons in the slPB and glucagon-like peptide-1 neurons in the NTS were activated by leptin. We also investigated the coexpression of Fos-IR and the long form of the leptin receptor (OBRb) mRNA. We found double-labeled neurons surrounding the median eminence and in the RCA, Arc, VMH, DMH, and PMV. However, in brainstem sites, very little OBRb mRNA was found; thus, there were very few double-labeled cells. These results suggest that leptin stimulates brain pathways containing neuropeptides that are involved in the regulation of energy balance, autonomic homeostasis, and neuroendocrine status.

Anatomical distribution of prolactin-releasing peptide and its receptor suggests additional functions in the central nervous system and periphery.

A recently identified neuropeptide with PRL-releasing capabilities binds to and activates a previously known orphan G protein-coupled receptor, GPR10. We initiated a study to define the pharmacology of the peptide/receptor interaction and to identify the distribution of the peptide and its receptor in the central nervous system to elucidate sites of action of the peptide. The PRL-releasing peptide (PrRP) is a C-terminally amidated, 31-amino acid peptide derived from a 98-amino acid precursor. Radioiodinated PrRP-(1-31) binds to its receptor with high affinity (1 nM) and stimulates calcium mobilization in CHOK1 cells stably transfected with the receptor. A series of N-terminal deletions reveals that the PrRP-(12-31) amino acid is equipotent to PrRP-(1-31). Further N-terminal deletions reduce the affinity of the ligand considerably, although PrRP-(25-31) is still able to compete for binding and behaves as an agonist. The arginine residues at position 26 and 30 are critical for binding, as substitution with either lysine or citrulline reduces the affinity substantially. In situ hybridization reveals a distinct tissue distribution for both the peptide and receptor messenger RNAs. The receptor is expressed abundantly in the reticular thalamic nucleus, periventricular hypothalamus, dorsomedial hypothalamus, nucleus of the solitary tract, area postrema, anterior pituitary, and adrenal medulla. The peptide messenger RNA is expressed in the dorsomedial hypothalamus, nucleus of the solitary tract, ventrolateral reticular nucleus, and intestine. This tissue distribution suggests an alternative function of PrRP than its purported hypophysiotropic function, such as a potential role for PrRP in the central feedback control of neuroendocrine and autonomic homeostasis. Further work using selective agonists and antagonists should help define additional physiological roles of this novel mammalian neuropeptide.

Changes of environment and darkness enhance the NADPH-diaphorase staining in the rat paraventricular nucleus

Nitric oxide (NO) plays an important role in the maintenance of autonomic homeostasis of the body. NO-producing neurons are activated in the brain during exposure to different levels of environmentally produced stimulations. These facts prompted the authors to investigate the levels of activation of NO-producing neurons of the paraventricular nucleus of the hypothalamus (PVN) following change of environment and darkness. Cryostat sections were cut and processed for the histochemical detection of the NADPH-diaphorase (ND)-activity. Following change of the environment and darkness for 12 and 24 h, statistical analysis displayed a significant increase in the number of ND-neurons, especially in the posterior magnocellular and the lateral parvicellular subdivisions of the PVN. These data indicate that the ND-neurons of the PVN are influenced by changes of the environment and darkness.

The dorsomedial hypothalamic nucleus revisited: 1998 update.

This article reviews data that have accumulated since the early 1970s on the role of the dorsomedial hypothalamic nucleus (DMN) in neuroendocrine and autonomic homeostasis. Both the ventromedial hypothalamic nucleus (VMN) and the lateral hypothalamic area (LHA) project to the DMN, which in turn projects to the paraventricular nucleus of the hypothalamus (PVN), thus placing the DMN at an important nodal point of neuroendocrine/autonomic circuitries. The DMN is composed of cells and fibers containing neuropeptide Y (NPY), and the nutritional status (starvation-refeeding) is reflected in NPY levels of both VMN and DMN in Sprague-Dawley, Zucker (fa/fa), and corpulent rats (cp/cp JCR:LA). The DMN is involved in the final common pathway of corticotrophin-releasing hormone (CRH) secretion by the PVN, sympathetic nervous system outflow to the adrenal gland, and brown adipose tissue (BAT) thermogenesis. The DMN is also part of a "fear circuitry" regulating cardiovascular responses to stress such as myocardial blood flow and the tachycardia associated with the defense reaction. This appears to be mediated by a gamma amino butyric acid (GABA) mechanism. Although exhibiting reduced ponderal and linear growth and hypophagia and hypodipsia, the rat with DMN lesions (DMNL rat) has normal body composition, anabolic hormone levels, and intermediary metabolism, and it responds normally to numerous endocrine, nutritional, intra- and extracellular thirst and body weight-regulatory challenges. The DMNL rat shows normal efficiency of food utilization, but shows an attenuated response to the feeding-stimulatory effect of insulin. The only other lesion-induced abnormalities are hyperprolactinemia and a disrupted circadian corticosterone rhythm. The hyperprolactinemia in DMNL rats appears to be related to an attenuation of dopamine (DA). Rats with DMNL are capable of mating and can bear offspring, but there is a dramatic effect on litter size and other litter parameters that only improves when one parent is a DMNL rat. Antiaging effects produced by DMNL are evident in the prevention of age-associated microalbuminuria and kidney lesions, as well as, in prevention of the age-related decline in circulating insulin-like growth factor I (IGF-I). Recent evidence suggests that DMN, together with the VMN and the arcuate nucleus (ARC) of the hypothalamus, may be part of the circuitry that is responsive to the feedback signal from adipose tissue by the hormone leptin. The above findings and others suggest that the DMN plays a diverse role in physiological regulatory processes.

Neurally mediated syncope: a review of cardiac and arterial receptors.

This article reviews the basic physiology of the reflexogenic areas of the heart and the mechano- and baroreceptors that regulate cardiovascular and autonomic homeostasis, all of which contribute to our understanding of the pathogenesis of neurally mediated syncope. The mechanisms of neurally mediated syncope may involve excessive activation of ventricular receptors that trigger severe hypotension and bradycardia. Thus, neurally mediated syncope may be the clinical expression of the Bezold-Jarisch reflex, which occurs in situations of increased sympathetic activity, perhaps as a result of heightened cardiac receptor sensitivity. The arterial baroreceptors exert a ubiquitous influence on the heart and circulation, and serve primarily to buffer transient changes in arterial pressure by transmitting sensory information regarding their stretch to the central nervous system. This information, in conjunction with cardiac receptor input, elicits alterations in neural efferent output from sympathetic and parasympathetic fibers to provide subtle, continuous regulation of beat-to-beat cardiovascular hemodynamics to an array of physiologic and psychological stressors.

Spatial Working and Reference Memory in Rats Bred for Autonomic Sensitivity to Cholinergic Stimulation: Acquisition, Accuracy, Speed, and Effects of Cholinergic Drugs

Rat lines were selected by breeding for sensitivity to signs of autonomic stimulation (hypothermia, loss of body weight, and reduced water intake) induced by the cholinesterase inhibitor diisopropyl fluorophosphate (DFP). These lines have since been maintained for 10 generations by continued selection for hypothermic responsiveness to the muscarinic agonist oxotremorine. The sensitive rats (Flinders Sensitive Line, FSL) differ from the resistant rats (Flinders Resistant Line, FRL) both neurochemically and behaviorally, particularly in aversively motivated test situations in which response speed is assessed. This study was conducted to determine whether the selected differences in cholinergic autonomic sensitivity would be expressed as differences in cognitive ability based on choice accuracy in appetitive tasks. The working and reference memory of rats of these two strains was thus assessed using operant delayed matching-to-position/visual discrimination (DMTP/VD) and the radial-arm maze. A Long-Evans (L-E) reference group was included in the DMTP/VD study. FSL rats responded more slowly than the other rats during acquisition of both tasks, but showed no differences in response accuracy either during acquisition or during asymptotic performance of either task. In addition, challenges with muscarinic and nicotinic antagonists and agonists [scopolamine (0.06-1.0 mg/kg), pilocarpine (1.0-4.0 mg/kg), mecamylamine (1.0-10.0 mg/kg), and nicotine (0.1-0.3 mg/kg)] demonstrated predicted differences in sensitivity among the lines only on performance measures such as response latency and trial completion. Counter to prediction, the sensitivity of the FRL rats to the ability of scopolamine to reduce matching accuracy was lower than those of the L-E and FSL rats. Thus selection based upon physiological endpoints related to cholinergic autonomic homeostasis did not produce analogous differences in cognitive function in rats.

ATRIAL FIBRILLATION ASSOCIATED WITH AUTONOMIC DYSREFLEXIA

Autonomic dysreflexia is an acute disorder of autonomic homeostasis occurring in persons with spinal cord lesions above the major splanchnic sympathetic outflow. Atrial fibrillation is a serious cardiac arrhythmia characterized by disorganized atrial depolarization and an irregular ventricular response. Previously reported complications of autonomic dysreflexia have included seizures, strokes and cardiac arrhythmias other than atrial fibrillation. We present a 60-yr-old man with C-5 incomplete quadriplegia in whom atrial fibrillation was apparently induced by an episode of autonomic dysreflexia. Mechanisms by which autonomic dysreflexia may cause this arrhythmia include altered cardiac autonomic tone as well as atrial distention. The simultaneous occurrence of autonomic dysreflexia and atrial fibrillation poses special diagnostic problems and treatment risks. Atrial fibrillation incidence increases with age in the general population. With the aging of the spinal cord-injured population, we expect to see more episodes of atrial fibrillation associated with autonomic dysreflexia.

Summation and Reciprocal Innervation in Autonomic Control

The mechanism of autonomic control of homeostasis are not yet fully understood. Thus, although it is well accepted that the central nervous regulation of vasomotricity and cardiac activity is subserved by a series of superposed nervous centres, the manner in which these centres influence one another is not sufficiently known. On the other hand, the role played by the mesencephalic reticular formation (MRF) in the autonomic homeostasis has not been systematically studied yet. In view of these facts, we have undertaken in dogs and cats a series of investigations concerning the interrelations of higher nervous centres and their reciprocal influence in the control of autonomic homeostasis. The results obtained are indicative of complex relations between these centres. Attention must be focussed at least on the following evidences:1. the occurence of a pressor tensional effect after subliminar simultaneous stimulation of some vasopressor points in the central nervous system represents a very clear case of spatial summation;2. the study of the autonomic control exerted by the MRF demonstrates, apart from overall activatory effects, influences of the reciprocal innervation type, the latter seeming to be dispersed over a wide projection area.

The effect of partial beta adrenergic blockade on the bronchial response of hay fever subjects to ragweed aerosol

One hypothesis of the cause of asthma proposes that it is the result of impaired autonomic homeostasis manifested by a partial blockade of the adrenergic beta receptors of cells. This study was undertaken to determine whether a pharmacologically induced beta blockade would increase the bronchial obstruction produced by ragweed aerosol challenge in subjects with hay fever. Ten volunteers with ragweed hay fever were studied before the ragweed season. Each subject was his own control. On each of two separate days the subject was challenged with progressively increased doses of an aerosol of ragweed extract. Before the second challenge, 5 mg. of propranolol, a potent beta adrenergic blocking agent, was given intravenously. A year later, these 5 subjects were again studied with the order of the propranolol and control tests reversed. The response to the aerosol was determined by comparing the volumes of the first second of a forced expiration (FEV 1) before and 15 minutes after the aerosol. The mean change in FEV 1 was −13 per cent with the control and −22 per cent with the propranolol. When the order of challenge with propranolol and the control was reversed, these values were much the same, −6 and −19. Partial beta blockade increased the bronchial response to inhaled allergen, a result consistent with the stated hypothesis.