NPY/neuropeptide Y enhances autophagy in the hypothalamus: a mechanism to delay aging?

Aging was recently described as a life event programmed by the hypothalamus, a key brain region that is crucial for the neuroendocrine interaction between the central nervous system and the periphery. Autophagy impairment is a hallmark of aging, contributing to the aging phenotype and to the aggravation of age-related diseases. Since hypothalamic autophagy decreases with age, strategies to promote autophagy in the hypothalamus may be relevant for control of the aging process. NPY (neuropeptide Y) is an endogenous neuropeptide mainly produced by the hypothalamus. We recently reported, for the first time, that NPY stimulates autophagy in rodent hypothalamus and mediates caloric restriction-induced autophagy in hypothalamic neurons. Moreover, we observed that NPY acts through NPY1R (neuropeptide Y receptor Y1) or NPY5R activation involving a concerted action of different signaling pathways. Since both hypothalamic autophagy and NPY levels decrease with age, modulation of NPY levels could provide new putative therapeutic tools to ameliorate age-related deteriorations and extend longevity.     

Diurnal rhythmicity of norepinephrine activity associated with the estradiol-stimulated luteinizing hormone surge: effect of age and long-term ovariectomy on hemispheric asymmetry

The age-related decline in female reproductive capacity in rats is accompanied by an inability to respond positively to estradiol (E2) treatment. This age-related change is associated with a loss in diurnal rhythmicity of norepinephrine (NE) activity in brain areas important in the control of LH. Decreased exposure to ovarian secretions during adulthood delays certain aspects of neuroendocrine aging. We tested the hypothesis that long-term ovariectomy (OVX) would delay the age-related loss of diurnal rhythmicity in NE activity in microdissected hypothalamic nuclei. Intrigued by reports of lateralization of hypothalamic function, we also assayed NE activity in the left and right sides of the hypothalamus separately. Young (2-3 mo) and middle-aged (11-12 mo) rats that exhibited regular estrous cycles were OVX. One week later (Day 0) these short-term OVX animals (Y-ST, MA-ST) plus a group of middle-aged (11-12 mo) rats that were OVX at 3 mo (MA-LT) were treated with E2. On Day 4, the rate constant of NE activity in microdissected hypothalamic nuclei was determined at 0900 h and 1500 h using the alpha-methyl-para-tyrosine method. Rate constants were compared by t-test to determine diurnal rhythmicity. Y-ST rats exhibited a diurnal rhythm in NE activity in the median eminence, which was absent in MA-ST rats. Long-term OVX spared animals this "age-related" loss in rhythmicity since MA-LT rats demonstrated a significant increase in NE activity from morning to afternoon.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disruption of neuroendocrine control of luteinizing hormone secretion by aroclor 1254 involves inhibition of hypothalamic tryptophan hydroxylase activity

Mechanisms governing the effect of polychlorinated biphenyl (PCB) toxicity on hypothalamic serotonergic function and the neuroendocrine system controlling LH secretion were investigated in Atlantic croaker (Micropogonias unulatus) exposed to the PCB mixture Aroclor 1254 (1 microg x g body weight(-1) x day(-1)) in the diet for 30 days. PCB treatment caused a decrease in hypothalamic 5-hydroxytryptamine (5-HT) concentrations and significant inhibition of hypothalamic tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT synthesis, but did not alter the activity of monoamine oxidase, the catabolic enzyme. Further, PCB treatment caused significant decreases in GnRH content in the preoptic-anterior hypothalamic area. Significant decreases in pituitary GnRH receptor concentrations and the LH response to the GnRH analogue (GnRHa) were also observed in PCB-exposed fish, possibly as a consequence of a decline in GnRH release. The possible association between impaired serotonergic and neuroendocrine functions after PCB treatment was explored using serotonergic drugs. Treatment of croaker with p-chlorophenylalanine, an irreversible TPH inhibitor, mimicked the effects of PCB on the GnRH system and the LH response to GnRHa. Bypassing the TPH-dependent hydroxylation step with the administration of 5-hydroxytryptophan restored 5-HT to control levels and prevented the deleterious effects of PCB on the neuroendocrine parameters. Moreover, slow-release GnRH implants prevented the PCB-induced decline in GnRH receptors and restored the LH response to GnRHa, suggesting that GnRH therapy can reverse PCB-induced disruption of LH secretion. These results demonstrate that TPH is one of the targets of PCB neurotoxicity and indicate that a decrease in 5-HT availability in PCB-exposed croaker results in disruption of the stimulatory 5-HT/GnRH pathway controlling LH secretion.     

Effect of Interferon-Alpha on Mouse Hypothalamic-Pituitary-Adrenocortical System in Aging

The state of the hypothalamic-pituitary-adrenocortical system (HPAS) in aged mice was compared with that in young mice after administration of interferon-alpha (IA). In the aged mice, IA produced an increase of morpho-functional activity of neurosecretory cells (NSC) of hypothalamic paraventricular nucleus. In the young mice, no effects of IA on neuroendocrine centers (paraventricular and supraoptic nuclei) were found, but an increase of the number of apoptotic cells in the adrenal cortex was revealed. The differences in the IA effects can be due to age-related changes revealed in the HPAS. They consist in intact old animals in a decrease of functional activity of hypothalamic centers as a result of loss of NSC (an increase of apoptosis level) with a simultaneous rise of activity of adrenal cortex, which seems to have a compensatory character. Thus, in aging, first of all, function of the central part of the HPAS decreases, which subsequently might lead to age-related changes in the peripheral link of the endocrine system. The results obtained indicate that the effect of IA on the HPAS depends on the stage of ontogenesis.     

Aging: hypothalamic catecholamines, neuroendocrine-immune interactions, and dietary restriction

The decline in hypothalamic catecholamine (CA) activity with age in rats leads to a reduction in hormone secretion by the neuroendocrine system, and results in decreased reproductive function, a reduction in protein synthesis, development of numerous mammary and pituitary tumors, and probably contributes to the decline in immune function. Some of these same effects can be produced in young rats by administration of drugs that lower hypothalamic CA activity. Administration of drugs to old rats that elevate hypothalamic CA activity can inhibit or reverse the reproductive decline, increase protein synthesis, induce regression of mammary and pituitary tumors, decrease disease incidence, probably elevate immune function, and significantly extend the life span. Therefore, hypothalamic CA have a critical role in the development of aging processes. When young or mature rats or mice are fed a caloric restricted diet, aging processes are inhibited and life span is significantly lengthened. These effects are believed to be mediated primarily via the neuroendocrine system, since calorie restriction results in decreased secretion of hypothalamic, pituitary, and target gland hormones. The decline in hormone secretion leads to a reduction in most body functions, lowers whole body metabolism, and reduces gene expression, and thereby results in a decreased rate of aging of body tissues and longer life. These effects of caloric restriction can be counteracted by administration of hormones, providing evidence that the favorable effects on aging are mediated by reducing hormone secretion.     

Noradrenaline and “Chemical Coding” of Hypothalamic Neurones

FIRING rates of single neurones in the “feeding system”—the perifornical and ventromedial areas of the hypothalamus—are altered by the systemic administration of an anorexigenic agent, such as amphetamine or glucose^1–4. Using the micro-iontophoretic technique which involves releasing chemicals directly on individual neurones, Oomura et al. confirmed that glucose can alter the spontaneous firing rates of some neurones in the hypothalamus of the rat⁵. We wish to report that micro-iontophoretic applications of glucose, amphetamine and noradrenaline to hypothalamic neurones yield a pattern of results not readily reconcilable with the current views of the role of adrenergic substances as “transmitters” in the regulation of hypothalamic feeding function.     

Immortalized neurons for the study of hypothalamic function

The hypothalamus is a vital part of the central nervous system: it harbors control systems implicated in regulation of a wide range of homeostatic processes, including energy balance and reproduction. Structurally, the hypothalamus is a complex neuroendocrine tissue composed of a multitude of unique neuronal cell types that express a number of neuromodulators, including hormones, classical neurotransmitters, and specific neuropeptides that play a critical role in mediating hypothalamic function. However, neuropeptide and receptor gene expression, second messenger activation, and electrophysiological and secretory properties of these hypothalamic neurons are not yet fully defined, primarily because the heterogeneity and complex neuronal architecture of the neuroendocrine hypothalamus make such studies challenging to perform in vivo. To circumvent this problem, our research group recently generated embryonic- and adult-derived hypothalamic neuronal cell models by utilizing the novel molecular techniques of ciliary neurotrophic factor-induced neurogenesis and SV40 T antigen transfer to primary hypothalamic neuronal cell cultures. Significant research with these cell lines has demonstrated their value as a potential tool for use in molecular genetic analysis of hypothalamic neuronal function. Insights gained from hypothalamic immortalized cells used in conjunction with in vivo models will enhance our understanding of hypothalamic functions such as neurogenesis, neuronal plasticity, glucose sensing, energy homeostasis, circadian rhythms, and reproduction. This review discusses the generation and use of hypothalamic cell models to study mechanisms underlying the function of individual hypothalamic neurons and to gain a more complete understanding of the overall physiology of the hypothalamus.     

Behavioral specialization of cortical and hypothalamic neurons in the rabbit

Behavioural specialization was analyzed of hypothalamic and limbic neurones, with their activity recorded in rabbits during food-acquisition behaviour. The neurones with activity changed during staying of the animal in a definite place of the cage or during behavioural acts, characteristic of a specific behaviour in the cage, are considered as specialized in relation to the most "new" systems, acquired by the rabbit directly during learning of the given behaviour. Neurones with the activity changed with rabbit's turns, i.e. connected with behavioural acts, which the rabbit has not specially learnt, are considered specialized in relation to more "old" inborn systems. Neurones, in which no constant connection with any part of the studied behaviour was observed, are related to the most "ancient" systems. Comparison of the number of hypothalamic and limbic neurones of different groups showed that in the cortex there were some more neurones specialized in relation to behavioural acts, which were formed directly during learning of the rabbit in the experimental cage.     

Synapse-specific changes in serotonin signalling contribute to age-related changes in the feeding behaviour of the pond snail, Lymnaea

This study utilised the pond snail, Lymnaea to examine the contribution that alterations in serotonergic signalling make to age-related changes in feeding. Age-related decreases in 5-HIAA levels in feeding ganglia were positively correlated with a decrease in the number of sucrose-evoked bites and negatively correlated with an increase in inter-bite interval, implicating alterations in serotonergic signalling in the aged phenotype. Analysis of the serotonergic cerebral giant cell (CGC) input to the protraction motor neurone (B1) demonstrated that fluoxetine (10–100 nM) increased the amplitude/duration of the evoked EPSP in both young and middle aged but not in old neurones, suggesting an age-related attenuation of the serotonin transporter. 5-HT evoked a concentration-dependent increase in the amplitude/duration of B1 EPSP, which was greater in old neurones compared to both young and middle aged. Conversely, the 5-HT-evoked depolarisation and conditional bursting of the swallow motor neurone (B4) were attenuated in old neurones, functions critical for a full feeding rhythm. The CGCs' ability to excite B1 was blocked by cinanserin but not by methysergide. Conversely, the CGC to B4 connection was completely blocked by methysergide and only partially by cinanserin suggesting that age-related changes may be receptor-specific. In summary, synapse-specific attenuation of the CGC-B4 connection and enhancement of the CGC-B1 connection would slow the swallow phase and maintain protraction, consistent with behavioural observations.     

Comparative study of the activity of medullary respiratory neurones during polypnea triggered by hypothalamic electrical stimulation or by hypothalamic heating (author's transl)

We have compared in "encéphale isolé bas" cats the activity of medullary respiratory neurones during polypnea triggered by electrical stimulation (PSt) or by heating (PTh) of the hypothalamus. The medullary respiratory neurones are classified according to:--their anatomical localization (dorsal or ventral respiratory nucleus);--their axon destination (spinal : bulbo-spinal respiratory neurones; non spinal : propriobulbar neurones);--their discharge pattern;--the correlation coefficient between the number of spikes delivered in each burst and the duration of the corresponding respiratory phase (HILAIRE et MONTEAU, 1975). 1. During the two polypneas (PSt and PTh), we observe:--a reduction of activity that preferentially affects some groups of neurones (propriobulbar neurones) (fig. 3);--an inversion of the discharge firing rate, which increases during inspiration in normopnea and decreases in polypnea (fig. 1; fig. 6);--a decrease of the maximal discharge firing rate for the neurones of different groups (Table V). 2. However, two differences exist : during PSt, the maximal discharge firing rate increases for the inspiratory bulbo-spinal neurones of the dorsal nucleus and for the early-burster inspiratory propriobulbar neurones. The recruitment of the bulbo-spinal inspiratory neurones seems to be different; they are activated earlier during PSt than during PTh (Table VI). 3. Some of the observed differences are probably quantitative and we think that polypnea triggered by hypothalamic electrical stimulation is a good model for thermal polypnea.     

Endocrine and non-endocrine activities of growth hormone secretagogues in humans

Growth hormone (GH) secretagogues (GHS) are synthetic peptidyl and non-peptidyl molecules which possess strong, dose-dependent and reproducible GH releasing effects as well as significant prolactin (PRL) and adrenocorticotropic hormone (ACTH) releasing effects. The neuroendocrine activities of GHS are mediated by specific receptors mainly present at the pituitary and hypothalamic level but also elsewhere in the central nervous system. GHS release GH via actions at the pituitary and (mainly) the hypothalamic level, probably acting on GH releasing hormone (GHRH) secreting neurons and/or as functional somatostatin antagonists. GHS release more GH than GHRH and the coadministration of these peptides has a synergistic effect but these effects need the integrity of the hypothalamo-pituitary unit. The GH releasing effect of GHS is generally gender-independent and undergoes marked age-related variations reflecting age-related changes in the neural control of anterior pituitary function. The PRL releasing activity of GHS probably comes from direct pituitary action, which indeed is slight and independent of both age and gender. The acute stimulatory effect of GHS on ACTH/cortisol secretion is similar to that of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP). In physiological conditions, the ACTH releasing activity of GHS is mediated by central mechanisms, at least partially, independent of both CRH and AVP but probably involving GABAergic mechanisms. The ACTH releasing activity of GHS is gender-independent and undergoes peculiar age-related variations showing a trend towards increase in ageing. GHS possess specific receptors also at the peripheral levels in endocrine and non-endocrine human tissues. Cardiac receptors are specific for peptidyl GHS and probably mediate GH-independent cardiotropic activities both in animals and in humans.     

Effects of neonatal administration of monosodium glutamate and castration on neurokinin A levels in the hypothalamus and anterior pituitary of rats.

The effects of neonatal administration of monosodium glutamate (MSG) and castration on hypothalamic and anterior pituitary levels of neurokinin A (NKA) were studied in male and female rats killed at 46 days of age. In male rats treated neonatally with MSG, body, anterior pituitary, testis, ventral prostate, and seminal vesicle weights and serum testosterone levels were significantly lower than in saline-injected controls. Hypothalamic NKA was significantly lower in MSG-treated male rats as compared with the controls, and no apparent changes were recorded in anterior pituitary NKA. Orchidectomy was followed by a significant decrease in hypothalamic NKA in saline controls, but not in MSG-treated rats. In female rats treated with MSG, there was a significant decrease in body, anterior pituitary, and ovarian weights, as compared with saline-injected controls, but no significant differences were observed in uterine weights and serum estradiol levels. Hypothalamic NKA was lower, although not significantly, in MSG-treated rats as compared with the respective controls, and no differences were recorded in anterior pituitary NKA levels. Ovariectomy was followed by a significant decrease in hypothalamic NKA in both MSG-treated and control rats, but NKA in the anterior pituitary was significantly increased after ovariectomy only in saline-treated controls, whereas MSG-treated females failed to show this response. It is concluded that neonatal MSG treatment resulted in a decrease of hypothalamic NKA, which was particularly pronounced in male rats without any significant change in anterior pituitary NKA levels. The response of hypothalamic NKA to castration and the response of anterior pituitary NKA to ovariectomy were also altered in MSG-treated rats; this may reflect a functional block of some neuroendocrine functions of the hypothalamus that resulted from the neuronal lesions induced by MSG.     

Arterial and venous responses to hypothalamic stimulation in the dog.

Stimulation of the ventro-medial nucleus of the hypothalamus induces active constriction of both pre- and post-capillary vessels in the dog's hindlimb. Alpha-adrenolytic agents reduce these responses, indicating that they are mediated by the sympathetic nervous system. Stimulation of the paraventricular nucleus dilates both resistance and capacitance vessels. The present study demonstrates that hypothalamic neurones can control venomotor tone.     

Effects of temperature and neuroactive substances on hypothalamic neurones in vitro: possible implications for the induction of fever.

This paper reviews some of our findings which have shown the usefulness of in vitro methods in the study of hypothalamic neurones. (1) Membrane current analyses of dispersed neurones of the rat preoptic and anterior hypothalamus (POA) during thermal stimulation have revealed that warm-sensitive neurones are endowed with a non-inactivating Na+ channel having a high Q10 in the hyperthermic range (35-41 degrees C). (2) A brain slice study has shown that neurones in the organum vasculosum lamina terminalis (OVLT) region have much higher sensitivity to PGE2 than POA neurones. This provides further evidence of a critical role of the OVLT in translation of blood-borne cytokine signals into brain signals for fever induction. (3) Local application of IL-1 beta and IFN alpha altered the activity of thermosensitive (TS) neurones and glucose responsive (GR) neurones in vitro in an appropriate way to produce fever and anorexia. While the responses to IL-1 beta required the local release of prostaglandins, the responses to IFN alpha were found to be mediated by opioid receptor mechanisms. (4) The responses of POA TS neurones and VMH GR neurones to IL-1 beta but not those to IFN alpha, were reversibly blocked by alpha MSH, an endogenous antipyretic peptide. Thus, immune cytokines and their related neuroactive substances may affect hypothalamic TS and GR neurones thereby producing elaborately regulated changes in homeostatic functions such as thermoregulation (fever) and feeding (anorexia), which are considered as host defence responses.     

The effect of PGE2 on activity and thermosensitivity of hypothalamic neurones in rat brain slices.

Using brain slices the effect of prostaglandin E2 (PGE2) on neurones from different locations of the rat hypothalamus was analysed. PGE2 (150 ng), when injected into the perfusion chamber, influences all hypothalamic neurones studied. The pattern of firing rate changes after PGE2 is variable, but the depressive effect predominates--72% of neurones decrease their firing rate in long-term experiments. PGE2 also lowers the thermosensitivity of warm sensitive neurones and increases the thermosensitivity of temperature insensitive neurones.     

Early leptin response to a palatable diet predicts dietary obesity in rats: key role of melanocortin-4 receptors in the ventromedial hypothalamic nucleus

We have investigated whether interactions between leptin and hypothalamic melanocortin-4 receptors (MC4-Rs) determine individual susceptibility to dietary obesity in rats. Animals with relatively high plasma leptin levels 1 week after presentation of palatable food, before weight increased significantly, subsequently showed lower food intake and weight gain after 8 weeks of palatable feeding than those with low early leptin levels. The rats with lesser weight gain also showed significantly greater down-regulation of MC4-Rs, which mediate hypophagia, in specific hypothalamic areas, namely, the arcuate, dorsomedial, and ventromedial (VMH) nuclei and the median eminence. We suggest that this reflects enhanced receptor exposure to endogenous alpha-melanocyte-stimulating hormone, an appetite-suppressing peptide produced by hypothalamic proopiomelanocortin neurones. It is striking that plasma leptin levels at 1 week were inversely correlated with MC4-R density in the VMH, suggesting that this is a key site of leptin action. The early leptin response to palatable feeding may therefore "program" subsequent feeding behaviour and weight gain by regulating neurones that project selectively to the VMH.     

Evolutionary significance of the phylogenetic distribution of the mammalian hypothalamic releasing hormones

The hypophysiotrophic hormones isolated from the mammalian hypothalamus are distributed throughout the nervous system of vertebrate species. Although their role in regulating pituitary hormone secretion in mammals is clear, a similar function in lower species has not been established. Thyrotropin-releasing hormone is unable to stimulate thyroid function in amphibia and fish, despite being present in the hypothalamus and brain of these species of high concentration. The tripeptide is also found in high concentration in frog skin, a tissue derived from (or programed by) primitive neuroectoderm that is also a rich source of other peptides structurally related to neural peptides located in mammalian brain and gut. Luteinizing hormone-releasing hormone (LHRH) is able to activate gonadotropin secretion in submammalian species but there is evidence that the LHRH material present in avian, reptilian, and piscine brain is not identical to the mammalian decapeptide. An LHRH-like material present in frog sympathetic ganglia appears to function as a neurotransmitter in this location. Somatostatin is present in high concentrations in the hypothalamus, brain, pancreas, and gastrointestinal tract of all vertebrates and chromatographically is identical to the mammalian material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It an material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It an material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It appears likely that the releasing hormones initially arose with a neurocrine or paracrine function, and that only later in evolution did they acquire the role of regulating adenohypophysial secretion.     

The aging reproductive neuroendocrine axis

It is well known that the reproductive system is one of the first biological systems to show age-related decline. While depletion of ovarian follicles clearly relates to the end of reproductive function in females, evidence is accumulating that a hypothalamic defect is critical in the transition from cyclicity to acyclicity. This minireview attempts to present a concise review on aging of the female reproductive neuroendocrine axis and provide thought-provoking analysis and insights into potential future directions for this field. Evidence will be reviewed, which shows that a defect in pulsatile and surge gonadotropin hormone-releasing hormone (GnRH) secretion exists in normal cycling middle-aged female rats, which is thought to explain the significantly attenuated pulsatile and surge luteinizing hormone (LH) secretion at middle-age. Evidence is also presented, which supports the age-related defect in GnRH secretion as being due to a reduced activation of GnRH neurons. Along these lines, stimulation of GnRH secretion by the major excitatory transmitter glutamate is shown to be significantly attenuated in middle-aged proestrous rats. Corresponding age-related defects in other major excitatory regulatory factors, such as catecholamines, neuropeptide Y, and astrocytes, have also been demonstrated. Age-related changes in hypothalamic concentrations of neurotransmitter receptors, steroid receptors, and circulating steroid hormone levels are also reviewed, and discussion is presented on the complex interrelationships of the hypothalamus-pituitary-ovarian (HPO) axis during aging, with attention to how a defect in one level of the axis can induce defects in other levels, and thereby potentiate the dysfunction of the entire HPO axis.     

The role of the hypothalamus in aging of the female reproductive system

We have investigated the role of neuroendocrine and neurochemical changes in the age-related deterioration of cyclic female reproductive function. During middle age the timing and amplitude of the proestrous and estradiol-induced LH surge is altered. We have found that the diurnal pattern of norepinephrine turnover is altered in critical hypothalamic areas known to regulate the release of LHRH. These changes may contribute to alterations in the timing and the amplitude of LH release, which may, in turn, affect the ability of rats to maintain regular estrous cycles.