Hypothalamic Neuroendocrine System Research Articles

Transcription Factor TonEBP Stimulates Hyperosmolality-Dependent Arginine Vasopressin Gene Expression in the Mouse Hypothalamus.

The hypothalamic neuroendocrine system is strongly implicated in body energy homeostasis. In particular, the degree of production and release of arginine vasopressin (AVP) in the hypothalamus is affected by plasma osmolality, and that hypothalamic AVP is responsible for thirst and osmolality-dependent water and metabolic balance. However, the osmolality-responsive intracellular mechanism within AVP cells that regulates AVP synthesis is not clearly understood. Here, we report a role for tonicity-responsive enhancer binding protein (TonEBP), a transcription factor sensitive to cellular tonicity, in regulating osmosensitive hypothalamic AVP gene transcription. Our immunohistochemical work shows that hypothalamic AVP cellular activity, as recognized by c-fos, was enhanced in parallel with an elevation in TonEBP expression within AVP cells following water deprivation. Interestingly, our in vitro investigations found a synchronized pattern of TonEBP and AVP gene expression in response to osmotic stress. Those results indicate a positive correlation between hypothalamic TonEBP and AVP production during dehydration. Promoter and chromatin immunoprecipitation assays confirmed that TonEBP can bind directly to conserved binding motifs in the 5’-flanking promoter regions of the AVP gene. Furthermore, dehydration- and TonEBP-mediated hypothalamic AVP gene activation was reduced in TonEBP haploinsufficiency mice, compared with wild TonEBP homozygote animals. Therefore, our result support the idea that TonEBP is directly necessary, at least in part, for the elevation of AVP transcription in dehydration conditions. Additionally, dehydration-induced reductions in body weight were rescued in TonEBP haploinsufficiency mice. Altogether, our results demonstrate an intracellular machinery within hypothalamic AVP cells that is responsible for dehydration-induced AVP synthesis.

Maternal separation changes maternal care, anxiety-like behaviour and expression of paraventricular oxytocin and corticotrophin-releasing factor immunoreactivity in lactating rats.

The early postnatal period is a time of tremendous change for the dam and her offspring. During this time, environmental insults such as repeated stress exposure can have detrimental effects. In research that has focused on the effect of postnatal stress exposure on the dams, conflicting changes in maternal care and anxiety-like behaviour have been reported. Additionally, changes to hypothalamic neuropeptides that are crucially involved in the transition to motherhood and stress regulation, namely oxytocin and corticotrophin-releasing factor (CRF), have not been examined. Accordingly, the present study aimed to determine (i) whether repeated postpartum stress increases engagement in maternal care behaviours and anxiety-like behaviour and (ii) whether these behavioural changes correspond with changes to CRF- or oxytocin-immunoreactive (-IR) cells in the paraventricular nucleus (PVN) of the hypothalamus. A non-lactating group was also included to control for the effects of lactation on anxiety and the hypothalamic neuroendocrine system. Following the birth of their litters, Long-Evans dams were separated from their pups from postnatal day (PND) 1 to PND21 for either 15minutes (maternal separation [MS]15) or 6hours (MS360). Maternal behaviours were recorded for 30minutes on select PNDs following the separation. On PND22, dams were exposed to the elevated plus maze, brains were collected, and immunofluorescence analysis of PVN oxytocin- and CRF-IR cells was conducted. Our findings demonstrate that prolonged maternal separation altered typical maternal behaviours and reduced anxiety relative to MS15 dams. At the cellular level, oxytocin-IR cells in the caudal PVN were reduced in MS360 dams to a level similar to that in non-lactating controls, and PVN CRF-IR cells were reduced relative to both MS15 and non-lactating controls. Taken together, these data reveal the behavioural and neuronal changes that occur in the mother dam following repeated postnatal stress exposure.

Stimulatory effect of dopamine derivative, salsolinol, on pulsatile luteinizing hormone secretion in seasonally anestrous sheep: Focus on dopamine, kisspeptin and gonadotropin-releasing hormone

In the present study, there was testing of the hypothesis that a centrally administered dopamine (DA) derivative, salsolinol, could affect pulsatile luteinizing hormone (LH) secretion in seasonally anestrous sheep by affecting the neuronal components of the estradiol (E2) negative feedback. In two experiments performed during early spring (increasing day length – March/April), salsolinol or Ringer-Locke solution (control) were administered into the third brain ventricle (IIIv): 1) in several injections for three consecutive days; and 2) in several hour-long infusions. In addition to determining the LH concentration (in both experiments), the abundances of gonadotropin-releasing hormone (GnRH) and kisspeptin mRNA were examined in the hypothalamus and LHβ subunit mRNA in the pituitary (Experiment 1). In Experiment 2, concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in perfusates collected from the infundibular nucleus/median eminence (IN/ME) by the push-pull method. In both experiments, salsolinol increased both LH pulse frequency (P < 0.05) and plasma LH concentration (P < 0.001) compared to controls. The injected salsolinol also increased (P < 0.05) the abundance of GnRH mRNA in the mediobasal hypothalamus and kisspeptin mRNA in the arcuate nucleus. The two doses of infused salsolinol decreased DA to undetectable concentrations and DOPAC concentration by 60% in perfusates collected from the IN/ME. In conclusion, exogenous salsolinol functioning centrally stimulates pulsatile LH secretion in sheep during seasonal anestrus. It is suggested that salsolinol may have this effect by reducing the activity of the hypothalamic neuroendocrine dopaminergic system, which results in an increase in both kisspeptin and GnRH neurons activity.

Approaches Mediating Oxytocin Regulation of the Immune System.

The hypothalamic neuroendocrine system is mainly composed of the neural structures regulating hormone secretion from the pituitary gland and has been considered as the higher regulatory center of the immune system. Recently, the hypothalamo-neurohypophysial system (HNS) emerged as an important component of neuroendocrine–immune network, wherein the oxytocin (OT)-secreting system (OSS) plays an essential role. The OSS, consisting of OT neurons in the supraoptic nucleus, paraventricular nucleus, their several accessory nuclei and associated structures, can integrate neural, endocrine, metabolic, and immune information and plays a pivotal role in the development and functions of the immune system. The OSS can promote the development of thymus and bone marrow, perform immune surveillance, strengthen immune defense, and maintain immune homeostasis. Correspondingly, OT can inhibit inflammation, exert antibiotic-like effect, promote wound healing and regeneration, and suppress stress-associated immune disorders. In this process, the OSS can release OT to act on immune system directly by activating OT receptors or through modulating activities of other hypothalamic–pituitary–immune axes and autonomic nervous system indirectly. However, our understandings of the role of the OSS in neuroendocrine regulation of immune system are largely incomplete, particularly its relationship with other hypothalamic–pituitary–immune axes and the vasopressin-secreting system that coexists with the OSS in the HNS. In addition, it remains unclear about the relationship between the OSS and peripherally produced OT in immune regulation, particularly intrathymic OT that is known to elicit central immunological self-tolerance of T-cells to hypophysial hormones. In this work, we provide a brief review of current knowledge of the features of OSS regulation of the immune system and of potential approaches that mediate OSS coordination of the activities of entire neuroendocrine–immune network.

Developmental programming of hypothalamic neuroendocrine systems

There is increasing evidence to suggest that the perinatal environment may alter the developmental programming of hypothalamic neuroendocrine systems in a manner that predisposes offspring to the development of metabolic syndrome. Although it is unclear how these effects might be mediated, it has been shown that changes in neuroendocrine programing during critical periods of development, either via maternal metabolic programming or other factors, can alter a fetus's metabolic fate. This review summarizes the hypothalamic circuits that mediate energy homeostasis and discusses the various factors that may influence the development and functioning of these neural systems, as well as the possible cognitive impairments that may arise as a result of these metabolic influences.

Testing the Critical Window Hypothesis of Timing and Duration of Estradiol Treatment on Hypothalamic Gene Networks in Reproductively Mature and Aging Female Rats.

At menopause, the dramatic loss of ovarian estradiol (E2) necessitates the adaptation of estrogen-sensitive neurons in the hypothalamus to an estrogen-depleted environment. We developed a rat model to test the "critical window" hypothesis of the effects of timing and duration of E2 treatment after deprivation on the hypothalamic neuronal gene network in the arcuate nucleus and the medial preoptic area. Rats at 2 ages (reproductively mature or aging) were ovariectomized and given E2 or vehicle replacement regimes of differing timing and duration. Using a 48-gene quantitative low-density PCR array and weighted gene coexpression network analysis, we identified gene modules differentially regulated by age, timing, and duration of E2 treatment. Of particular interest, E2 status differentially affected suites of genes in the hypothalamus involved in energy balance, circadian rhythms, and reproduction. In fact, E2 status was the dominant factor in determining gene modules and hormone levels; age, timing, and duration had more subtle effects. Our results highlight the plasticity of hypothalamic neuroendocrine systems during reproductive aging and its surprising ability to adapt to diverse E2 replacement regimes.

Pregnancy-Induced Changes in Breast Cancer Risk

Breast cancer is the malignant disease most frequently diagnosed in women of all races and nationalities. Since the 1970s the worldwide incidence of this disease has increased 30-40% in postmenopausal women, in whom, paradoxically, the risk of developing breast cancer is significantly reduced by an early first full term pregnancy (FTP) as compared to nulliparous and late parous women. Although the cause of breast cancer is not known, the mechanisms mediating the protection conferred by an early FTP have been identified to reside in the breast itself, and to be modulated by endogenous and environmental exposures that might negatively affect this organ during specific windows in its development that extend from prenatal life until the first pregnancy. Soon after conception the embryo initiates the production of human chorionic gonadotropin (hCG), the glycoprotein hormone that is diagnostic of pregnancy. HCG in conjunction with ovarian steroid hormones primes the hypothalamic neuroendocrine system for maintaining the pregnancy. Higher levels of hCG during the first trimester of pregnancy have been associated with a reduction in maternal breast cancer incidence after age 50. In preclinical studies it has been demonstrated that both FTP and hCG treatment of virgin rats prevent the development of chemically-induced mammary tumors, a phenomenon mediated by the differentiation of the mammary gland epithelial cells prior to carcinogen exposure. Complete differentiation proceeds through complex morphological, physiological and molecular changes that occur during pregnancy and lactation, that ultimately result in increased DNA repair capabilities of the mammary epithelium, activation of genes controlling differentiation and programmed cell death and imprinting in the breast epithelium a specific and permanent genomic signature of pregnancy. This signature is indicative of a reduced breast cancer risk and serves as a molecular biomarker of differentiation for evaluating the potential use of chemopreventive agents.

Effects of electro-acupuncture on signal transduction pathway of hypothalamic neuroendocrine system in ovariectomized rats

To compare the varieties and contents of the main nerval information molecules in perfusate from hypothalamic medial preoptic area (MPOA) of the rats in different sexual cycles and the ovariectomized rats treated by electro-acupuncture, so as to observe the similarities and differences of hypothalamic neuroendocrine signal transduction pathway under the physiological and pathological status, and to explore the mechanisms of neuroendocrine signal transduction of electro-acupuncture therapeutic effect in perimenopausal syndrome. The stereo localization technique and push-and-pull perfusion of the rat brain nucleus were adopted for collecting the hypothalamic MPOA perfusate of the female rats with normal sexual cycle, and also for collecting the MPOA perfusate of ovariectomized rats after electro-acupuncture treatment as acupuncture perfusate (AP). After being respectively microinjected into MPOA of the ovariectomized rats, the influence of the different perfusates on vagina cytology and serum estradiol (E2) level was observed. The contents of gonadotropin-releasing hormone (GnRH), dopamine (DA), gamma-aminobutyric acid (GABA), glutamate (Glu), aspartate (Asp) and beta-endorphin (beta-EP) in the perfusate of each group were detected by radioimmunoassay or high performance liquid chromatography, and then the varieties and contents of these substances in the perfusate of each group were compared and analyzed. The contents of neural active substances including DA, GABA, Glu, and beta-EP in the perfusate from the rats' MPOA during different stages of sexual cycle showed some regular changes. After the perfusate was microinjected respectively into the MPOA of the ovariectomized rats, the changes of animal vaginal exfoliated cells and serum E2 level showed the similar four-stage cycle characteristics as normal rats; the changes of vaginal exfoliated cells and serum E2 level of the ovariectomized rats without electro-acupuncture treatment showed the acupuncture-like effects following the microinjection of AP in the MPOA. The information molecules in the perfusate from MPOA of rats in normal sexual cycle or electro-acupuncture-treated rats include classical neurotransmitters, amino acid neurotransmitters, and neuropeptides. Acupuncture may modulate the release and synthesis of these information molecules to normalize the subnormal function of MPOA in perimenopausal period. Thus, AP may be a neuroendocrine signal carrier of acupuncture effects for acupuncture signal transduction from one individual to another. This may provide a new thinking and method for studying acupuncture signal transduction of the acupuncture therapeutic effects on perimenopausal syndrome.

Zebrafish diencephalic A11-related dopaminergic neurons share a conserved transcriptional network with neuroendocrine cell lineages

Vertebrate dopaminergic neurons develop in distinct neural territories to constitute one of the major neuromodulatory systems. We have identified a zebrafish mutation in the bHLH-PAS family member arnt2, based on a strong reduction in cell number of specific dopaminergic neuron groups in the hypothalamus and posterior tuberculum. Knockdown of sim1 causes a dopaminergic phenotype similar to arnt2 mutants, suggesting that Sim1 acts as a binding partner of Arnt2, similar to their role in hypothalamic neuroendocrine cell specification. sim1, arnt2 and otp are co-expressed in dopaminergic neurons, and combined overexpression of Sim1 and Otp leads to formation of supernumerary dopaminergic neurons in the ventral diencephalon. Arnt2, Sim1 and Otp thus are core components of a conserved transcriptional network, which specifies neuroendocrine as well as A11-related dopaminergic neurons in the fish hypothalamus and posterior tuberculum. Our data suggest a common evolutionary origin of specific hypothalamic neuroendocrine and dopaminergic systems.

A peek inside the neurosecretory brain through Orthopedia lenses

The wealth of expression and functional data presented in this overview discloses the homeogene Orthopedia (Otp) as critical for the development of the hypothalamic neuroendocrine system of vertebrates. Specifically, the results depict the up-to-date portrait of the regulation and functions of Otp. The development of neuroendocrine nuclei relies on Otp from fish to mammals, as demonstrated for several peptide and hormone releasing neurons. Additionally, the activity of Otp is essential for the induction of the dopaminergic phenotype in the hypothalamus of vertebrates. Recent insights into the pathways required for Otp regulation have revealed the implication of the main extracellular signals acting during hypothalamic development. Alterations in these pathways are involved in several neuronal disorders, and the resultant downstream misregulation of Otp might impair the development of the hypothalamus, and be therefore responsible for the neuroendocrine dysfunctions that typify these diseases.

Neuroendocrine mechanisms of change in food intake during pregnancy: A potential role for brain oxytocin

During pregnancy body weight, and particularly adiposity, increase, due to hyperphagia rather than decreased energy metabolism. These physiological adaptations provide the growing fetus(es) with nutrition and prepare the mother for the metabolically-demanding lactation period following birth. Mechanisms underlying the hyperphagia are still poorly understood. Although the peripheral signals that drive appetite and satiety centers of the brain are increased in pregnancy, the brain may become insensitive to their effects. For example, leptin secretion increases but hypothalamic resistance to leptin actions develops. However, several adaptations in hypothalamic neuroendocrine systems may converge to increase ingestive behavior. Oxytocin is one of the anorectic hypothalamic neuropeptides. Oxytocin neurons, both centrally-projecting parvocellular oxytocin neurons and central dendritic release of oxytocin from magnocellular neurons, may play a key role in regulating energy intake. During feeding in non-pregnant rats, magnocellular oxytocin neurons, especially those in the supraoptic nucleus, become strongly activated indicating their imminent role in meal termination. However, in mid-pregnancy the excitability of these neurons is reduced, central dendritic oxytocin release is inhibited and patterns of oxytocin receptor binding in the brain alter. Our recent data suggest that lack of central oxytocin action may partly contribute to maternal hyperphagia. However, although opioid inhibition is a major factor in oxytocin neuron restraint during pregnancy and opioids enhance food intake, an increase in opioid orexigenic actions were not observed. While changes in several central input pathways to oxytocin neurons are likely to be involved, the high level of progesterone secretion during pregnancy is probably the ultimate trigger for the adaptations.

Co-expression of vasopressin and androgen-binding protein in the rat hypothalamus

In previous studies we have observed the expression of androgen binding protein (ABP) in the rat hypothalamo-neurohypophysial system. With immunocytochemical double staining we found partial co-localization with oxytocin. In the present study we used antibodies to the anti-diuretic hormone arginine vasopressin (AVP) for co-localization with ABP in the rat hypothalamus. Both antigens were seen in the magnocellular paraventricular and supraoptic nuclei. Dense fiber networks with varicosities containing both AVP and ABP immunoreactivity were visible throughout the hypothalamus, the median eminence and in the posterior pituitary lobe. Double immunostaining revealed also co-existence in the parvocellular portion of the paraventricular nucleus and in the suprachiasmatic nucleus. ABP immunoreactive neurons in the preoptic region were devoid of AVP staining, AVP neurons in the bed nucleus of the stria terminalis stained only occasionally for ABP. We conclude that both the magnocellular and the parvocellular hypothalamic vasopressin systems are capable of expressing the steroid binding globulin, which is probably subject to axonal transport, along with the peptide hormone. Intrahypothalamic expression of ABP may be among the mechanisms necessary for rapid actions of steroids on hypothalamic neuroendocrine systems.

Assessing the consequences of the pesticide methoxychlor: neuroendocrine and behavioral measures as indicators of biological impact of an estrogenic environmental chemical

Japanese quail provide an advantageous avian model for assessing long-term biological consequences of endocrine disrupting chemicals (EDCs). These studies examined route of exposure and vulnerability to biological impact of EDCs over the life cycle in a precocial avian model, the Japanese quail. Embryonic exposure occurs with maternal deposition and methoxychlor (MXC) accumulated with maternal exposure. Egg injections of MXC or estradiol at selected stages of development impacted hypothalamic neuroendocrine systems in hatchlings and affected sexual maturation, with evidence for long-term effects on neurotransmitters and male behavior. Two-generation dietary studies were conducted to examine transgenerational effects of EDCs. Adult quail (P1) were exposed to dietary MXC (0, 0.5 and 5 ppm), with continued exposure in their offspring (F1), and control diet for all F2 chicks. Toxicological end points, including fertility, hatching success, and 14-day viability were unaffected. F1 and F2 male offspring from MXC-treated pairs MXC had impaired mating behavior and altered plasma hormones. These studies confirm neuroendocrine and behavioral measures as reliable indices of exposure to an estrogenic EDC. Moreover, maternal deposition remains a primary route of EDC exposure, with potential deleterious consequences for field birds, especially precocial species that appear to be particularly sensitive to embryonic EDC exposure.

The role of leptin-->STAT3 signaling in neuroendocrine function: an integrative perspective.

The hormone leptin is secreted by adipose tissue in proportion to fat mass to signal the repletion of body energy stores to the neuroendocrine system. Leptin acts on neurons in the hypothalamus and elsewhere in the brain to decrease appetite and regulate the activity of the thyroid, adrenal, growth, gonadal, and lactational axes. Conversely, absence of leptin signaling initiates the neuroendocrine starvation response. Leptin mediates these effects by activating the long form (LRb) of its receptor. One LRb signal, STAT3, has recently been shown to play a critical role in the regulation of body weight and some elements of neuroendocrine function (thyroid, adrenal, lactation), although the participation of STAT3 in the gonadal and growth axes is negligible. We discuss these findings in the context of the hypothalamic neuroendocrine system as it is presently understood.

Neuroendocrinology of ageing.

Many common problems encountered in the ageing patient can be related to neuroendocrine phenomena. These include Alzheimer's disease, dementia and cognitive dysfunction, depression, Parkinson's disease, hyponatraemia and the postmenopausal increase in both vascular risk and osteoporosis. This review concentrates on the hypothalamic neuroendocrine system, including the dopaminergic, noradrenergic, serotoninergic, cholinergic and neurohypophyseal systems and the roles of the anterior pituitary and monoamine oxidases, luteinizing hormone-releasing hormone, corticotrophin-releasing factor, the pro-opiomelanocortin-derived and opioid peptides, peptides involved in growth hormone and thyrotropin regulation, and amino acid transmitters.

Differential localization and colocalization of two neuron-types of sodium-dependent inorganic phosphate cotransporters in rat forebrain

We studied by immunohistochemistry the distribution of differentiation-associated sodium-dependent inorganic phosphate (Pi) cotransporter (DNPI) in the rat forebrain, in comparison with brain-specific cotransporter (BNPI). DNPI-staining was principally seen in axonal synaptic terminals which showed a widespread but discrete pattern of distribution different from that of the BNPI-staining. In the diencephalon, marked DNPI-staining was seen in the dorsal lateral geniculate, medial geniculate, ventral posterolateral, ventral posteromedial, anterior, and reticular thalamic nuclei without the colocalization with BNPI-staining. DNPI-staining showed a strong mosaical pattern and overlapped well the BNPI-staining in the medial habenular nucleus. DNPI-staining was moderate over the hypothalamus and notably localized in neurosecretory terminals containing corticotropin-releasing hormone in the median eminence. In contrast, the BNPI-staining was region-related and strong in the ventromedial and mammillary nuclei. In the telencephalon, laminar DNPI-staining was seen over the neocortex, corresponding to the thalamocortical termination, and also found in the retrosplenial cortex and the striatum, with the highest intensity in the accumbens nucleus shell. The present results suggest that DNPI serves as a dominant Pi transport system in synaptic terminals of diencephalic neurons including thalamocortical and thalamostriatal pathways as well as the hypothalamic neuroendocrine system in the rat forebrain.

Cellular orientation of atrial natriuretic peptide in the human brain

Many peptide hormones and neurotransmitters have been detected in human neuronal tissue. The localisation of atrial natriuretic peptide (ANP) in the human brain was considered to be both interesting and relevant to the understanding of neurochemistry and brain water–electrolyte homeostasis. This vasoactive peptide hormone has been localised in rat and frog neuronal tissue. In the present study, we report the immunohistochemical localisation of ANP in autopsy samples of human brain tissue employing the avidin–biotin–peroxidase complex technique, using an antibody against a 28 amino acid fragment of human ANP. The most intense staining of immunoreactive ANP was detected in the neurones of preoptic, supraoptic and paraventricular nuclei of the hypothalamus, epithelial cells of the choroid plexus and ventricular ependymal lining cells. Immunoreactive neurones were also observed in the median eminence, lamina terminalis, infundibular and ventromedial nuclei of the hypothalamus, and in neurones of the brain stem, thalamic neurones and some neurones of the caudate nucleus. The network of ANP cells in numerous hypothalamic centres may regulate the salt and water balance in the body through a hypothalamic neuro-endocrine control system. ANP in the brain may also modulate cerebral fluid homeostasis by autocrine and paracrine mechanisms.

Neuroendocrine Regulation of GnRH and Behavior During Aging in Birds

Avian species exhibit a great variety of life-long patterns in reproduction. Japanese quail are relatively short lived and undergo an age-related loss of reproductive function, making this species an excellent model for the study of the basic biology of aging. Because individuals age at variable rates, sexual behavior has provided a useful index to assess reproductive status of individuals of the same chronological age. Further, exogenous testosterone restores sexual behavior in reproductively senescent male quail, thereby providing evidence for a continued ability of the system to respond. In addition, we have been studying hypothalamic neuroendocrine systems that regulate the endocrine as well as behavioral components of reproduction. Overall, our findings point to the hypothalamic neuroendocrine systems as the site of initial age-related alterations that contribute to the reproductive deterioration. Specifically, we studied adrenergic, opioid peptide, vasotocin, and aromatase systems to understand their relationship to the cGnRH-I system and their potential role in the deterioration of the cGnRH-I system during aging. Our findings provide evidence for qualitative and quantitative alterations in the aromatase enzyme system, which can be partially restored with exogenous testosterone. In addition, other neuronal systems, including the vasotocin system, decline with the loss of gonadal steroids and are restimulated with exogenous testosterone. We will synthesize the data relative to these neuroendocrine systems with attention to the effects of gonadal steroids on these systems during aging.

Aging in the hypothalamo-neurohypophysial-renal system

Ageing is characterised by a failure in the maintenance of the internal environment (homeostasis) which is regulated by the hypothalamic neuroendocrine system. Of the many systems that undergo age-related degeneration is the control of water metabolism which leads to a variety of complications in the elderly. The magnocellular neurons of the hypothalamus produce the peptide anti-diuretic hormone (vasopressin) which acts on the kidney regulating water loss in the urine. This physiological axis lends itself to both fundamental studies of the cellular and molecular biology of ageing, and to studies of age-related alterations in the functional ability of elderly people. This review summarises some of the recent research into age-related changes in this system. The morphological and functional changes in the hypothalamus, neurohypophysis and kidney are described for the various species examined and the results discussed in terms of ageing in humans.

Vasopressinergic innervation of the mouse suprachiasmatic nucleus: An immuno‐electron microscopic analysis

Attempts are being made to unravel the local circuitry of the suprachiasmatic nucleus, with a view toward eventually correlating specific neuronal systems with circadian events. Hence, the vasopressinergic innervation of this nucleus in the laboratory mouse has been analyzed immunocytochemically at the light and electron microscopical levels. Monoclonal antineurophysin and polyclonal antivasopressin were used on aldehyde-fixed brains. Serial vibratome sections of the appropriate forebrain region were prepared for pre-embedding immunoperoxidase staining and/or postembedding immunogold labeling. Immunoreactive somata, processes, varicosities, and synaptic terminals were found throughout the suprachiasmatic nucleus, their ratio and density varying at different locations. The predominant type of vasopressinergic soma was ovoid to rounded (7-10 microns), containing secretory granules (85-120 nm), a large proportion of which were immunoreactive. Axon terminals, both nonimmunoreactive and immunoreactive, impinged upon vasopressinergic somata and processes, often displaying synaptic specializations. Vasopressinergic terminals, containing secretory granules and microvesicles, were found throughout the nucleus, particularly within the dorsomedial neuropil. These labeled terminals varied in size (0.4-3.4 microns 2) and shape, ranging from compact boutons to pleomorphic profiles, some deeply indented by postsynaptic spines, either dendritic or somatic. Approximately 65% of the vasopressin-containing terminals were axodendritic and 30% axosomatic; about 5% appeared to be axoaxonic. At least a quarter of all vasopressinergic synaptic terminals were axospinous. Other forms of interneuronal contact involving vasopressinergic elements (somata, dendrites) included extensive membrane to membrane appositional sites, and multiple puncta adhaerentia. The versatility of interconnections between vasopressin-containing neurons in the mouse suprachiasmatic nucleus suggests a highly active and coordinated network, which contributes substantially to local intranuclear circuitry. In addition, a dense efferent vasopressinergic output is directed dorsally towards the periventricular hypothalamus, where direct associations may be established with diverse hypothalamic neuroendocrine systems.