Acute exposure to 2G phase shifts the rat circadian timing system

The circadian timing system (CTS) provides internal and external temporal coordination of an animal's physiology and behavior. In mammals, the generation and coordination of these circadian rhythms is controlled by a neural pacemaker, the suprachiasmatic nucleus (SCN), located within the hypothalamus. The pacemaker is synchronized to the 24 hour day by time cues (zeitgebers) such as the light/dark cycle. When an animal is exposed to an environment without time cues, the circadian rhythms maintain internal temporal coordination but exhibit a "free-running" condition in which the period length is determined by the internal pacemaker. Maintenance of internal and external temporal coordination are critical for normal physiological and psychological function in human and non-human primates. Exposure to altered gravitational environments has been shown to affect the amplitude, mean, and timing of circadian rhythms in species ranging from unicellular organisms to man. However, it has not been determined whether altered gravitational fields have a direct effect on the neural pacemaker, or affect peripheral physiological systems that express these circadian parameters. In previous studies, the ability of a stimulus to phase shift circadian rhythms was used to determine whether a stimulus has a direct effect on the neural pacemaker. The present experiment was performed in order to determine whether acute exposure to a hyperdynamic field could phase shift circadian rhythms.     

Changes in metabolic activity of neurons in the anterior hypothalamus nuclei during hyperthermia, fever, and hypothermia

Differently directed changes in metabolic activity of anterior hypothalamic nuclei's neurons in rats during hyperthermia, fever, and hypothermia were revealed with histochemical methods. During hyperthermia, the activity of energy metabolism enzymes increased as well as RNA content in the neurons of supraoptic, paraventricular and median preoptic anterior hypothalamic nuclei. This is shown by an increase in the metabolic activity of neurons of these nuclei. Metabolic activity in neurons of median preoptic nuclei decreased and was not changed considerably in neurons of supraoptic and paraventricular nuclei during endotoxin-induced fever. The development of hypothermia was characterised by a decrease in metabolic activity of neurons of supraoptic, paraventricular and medium preoptic nuclei. It is supposed that differently directed metabolic activity changes in neurons of anterior hypothalamic nuclei during hyperthermia are connected with the mechanisms of body temperature regulation (median preoptic nuclei) and neurosecretory processes (supraoptic and paraventricular nuclei).     

The effects of gravity on the circadian timing system

The physiological system responsible for the temporal coordination of an organism is the circadian timing system (CTS). This system provides two forms of temporal coordination. First, the CTS provides for synchronization of the organism with the 24 hour period of the external environment. This synchronization of the organism with the environment is termed entrainment. Second, this system also provides for internal coordination of the various physiological, behavioral, and biochemical events within the organism. When either of these two temporal relationships are disturbed, various dysfunctions can be manifest within the organism. Homeostatic capacity of other physiological systems may be reduced. Performance is decreased and sleep disorders, mental health impairment (e.g., depression), jet lag syndrome, and shift work maladaptation frequently occur. Over the last several years, several studies have evaluated the potential influence of gravity on this physiological control system by examining changes in rhythmic characteristics of organisms exposed to altered gravitational environments. The altered gravitational environments have included the microgravity of spaceflight as well as hyperdynamic fields produced via centrifugation.     

Influence of circadian disruption on neurotransmitter levels,physiological indexes,and behaviour in rats

Brain monoamines – such as noradrenaline (NA), dopamine (DA) and serotonin (5-HT) – regulate several important physiological functions, including the circadian rhythm. The purpose of this study was to examine changes in NA, DA and 5-HT levels in various brain regions and their effect on core body temperature (T_c), heart rate (HR) and locomotor activity (Act) in rats following exposure to an artificial light/dark (LD) cycle. For this, male Wistar rats were housed at an ambient temperature (T_a) of 23?°C and 50% relative humidity with free access to food and water. Rats were exposed to either natural (12?h:12?h) or artificial (6?h:6?h) LD cycles for 1 month, after which each brain region was immediately extracted and homogenized to quantify the amounts of NA, DA and 5-HT by high-performance liquid chromatography. Behavioural changes were also monitored by the ambulatory activity test (AAT). Notably, we found that artificial LD cycles disrupted the physiological circadian rhythms of T_c, HR and Act. Although the 5-HT levels of rats with a disrupted circadian rhythm decreased in cell bodies (dorsal and median raphe nuclei) and projection areas (frontal cortex, caudate putamen, preoptic area and suprachiasmatic nucleus) relative to the control group, NA levels increased both in the cell body (locus coeruleus) and projection area (paraventricular hypothalamus). No significant changes were found with respect to DA. Moreover, circadian rhythm-disrupted rats also showed anxious behaviours in AAT. Collectively, the results of this study suggest that the serotonergic and noradrenergic systems, but not the dopaminergic system, are affected by artificial LD cycles in brain regions that control several neural and physiological functions, including the regulation of physiological circadian rhythms, stress responses and behaviour.     

Galanin-like peptide and the regulation of feeding behavior and energy metabolism

The hypothalamic neuropeptides modulate physiological activity via G protein-coupled receptors (GPCRs). Galanin-like peptide (GALP) is a 60 amino acid neuropeptide that was originally isolated from porcine hypothalamus using a binding assay for galanin receptors, which belong to the GPCR family. GALP is mainly produced in neurons in the hypothalamic arcuate nucleus. GALP-containing neurons form neuronal networks with several other types of peptide-containing neurons and then regulate feeding behavior and energy metabolism. In rats, the central injection of GALP produces a dichotomous action that involves transient hyperphasia followed by hypophasia and a reduction in body weight, whereas, in mice, it has only one action that reduces both food intake and body weight. In the present minireview, we discuss current evidence regarding the function of GALP, particularly in relation to feeding and energy metabolism. We also examine the effects of GALP activity on food intake, body weight and locomotor activity after intranasal infusion, a clinically viable mode of delivery. We conclude that GALP may be of therapeutic value for obesity and life-style-related diseases in the near future.     

Role of neuronal nitric oxide synthase in the regulation of the neuroendocrine stress response in rodents: insights from mutant mice

Nitric oxide (NO) is a free radical gas synthesised from arginine and oxygen by enzymes of the family of the nitric oxide synthase. In particular, the neuronal nitric oxide synthase (nNOS) is highly expressed by cells of the hypothalamic paraventricular nucleus, where the sympatho-adrenal system, the hypothalamic-pituitary-adrenal axis and the hypothalamic-neurohypophyseal system originate. These structures are deputed to regulate the neuroendocrine stress response. In the past years, evidence has been accumulated to suggest that NO of nNOS origin plays a significant role in modulating the activity of the above mentioned systems under acute stressor exposure. The availability of nNOS knock-out mice allowed to investigate not only the physiological consequences of a constitutive lack of NO of nNOS origin at the hormonal and molecular level, but also to examine possible behavioural alterations. In this review, we shall discuss and confront the current trends of research in this area, especially focusing on the latest findings gained from genetically modified mice.     

Cytokines as mediators of neuroimmune interactions

Cytokines regulate numerous physiological and pathological processes in the central nervous system (CNS), i.e. they function both as immune regulators and neuromodulators. Acting upon the CNS via different ways, cytokines, mainly proinflammatory ones IL-1beta and TNF-alpha, can disturb physiological functions of the CNS, cause neurotoxic and neurodegenerative damage and stimulate IL-1beta synthesis in hypothalamus nuclei and posterior pituitary. They can produce stress-like effects upon the CNS and affect the activity of the axis hypothalamus--pituitary--adrenal glands, levels of neuropeptides in hypothalamic regions of brain, synthesis and utilization of central monoamines. These influences can implement the effects of sensitization, which enhances neuroendocrine responses to later stresses. Microglia and astrocytes, secondary messengers and interaction between hypothalamus and anterior pituitary play an important role in range of these processes as well as in the maintenance of Th1/Th2 cytokine balance.     

Localization and possible function of peptidergic neurons and their interactions with central catecholamine neurons, and the central actions of gut hormones.

The localization of various neuropeptides is described in the gut and in the hypothalamus in the rat. Evidence is given for the presence of material resembling corticotropin-like intermediate peptide in arcuate and periarcuate neurons, projecting to various hypothalamic nuclei, limbic areas and the thalamus. beta-Endorphin and glucagon decrease dopamine turnover in the median eminence, while secretin increases dopamine turnover and vasoactive intestinal polypeptide (VIP) has no effect. beta-Endorphin, VIP, secretin, and glucagon all produce discrete changes in norepinephrine turnover in various hypothalamic nuclei. Mainly increases of norepinephrine turnover were observed. These catecholamine turnover changes appear to cause changes in the secretion of prolactin and growth hormone. The results therefore indicate that gut hormones and opioid peptides may act directly on the hypothalamus on specific types of receptors to participate in the control of hypothalamic functions such as control of hormone secretion from the anterior pituitary and of food intake. It seems possible that gastrointestinal peptides released from the gastrointestinal tract into the circulation under certain circumstances could reach the hypothalamus and modulate its activity via the above-mentioned mechanisms. It may therefore be speculated that disturbances in gastrointestinal functions could lead to pathological changes in food intake via modulation of hypothalamic activity.     

Effect of heat acclimation on anxiety-like behavior of rats in an open field

To mitigate the impacts of heat exposure, animals can take some actions to maintain their core body temperature, such as heat acclimation; however, the effect of heat acclimation on anxiety-like behavior in an open field is still not understood. The purpose of this study was to examine the anxiety-like behavior of heat acclimated rats in a temperate or heated open field. After being raised in a 23 °C environment for one week, male Wistar rats were exposed to a heated environment (32 °C) for 3 h (3H), 14 days (14D), or 28 days (28D), with free access to food and water, and compared with rats reared in a temperate environment (23 °C; Cont). After heat exposure, behavioral changes were monitored using an open field test (OFT) in a heated (32 °C) or temperate environment (23 °C). Compared with those in the Cont group, the body weights of rats in the 14D and 28D groups were lower. The OFT in the heated environment showed that grooming time was longer in 3H and 14D rats. In the temperate environment, grooming time was longer in all the heated groups. Rats from the 3H and 28D groups spent longer time in the center square when tested in the temperate environment. Rearing activity increased in 28D rats in the temperate environment, while the number of line crossings did not differ significantly between the heated groups and the two open fields. These results suggest that heat acclimation affected not only the physiological index such as core body temperature but also the anxiety-like behavior, mainly in the temperate open field. These changes might be beneficial when rats are faced with an open field.     

Pre- and post-weaning cold exposure does not lead to an obese phenotype in adult Brandt's voles (Lasiopodomys brandtii)

Evidence has shown that postnatal undernutrition, overnutrition and cold stress are associated with imbalanced metabolic regulation as rodents achieve adulthood. In this study, we used a breeding colony of Brandt's voles (Lasiopodomys brandtii), a wild rodent species from the Inner Mongolia grasslands in China, to examine the effects of pre- and post-weaning cold exposure on the adult body (fat) mass, serum hormones and hypothalamic neuropeptides. Unlike laboratory rodents, vole offspring exposed to pre-weaning cold did not exhibit overweight or obese phenotypes in adulthood compared with unexposed controls. Moreover, adult male voles that remained in colder conditions had less body mass and lower serum leptin levels despite having higher food intake compared to other groups. To understand the mechanism of this unexpected regulation, hypothalamic gene expression was assessed for pre- and post-weaning cold exposure. Voles exposed to cold before weaning increased hypothalamic, orexigenic agouti-related protein (AgRP) and decreased anorexigenic proopiomelanocortin (POMC) mRNA expression at weaning. These expression changes were associated with hyperphagia and catch-up growth after weaning. Interestingly, these changes in hypothalamic neuropeptides were short lasting because in adult voles these differences were no longer apparent, which might explain why the pre-weaning, cold-exposed voles did not become obese in adulthood. These data suggest that some species do not develop an obese phenotype in response to early life cold stress.     

Peptidase inactivation of hypothalamic releasing hormones.

With the structural characterization of the hypothalamic hormones, luteinizing hormone-releasing hormone (LH-RH), thyrotrophin-releasing (TRH), melanocyte-stimulating hormone release-inhibiting hormine (MIH), and growth hormone release-inhibiting hormone, (GH-RIH or somatostatin), it has been possible to investigate their enzymic inactivation by peptidases which are present at various sites in the body. Enzymes may play an important part in the control of polypeptide hormone levels and the peptidases acting on these four hypothalamic hormones may regulate the amount of TRH, LH-RH, MIH and somatostatin released from the hypothalamus, or their action at the level of the pituitary and their removal from the circulation. By studying the peptidase enzymes, further information may be obtained on the physiological mechanisms controlling the secretion and actions of hypothalamic hormones, as well as on the design of analogues with increased or competitive activity.     

Evolutionary physiology

The tasks, methods and principles of the evolution of functions are overviewed at various levels of organization of physiological systems with the focus on the central problem of physiological evolution—the origin of life and formation of protocellular functions. This stage of evolution is associated with the emergence of the plasma membrane and ion asymmetry of the cell relative to the extracellular environment. For a long time, evolution proceeded in the sea, where extracellular sodium ions in tandem with the intracellular potassium dominance created conditions for the emergence of electrogenesis, polar cells and epithelia, as well as for the formation of the extracellular body fluid system, making up the internal environment of multicellular organisms. The features of the evolution of organs and functional systems are analyzed. During evolution, hormones, autakoids and incretins began to be involved in the regulation of functions alongside with the nervous system. Sodium-dependent processes in the plasma membrane stimulated the development of absorptive, digestive, excretory, respiratory and homeostatic functions. The substance and patterns of functional evolution are discussed.     

Leptin Dysfunction and Alzheimer’s Disease: Evidence from Cellular,Animal, and Human Studies

There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer’s disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.     

Chronic effects of copper exposure versus endocrine toxicity: two sides of the same toxicological process?

Chronic sub-lethal exposure to copper (Cu) causes a series of cellular and physiological changes in fish that enable the animal to survive. Copper is also an endocrine disrupting metal in the aquatic environment, and has a number of normal neuro-endocrine roles in vertebrates. This paper explores whether the chronic effects of Cu exposure can be explained by the effects of Cu on neuro-endocrine functions in fish. Chronic Cu exposure involves complex physiological adjustments in many body systems, including increased oxygen consumption, reduced mean swimming speed, up-regulation of ionic regulation, decreasing lymphocyte levels and increasing neutrophils, altered immunity, modulation of Cu-dependent and independent enzyme activities, and proliferation of epithelial cells in gills or intestine. These responses can occur with exposure via the food or the water and can be rationalised into three major categories: (1) up-regulation of enzymes/metabolism (2) altered haematopoietic responses and (3) altered cellularity (cell type, turnover or size) in tissues. Some of these responses can be explained by stimulation of general stress responses, including the adrenergic response and stimulated cortisol release via the hypothalamic-pituitary-interrenal axis. This can occur despite evidence of vacuolation and foci of necrosis in the brain, and increased macrophage activity, in the kidney of fish exposed to dietary Cu. In addition to generic stress responses, Cu regulates specific neuro-endocrine functions, including the loss of circadian rhythm during dietary Cu exposure that involves the failure to respond to circulating melatonin and a loss of circulating serotonin. We conclude that the chronic physiological effects of Cu and apparent endocrine disrupting effects of Cu are two sides of the same toxicological process.     

Neuroanatomical distribution of galectin-3 in the adult rat brain

Galectin-3 is a member of the lectin subfamily that enables the specific binding of β-galactosides. It is expressed in a broad spectrum of species and organs, and is known to have various functions related to cell adhesion, signal transduction, and proinflammatory responses. Although, expression of galectin-3 in some activated neuroglia under neuroinflammation has been well documented in the central nervous system, little is known about the neuronal expression and distribution of galectin-3 in normal brain. To describe the cellular and neuroanatomical expression map of galectin-3, we performed galectin-3 immunohistochemistry on the entire normal rat brain and subsequently analyzed the neuronal distribution. Galectin-3 expression was observed not only in some neuroglia but also in neurons. Neuronal expression of galectin-3 was observed in many functional parts of the cerebral cortex and various other subcortical nuclei in the hypothalamus and brainstem. Neuroanatomical analysis revealed that robust galectin-3 immuno-signals were present in many hypothalamic nuclei related to a variety of physiological functions responsible for mediating anxiety responses, energy balance, and neuroendocrine regulation. In addition, the regions highly connected with these hypothalamic nuclei also showed intense galectin-3 expression. Moreover, multiple key regions involved in regulating autonomic functions exhibited high levels of galectin-3 expression. In contrast, the subcortical nuclei responsible for the control of voluntary motor functions and limbic system exhibited no galectin-3 immunoreactivity. These observations suggest that galectin-3 expression in the rat brain seems to be regulated by developmental cascades, and that functionally and neuroanatomically related brain nuclei constitutively express galectin-3 in adulthood.     

Purinergic signaling in tanycytes and its contribution to nutritional sensing

Tanycytes are hypothalamic radial glial-like cells with an important role in the regulation of neuroendocrine axes and energy homeostasis. These cells have been implicated in glucose, amino acids, and fatty acid sensing in the hypothalamus of rodents, where they are strategically positioned. While their cell bodies contact the cerebrospinal fluid, their extensive processes contact neurons of the arcuate and ventromedial nuclei, protagonists in the regulation of food intake. A growing body of evidence has shown that purinergic signaling plays a relevant role in this homeostatic role of tanycytes, likely regulating the release of gliotransmitters that will modify the activity of satiety-controlling hypothalamic neurons. Connexin hemichannels have proven to be particularly relevant in these mechanisms since they are responsible for the release of ATP from tanycytes in response to nutritional signals. On the other hand, either ionotropic or metabotropic ATP receptors are involved in the generation of intracellular Ca²⁺ waves in response to hypothalamic nutrients, which can spread between glial cells and towards neighboring neurons. This review will summarize recent evidence that supports a nutrient sensor role for tanycytes, highlighting the participation of purinergic signaling in this process.     

Toxicological stress response and cadmium distribution in hybrid tilapia (Oreochromis sp.) upon cadmium exposure

Adult tilapia were exposed to 0 (control) and 4.45 microM Cd for 0 h, 5 h, 5 days, and 15 days, and the physiological responses of fish were described. The physiological responses were first expressed in gill tissue, in which mucus cells secretion increased, Cd accumulated, cortisol secretion was significantly higher, but serum ACH(50) activity (alternative complement hemolytic assay) was significantly lower than in controlled fish. After 5 days of Cd exposure, the ACH(50) activity showed a greater decrease, but lysozyme and cortisol contents showed significant increases over the control. Cd levels significantly increased in intestines, liver, and kidneys, and a significant induction of metallothionein (MT) protein in hepatic tissue was noted. Finally, the Cd accumulation rate still showed significant increases in these organs. However, the MT content was similar at 5 days and at 15 days after Cd exposure, and the cortisol contents had recovered to the pre-exposure level. In addition, Cd accumulation in muscle was higher after Cd exposure than in controls (t-test, p<0.05). Our results demonstrate (1) that tilapia readily regulate their physiological parameters in order to acclimate to a sublethal Cd environment; (2) these changes of physiological parameters may be related with a succession of cortisol levels following Cd exposure; (3) increasing rate of hepatic MT contents and Cd accumulation rate didn't appear identical after 5-15 days of Cd exposure. This was confirmed that hepatic MT was not a good indicator for Cd levels in tilapia.     

The deformation behavior and viscoelastic properties of chondrocytes in articular cartilage

Chondrocytes in articular cartilage utilize mechanical signals in conjunction with other environmental factors to regulate their metabolic activity. However, the sequence of biomechanical and biochemical events involved in the process of mechanical signal transduction has not been fully deciphered. A fundamental step in determining the role of various factors in regulating chondrocyte activity is to characterize accurately the biophysical environment within the tissue under physiological conditions of mechanical loading. Microscopic imaging studies have revealed that chondrocytes as well as their nuclei undergo shape and volume changes in a coordinated manner with deformation of the tissue matrix. Through micromechanical experiments, it has been shown that the chondrocyte behaves as a viscoelastic solid material with a mechanical stiffness that is several orders of magnitude lower than that of the cartilage extracellular matrix. These properties seem to be due to the structure of the chondrocyte cytoskeleton, and in part, the viscoelastic properties of the cell nucleus. The mechanical properties of the pericellular matrix that immediately surrounds the chondrocyte significantly differ from those of the chondrocyte and the extracellular matrix, suggesting that the pericellular matrix plays an important role in defining the mechanical environment of the chondrocyte. These experimentally measured values for chondrocyte and cartilage mechanical properties have been used in combination with theoretical constitutive modeling of the chondrocyte within articular cartilage to predict the non-uniform and time-varying stress-strain and fluid flow environment of the cell. The ultimate goal of these studies has been to elucidate the sequence of biomechanical and biochemical events through which mechanical stress influences chondrocyte activity in both health and in disease.     

Changes in monoamines in rat hypothalamus during cold acclimation

Action of norepinephrine (NE), serotonin (5-HT) and dopamine (DA) in the hypothalamus have been reported to play key roles in several homeostatic functions, including thermoregulation. The purpose of this study was to clarify differences in concentrations of NE, 5-HT and DA in several hypothalamic regions after cold exposure of different durations. Rats were exposed to a cold environment (5 °C) for 3 hours (3H), 1 day (1D), 7 days (7D), 14 days (14D), or 28 days (28D). After cold exposure, each hypothalamic region was immediately extracted and homogenized. NE, 5-HT and DA in the extract were measured by high-performance liquid chromatography. We observed marked differences in the concentration of NE in each hypothalamic region after cold exposures. NE in the preoptic area was high only in the 3H group, while it was elevated in the 7D, 14D and 28D groups in the ventromedial hypothalamus. On the other hand, NE in the posterior hypothalamus was low in the 3H, 1D, 7D and 14D groups. Cold exposure did not affect concentrations of 5-HT and DA in these hypothalamic regions. Our results suggest the involvement of NE in each hypothalamic region in maintenance of body temperature, and that the neuronally active site in the hypothalamus seems to change during cold acclimation.