Physiological arousal: a role for hypothalamic systems

The lateral hypothalamus (LH) has long been known as a homeostasis center of the brain that modulates feeding behavior, arousal and reward. The hypocretins (Hcrts, also called orexins) and melanin-concentrating hormone (MCH) are neuropeptides produced in two intermingled populations of a few thousand neurons in the LH. The Hcrts have a prominent role in regulating the stability of arousal, since Hcrt system deficiency leads to narcolepsy. MCH is an important modulator of energy balance, as MCH system deficiency in mice leads to leanness and increased metabolism. Recently, MCH has been proposed to modulate rapid eye movement sleep in rodents. In this review, we propose a working model of the cross-talk between Hcrt and MCH circuits that may provide an arousal balance system to regulate complex goal-oriented behaviors.     

Presence of neurons synthesizing LH-RH in the anterior hypothalamus of the duck (Anas platyrhynchos)]

Using histochemical techniques with LH-RH anti-serum, a large number of LH-RH producing neurons were identified in the Duck hypothalamus, under different physiological conditions. The LH-RH pericaryas were localized in a well delimited area of the anterior hypothalamus, including the dorsal part of the periventricular preoptic nucleus. The LH-RH containing axons were directed downwards towards the infundibulum, and terminated within the external layer of the rostral and caudal median eminence, in close vicinity to the capillaries of the pituitary portal system.     

Galanin – 25 years with a multitalented neuropeptide

Galanin has diverse physiological functions, including nociception, arousal/sleep regulation, cognition, and many aspects of neuroendocrine activities that are associated with feeding, energy metabolism, thermoregulation, osmotic and water balance, and reproduction. This review will provide a brief overview of galanin actions in some major neuroendocrine processes. Most of the recent data are about the role of galanin in the central regulation of food intake and energy metabolism, and to some extent, in the regulation of reproduction. It seems that galanin plays a modulatory rather than regulatory role in the central and peripheral branches of the neuroendocrine systems. In the hypothalamus, it functions as a neurotransmitter/neuromodulator. In the pituitary and the peripheral endocrine glands, it acts via its receptors (GALRs) in a paracrine/autocrine fashion. The development of new, selective and potent antagonists of GALRs should keep advancing our knowledge not only in the physiology but also the pathophysiology of galanin as well.     

Leptin signaling and circuits in puberty and fertility

Leptin is an adipocyte-derived hormone involved in a myriad of physiological process, including the control of energy balance and several neuroendocrine axes. Leptin-deficient mice and humans are obese, diabetic, and display a series of neuroendocrine and autonomic abnormalities. These individuals are infertile due to a lack of appropriate pubertal development and inadequate synthesis and secretion of gonadotropins and gonadal steroids. Leptin receptors are expressed in many organs and tissues, including those related to the control of reproductive physiology (e.g., the hypothalamus, pituitary gland, and gonads). In the last decade, it has become clear that leptin receptors located in the brain are major players in most leptin actions, including reproduction. Moreover, the recent development of molecular techniques for brain mapping and the use of genetically modified mouse models have generated crucial new findings for understanding leptin physiology and the metabolic influences on reproductive health. In the present review, we will highlight the new advances in the field, discuss the apparent contradictions, and underline the relevance of this complex physiological system to human health. We will focus our review on the hypothalamic circuitry and potential signaling pathways relevant to leptin’s effects in reproductive control, which have been identified with the use of cutting-edge technologies of molecular mapping and conditional knockouts.     

Ablation of LMO4 in glutamatergic neurons impairs leptin control of fat metabolism

The LIM domain only 4 (LMO4) protein is expressed in the hypothalamus, but its function there is not known. Using mice with LMO4 ablated in postnatal glutamatergic neurons, including most neurons of the paraventricular (PVN) and ventromedial (VMH) hypothalamic nuclei where LMO4 is expressed, we asked whether LMO4 is required for metabolic homeostasis. LMO4 mutant mice exhibited early onset adiposity. These mice had reduced energy expenditure and impaired thermogenesis together with reduced sympathetic outflow to adipose tissues. The peptide hormone leptin, produced from adipocytes, activates Jak/Stat3 signaling at the hypothalamus to control food intake, energy expenditure, and fat metabolism. Intracerebroventricular infusion of leptin suppressed feeding similarly in LMO4 mutant and control mice. However, leptin-induced fat loss was impaired and activation of Stat3 in the VMH was blunted in these mice. Thus, our study identifies LMO4 as a novel modulator of leptin function in selective hypothalamic nuclei to regulate fat metabolism.     

Insulin acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia in the rat

Microinjection of insulin (0.04-0.12 IU/microliter) into the anterior hypothalamus or the lateral hypothalamus, but not the ventromedial hypothalamus of the rat brain, caused a dose-dependent rise in blood glucose and in serum insulin. The majority (71.5%) of the glucose-facilitated neurons recorded in the lateral hypothalamic area were excited by intracerebral injection of insulin. The data indicate that insulin acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia. It is unknown whether insulin normally reaches the hypothalamic area, or how it might do so.     

Insulin acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia in the rat

Microinjection of insulin (0.04–0.12 IU/l) into the anterior hypothalamus or the lateral hypothalamus, but not the vertromedial hypothalamus of the rat brain, caused a dose-dependent rise in blood glucose and in serum insulin. The majority (71.5%) of the glucose-facilitated neurons recorded in the lateral hypothalamic area were excited by intracerebral injection of insulin. The data indicate that insulni acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia. It is unknown whether insulin normally reaches the hypothalamic area, or how it might do so.This work was supported by grants from the National Science Council (Taipei, Taiwan, Republic of China).     

Role of the infundibular complex and its neural afferents in the photosexual reflex in the quail]

The photosexual reflex was suppressed in quail after bilateral preoptic lesions. However an anterior-lateral de-afferentation of the hypothalamus of previously preoptic-lesioned quail resulted in partial photo-induced testis growth. As a working hypothesis, it is suggested that the preoptic area may control some unknown extrahypothalamic influences in order to modulate the gonadotropin controlling function of the infundibular area.     

Neuroanatomy and neurochemistry of sleep

Sleep is regulated by homeostatic and circadian factors, and the regulation of sleep of mammals shares many molecular properties with the rest state of submammalian species. Several brain structures take part in waking: the basal forebrain, posterior and lateral hypothalamus, and nuclei in the tegmentum and pons. Active sleep mechanisms are located to the preoptic/anterior hypothalamic area. In addition to acetylcholine and monoamines, glutamate and hypocretin/orexin are important waking factors. Gamma-aminobutyric acid and several peptide factors, including cytokines, growth hormone-releasing hormone and prolactin, are related to sleep promotion. Adenosine is an important homeostatic sleep factor acting in basal forebrain and preoptic areas through A1 and A2A receptors. Prolonged waking activates inducible nitric oxide synthase in the basal forebrain, which through energy depletion causes adenosine release and recovery sleep. Numerous genes have been found differentially displayed in waking compared with sleep, and they relate to neural transmission, synaptic plasticity, energy metabolism and stress protection. The genetic background of a few sleep disorders has been solved.     

Immunohistochemical detection of a substance resembling growth hormone-releasing factor in the brain of the rainbow trout (Salmo gairdneri)

We studied the distribution of an immunoreactive substance resembling growth hormone-releasing factor (GRF) in the hypothalamus and pituitary gland of the rainbow trout by immunofluorescence methods. The GRF-like immunoreactive perikaryon was observed in colchicine-treated fish. The majority of GRF-containing neurons were located in the nucleus lateral tuberis; others were located in the caudal part of the preoptic nucleus of the hypothalamus. The GRF-like immunoreactive neuronal processes projected into the pars distalis via the pars nervosa of the pituitary gland. The distribution of the GRF-like immunoreactive substance in the hypothalamus and pituitary gland suggests that GRF plays a physiological role in the regulation of growth hormone release from the pituitary gland of rainbow trout, as it does in mammals.     

Immunohistochemical detection of a substance resembling growth hormone-releasing factor in the brain of the rainbow trout (Salmo gairdneri)

Summary We studied the distribution of an immunoreactive substance resembling growth hormone-releasing factor (GRF) in the hypothalamus and pituitary gland of the rainbow trout by immunofluorescence methods. The GRF-like immunoreactive perikaryon was observed in colchicine-treated fish. The majority of GRF-containing neurons were located in the nucleus lateral tuberis; others were located in the caudal part of the preoptic nucleus of the hypothalamus. The GRF-like immunoreactive neuronal processes projected into the pars distalis via the pars nervosa of the pituitary gland. The distribution of the GRF-like immunoreactive substance in the hypothalamus and pituitary gland suggests that GRF plays a physiological role in the regulation of growth hormone release from the pituitary gland of rainbow trout, as it does in mammals.     

The hypothalamus and the neurobiology of drug seeking

The hypothalamus is a neural structure critical for expression of motivated behaviours that ensure survival of the individual and the species. It is a heterogeneous structure, generally recognised to have four distinct regions in the rostrocaudal axis (preoptic, supraoptic, tuberal and mammillary). The tuberal hypothalamus in particular has been implicated in the neural control of appetitive motivation, including feeding and drug seeking. Here we review the role of the tuberal hypothalamus in appetitive motivation. First, we review evidence that different regions of the hypothalamus exert opposing control over feeding. We then review evidence that a similar bi-directional regulation characterises hypothalamic contributions to drug seeking and reward seeking. Lateral regions of the dorsal tuberal hypothalamus are important for promoting reinstatement of drug seeking, whereas medial regions of the dorsal tuberal hypothalamus are important for inhibiting this drug seeking after extinction training. Finally, we review evidence that these different roles for medial versus lateral dorsal tuberal hypothalamus in promoting or preventing reinstatement of drug seeking are mediated, at least in part, by different populations of hypothalamic neurons as well as the neural circuits in which they are located.     

Effects of ovariectomy on the oxidative metabolism of the central nervous system and adrenal glands in female hamster (Mesocricetus auratus)

We have studied the influence of ovariectomy on the oxidative activity of hypophysis, hypothalamus, posterior cortex, septal area, amygdala and adrenal glands, in female hamsters, because their neuroendocrine behavior seems to differ from that of rats. Our results show a decreasing the O2 uptake in the hypothalamus and adrenal glands and an increase in the rest of the structures.     

Effects of ovariectomy on the oxidative metabolism of the central nervous system and adrenal glands in female hamster (Mesocricetus auratus)

Summary We have studied the influence of ovariectomy on the oxidative activity of hypophysis, hypothalamus, posterior cortex, septal area, amygdala and adrenal glands, in female hamsters, because their neuroendocrine behavior seems to differ from that of rats. Our results show a decreasing the O₂ uptake in the hypothalamus and adrenal glands and an increase in the rest of the structures.     

Effect of estradiol on aminoacid incorporation into proteins of different hypothalamic areas in prepuberal rats.

Estradiol in vitro produces a significant increase in the incorporation of 3H-leucine into proteins of the anterior hypothalamic area in prepuberal female rats, 15 and 20 days old, but not in younger animals. The ovarian hormone induced no changes in the protein synthetic activity of middle and posterior hypothalamus and cerebral cortex in prepuberal female rats of different ages. Estradiol did not modify the protein synthesis of the hypothalamus and cerebral cortex in prepuberal male rats.     

Physiological functions of D-amino acid oxidases: from yeast to humans

D-Amino acid oxidase (DAAO) is a FAD-containing flavoenzyme that catalyzes the oxidative deamination of D-isomers of neutral and polar amino acids. This enzymatic activity has been identified in most eukaryotic organisms, the only exception being plants. In the various organisms in which it does occur, DAAO fulfills distinct physiological functions: from a catabolic role in yeast cells, which allows them to grow on D-amino acids as carbon and energy sources, to a regulatory role in the human brain, where it controls the levels of the neuromodulator D-serine. Since 1935, DAAO has been the object of an astonishing number of investigations and has become a model for the dehydrogenase-oxidase class of flavoproteins. Structural and functional studies have suggested that specific physiological functions are implemented through the use of different structural elements that control access to the active site and substrate/product exchange. Current research is attempting to delineate the regulation of DAAO functions in the contest of complex biochemical and physiological networks.     

Depletion of hypothalamic norepinephrine reduces the fever induced by polyriboinosinic acid: polyribocytidylic acid (Poly I:Poly C) in rats

Summary Administration of either Poly I:Poly C (0.05–0.50 g) or norepinephrine (2–8 g) into the anterior hypothalamic area produced a dose-related fever in rats. The fever induced by Poly I:Poly C was attenuated after selective depletion of norepinephrine in the hypothalamus. However, selective depletion of hypothalamic norepinephrine did not affect the fever induced by intrahypothalamic norepinephrine. The data indicate that Poly I:Poly C may act to induce fever through the endogenous release of norepinephrine from the rat's hypothalamus.This work was supported by grants from the National Science Council (Taipei, Republic of China).     

Polyamines as activators of AMP nucleosidase from Azotobacter vinelandii.

Polyamines at physiological concentrations activate AMP nucleosidase from Azotobacter vinelandii. Biological significance of the activation is discussed in relation to the control of adenylate energy charge and the purine nucleotide synthesis in prokaryotes.     

Depletion of hypothalamic norepinephrine reduces the fever induced by polyriboinosinic acid: polyribocytidylic acid (Poly I:Poly C) in rats

Administration of either Poly I:Poly C (0.05-0.50 micrograms) or norepinephrine (2-8 micrograms) into the anterior hypothalamic area produced a dose-related fever in rats. The fever induced by Poly I:Poly C was attenuated after selective depletion of norepinephrine in the hypothalamus. However, selective depletion of hypothalamic norepinephrine did not affect the fever induced by intrahypothalamic norepinephrine. The data indicate that Poly I:Poly C may act to induce fever through the endogenous release of norepinephrine from the rat's hypothalamus.