Interaction of neuronal nitric-oxide synthase with alpha1-syntrophin in rat brain

Neuronal nitric-oxide synthase (nNOS) has a PSD-95/Dlg/ZO-1 (PDZ) domain that can interact with multiple proteins. nNOS has been known to interact with PSD-95 and a related protein, PSD-93, in brain and with alpha1-syntrophin in skeletal muscle in mammals. In this study, we have purified an nNOS-interacting protein from bovine brain using an affinity column made of Sepharose conjugated with glutathione S-transferase-rat nNOS fusion protein and identified it as alpha1-syntrophin by microsequencing. Immunostaining of primary cultures of rat embryonic brain neuronal cells with antibodies against these proteins showed that nNOS and alpha1-syntrophin were colocalized in neuronal cell bodies and neurites. Immunohistochemical analysis indicated that the nNOS- and alpha1-syntrophin-like immunoreactive substances were highly expressed in the rat hypothalamic suprachiasmatic nucleus (SCN) and paraventricular nucleus. In the SCN, nNOS- and alpha1-syntrophin-like immunoreactive substances were colocalized in the same neurons as detected by confocal microscopy. These results indicate that nNOS in brain interacts with alpha1-syntrophin in specific neurons of the SCN and paraventricular nucleus and that this interaction might play a physiological role in functions of these neurons.     

Effects of adiponectin on the renal sympathetic nerve activity and blood pressure in rats

Adiponectin is an adipocytokine that modulates energy homeostasis and glucose metabolism. Here, we examined the effects of acute intravenous (iv) and lateral cerebral ventricular (LCV) injections of adiponectin on the renal sympathetic nerve activity (RSNA) and blood pressure (b/p) in urethane-anesthetized rats. Both iv and LCV injections of adiponectin induced dose-dependent suppressions of RSNA and b/p. Moreover, we found that bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of iv injection of adiponectin on RSNA and b/p. These findings suggest that adiponectin decreases the RSNA and b/p in a dose-dependent manner and that the SCN is implicated in mechanism of adiponectin actions on RSNA and b/p. These findings also suggest that the hypotensive-action activity of adiponectin is realized, at least partially, via changes in activities of autonomic nerves activity.     

Nesfatin‐1, corticotropin‐releasing hormone,thyrotropin‐releasing hormone,and neuronal histamine interact in the hypothalamus to regulate feeding behavior

Nesfatin‐1, corticotropin‐releasing hormone (CRH), thyrotropin‐releasing hormone (TRH), and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin‐1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesfatin‐1, α‐fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti‐TRH antibody affects the anorectic effect of nesfatin‐1, whether nesfatin‐1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin‐1 content in the hypothalamus. We also investigated whether nesfatin‐1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1‐R) co‐localizes in nesfatin‐1 neurons. Nesfatin‐1‐suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti‐TRH antibody, and in H1KO mice. Nesfatin‐1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin‐1 in the hypothalamus. Immunohistochemical analysis revealed H1‐R expression on nesfatin‐1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin‐1 on feeding behavior.     

SCN efferents to peripheral tissues: implications for biological rhythms.

The suprachiasmatic nucleus (SCN) is the principal generator of circadian rhythms and is part of an entrainment system that synchronizes the animal with its environment. Here, we review the possible communication of timing information from the SCN to peripheral tissues involved in regulating fundamental physiological functions as revealed using a viral, transneuronal tract tracer, the pseudorabies virus (PRV). The sympathetic nervous system innervation of the pineal gland and the sympathetic outflow from brain to white adipose tissue were the first demonstrations of SCN-peripheral tissue connections. The inclusion of the SCN as part of these and other circuits was the result of lengthened postviral injection times compared with those used previously. Subsequently, the SCN has been found to be part of the sympathetic outflow from the brain to brown adipose tissue, thyroid gland, kidney, bladder, spleen, adrenal medulla, and perhaps the adrenal cortex. The SCN also is involved in the parasympathetic nervous system innervation of the thyroid, liver, pancreas, and submandibular gland. Individual SCN neurons appear connected to more than one autonomic circuit involving both sympathetic and parasympathetic innervation of a single tissue, or sympathetic innervation of two different peripheral tissues. Collectively, the results of these PRV studies require an expansion of the traditional roles of the SCN to include the autonomic innervation of peripheral tissues and perhaps the modulation of neuroendocrine systems traditionally thought to be controlled solely by hypothalamic stimulating/inhibiting factors.     

Serotonergic Modulation of Photic Entrainment in the Syrian Hamster

In this review, we describe six lines of evidence that reveal a modulatory role for serotonin (5-HT) in the regulation of the response of suprachiasmatic nucleus (SCN) neurons to retinal illumination in the Syrian hamster. Electrical stimulation of the median raphe nucleus, sufficient to elicit the release of 5-HT in the SCN, inhibits light-induced phase shifts of the hamster circadian activity rhythm. Two 5-HT receptors capable of mediating the effects of 5-HT on photic responses, the 5-HT₇ receptor and the 5-HT_1B receptor, are present in the hamster SCN. Light-induced phase shifts are attenuated by systemic and local administration of two 5-HT receptor agonists, 8-OH-DPAT, and TFMPP, and these agents attenuate photic phase shifts by acting on pharmacologically distinct receptors. Furthermore, both compounds also attenuate light-induced Fos expression and photic suppression of pineal melatonin content, indicating that serotonergic modulation of photic signal transduction in the SCN is not limited to the regulation of circadian phase. Finally, both 8-OH-DPAT and TFMPP inhibit RHT neurotransmission in the hypothalamic slice preparation. Further, TFMPP fails to attenuate responses to exogenous glutamate on retinorecipient SCN neurons, consistent with a presynaptic site of action for the drug. Based on these data, we propose that 5-HT modulates RHT neurotransmission in the SCN through at least two distinct mechanisms: (1) via activation of 5-HT₇ receptors probably located on retinorecipient neurons; and (2) via activation of presynaptic 5-HT_1B receptors leading to reduced release of glutamate from RHT terminals in the SCN.     

Autonomic and neuroendocrine actions of adrenomedullin in the brain: mechanisms for homeostasis

In addition to its role as a potent vasodilator, adrenomedullin (ADM) affects an animal's physiological status through its effects in the brain. We have shown that circulating ADM activates neurons, including nitric oxide (NO)-producing neurons, in autonomic centers of the brain such as the hypothalamic paraventricular nucleus (PVN). Systemic ADM gains access to the brain through the area postrema (AP), a brainstem circumventricular organ, and the PVN is a major target of these ADM-sensitive AP neurons. Neurons expressing the preproADM (ppADM) gene are distributed throughout the brain, with high levels in autonomic centers. Lipopolysaccharide (LPS, immune stress), restraint (psychological stress), and 24 h dehydration all down-regulate ppADM gene expression in different subsets of autonomic centers. Receptor-activity-modifying protein (RAMP) 2 and RAMP3, ADM receptor subunits, are expressed in autonomic centers including the PVN and supraoptic nucleus. Intracerebroventricular injections of ADM increase arterial pressure, heart rate, tyrosine hydroxylase mRNA levels in the locus coeruleus, plasma levels of ACTH, and NO production in the hypothalamus. ADM excites putative GABAergic and cholinergic neurons in dissociated cells from a basal forebrain integrative center, the diagonal band of Broca. These results demonstrate that the signalling components necessary for ADM to influence physiological systems are present in the brain and that ADM is an important transmitter of brain autonomic pathways which are involved in regulating homeostatic balance.     

Efferent Projections of Prokineticin 2 Expressing Neurons in the Mouse Suprachiasmatic Nucleus

The suprachiasmatic nucleus (SCN) in the hypothalamus is the predominant circadian clock in mammals. To function as a pacemaker, the intrinsic timing signal from the SCN must be transmitted to different brain regions. Prokineticin 2 (PK2) is one of the candidate output molecules from the SCN. In this study, we investigated the efferent projections of PK2-expressing neurons in the SCN through a transgenic reporter approach. Using a bacterial artificial chromosome (BAC) transgenic mouse line, in which the enhanced green fluorescence protein (EGFP) reporter gene expression was driven by the PK2 promoter, we were able to obtain an efferent projections map from the EGFP-expressing neurons in the SCN. Our data revealed that EGFP-expressing neurons in the SCN, hence representing some of the PK2-expressing neurons, projected to many known SCN target areas, including the ventral lateral septum, medial preoptic area, subparaventricular zone, paraventricular nucleus, dorsomedial hypothalamic nucleus, lateral hypothalamic area and paraventricular thalamic nucleus. The efferent projections of PK2-expressing neurons supported the role of PK2 as an output molecule of the SCN.     

Development of the human hypothalamus

The hypothalamus has been claimed to be involved in a great number of physiological functions in development, such as sexual differentiation (gender, sexual orientation) and birth, as well as in various developmental disorders including mental retardation, sudden infant death syndrome (SIDS), Kallman's syndrome and Prader-Willi syndrome. In this review a number of hypothalamic nuclei have therefore been discussed with respect to their development in health and disease. The suprachiasmatic nucleus (SCN) is the clock of the brain and shows circadian, and seasonal fluctuations in vasopressin-expressing cell numbers. The SCN also seems to be involved in reproduction, adding interest to the sex differences in shape of the vasopressin-containing SCN subnucleus and in its VIP cell number. In addition, differences in relation to sexual orientation can be seen in this perspective. The vasopressin and VIP, neurons of the SCN develop mainly postnatally, but as premature children may have circadian temperature rhythms, a different SCN cell type is probably more mature at birth.Thesexually dimorphic nucleus (SDN, intermediate nucleus, INAH-1), is twice as large in young male adults as in young females. At the moment of birth only 20% of the SDN cell number is present. From birth until two to four years of age cell numbers increase equally rapidly in both sexes. After this age cell numbers start to decrease in girls, creating the sex difference. The size of the SDN does not show any relationship to sexual orientation in men. The large neurosecretory cells of thesupraoptic (SON) andparaventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. In the fetus these hormones play an active role in the birth process. Fetal oxytocin may initiate or accelerate the course of labor. Fetal vasopressin plays a role in the adaptation to stress—caused by the birth process—by redistribution of the fetal blood flow.Corticotropin-releasing hormone (CRH) neurons of the PVN play a central role in stress response. Thus fetal CRH neurons may play a role in the timing of the moment of birth. Recently, alterations have been described in peptidergic, aminergic and cholinergic transmitters in the hypothalamus in SIDS. Future research will have to establish whether these changes are part of the course of SIDS. A large proportion of the SON and PVN neurons also produce tyrosine hydroxylase (TH). In neonates the majority of TH-immunoreactive neurons colocalizes vasopressin, while in the adult the majority of TH-positive neurons colocalizes oxytocin. TH-expression might be a sign of hyperactivation, for example from perinatal hypoxia.Oxytocin neurons also project to the brain stem. These neurons have an inhibitory effect on eating. Interestingly, in the Prader-Willi syndrome, characterized for example by insatiable hunger, we have found that the number of oxytocin-expressing neurons is about half the normal value. It can be concluded that the various hypothalamic nuclei are involved in a great number of functions and show clear and differential changes in development with respect to sexual differentiation, birth and a number of diseases. I believe that only a small proportion of such changes has at present been revealed.Special issue dedicated to Dr. Robert Balázs     

Serotonergic Modulation of Photic Entrainment in the Syrian Hamster

In this review, we describe six lines of evidence that reveal a modulatory role for serotonin (5-HT) in the regulation of the response of suprachiasmatic nucleus (SCN) neurons to retinal illumination in the Syrian hamster. Electrical stimulation of the median raphe nucleus, sufficient to elicit the release of 5-HT in the SCN, inhibits light-induced phase shifts of the hamster circadian activity rhythm. Two 5-HT receptors capable of mediating the effects of 5-HT on photic responses, the 5-HT₇ receptor and the 5-HT_1B receptor, are present in the hamster SCN. Light-induced phase shifts are attenuated by systemic and local administration of two 5-HT receptor agonists, 8-OH-DPAT, and TFMPP, and these agents attenuate photic phase shifts by acting on pharmacologically distinct receptors. Furthermore, both compounds also attenuate light-induced Fos expression and photic suppression of pineal melatonin content, indicating that serotonergic modulation of photic signal transduction in the SCN is not limited to the regulation of circadian phase. Finally, both 8-OH-DPAT and TFMPP inhibit RHT neurotransmission in the hypothalamic slice preparation. Further, TFMPP fails to attenuate responses to exogenous glutamate on retinorecipient SCN neurons, consistent with a presynaptic site of action for the drug. Based on these data, we propose that 5-HT modulates RHT neurotransmission in the SCN through at least two distinct mechanisms: (1) via activation of 5-HT₇ receptors probably located on retinorecipient neurons; and (2) via activation of presynaptic 5-HT_1B receptors leading to reduced release of glutamate from RHT terminals in the SCN.     

Brain‐derived neurotrophic factor,corticotropin‐releasing factor,and hypothalamic neuronal histamine interact to regulate feeding behavior

Brain‐derived neurotrophic factor (BDNF), corticotropin‐releasing factor (CRF), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among BDNF, CRF, and histamine during the regulation of feeding behavior in rodents. Food intake was measured after treatment with BDNF, α‐fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), or CRF antagonist. We measured food intake in wild‐type mice and mice with targeted disruption of the histamine H1 receptor (H1KO mice) after central BDNF infusion. Furthermore, we investigated CRF content and histamine turnover in the hypothalamus after BDNF treatment, and conversely, BDNF content in the hypothalamus after histamine treatment. We used immunohistochemical staining for histamine H1 receptors (H1‐R) in BDNF neurons. BDNF‐induced feeding suppression was partially attenuated in rats pre‐treated with FMH or a CRF antagonist, and in H1KO mice. BDNF treatment increased CRF content and histamine turnover in the hypothalamus. Histamine increased BDNF content in the hypothalamus. Immunohistochemical analysis revealed that H1‐Rs were expressed on BDNF neurons in the ventromedial nucleus of the hypothalamus. These results indicate that CRF and hypothalamic neuronal histamine mediate the suppressive effects of BDNF on feeding behavior and body weight.     

The effect of autonomic nerve stimulation cyclic adenosine monophosphate in skeletal muscle

The effect of electrical stimulation of autonomic nerves on c-AMP levels in the tibial muscle of rats was studied after pretreatment with a phosphodiesterase inhibitor and a muscle paralyzant. Cyclic-AMP levels in the skeletal muscle increase significantly. This increase is not the result of changes in muscle blood flow which might have resulted from autonomic nerve stimulation. These studies indicate that the adenyl cyclase-cyclic AMP system in skeletal muscle may be controlled by the autonomic nervous system.     

Differential involvement of the suprachiasmatic nucleus in lipopolysaccharide-induced plasma glucose and corticosterone responses

The hypothalamic suprachiasmatic nucleus (SCN) is an essential component of the circadian timing system, and an important determinant of neuroendocrine and metabolic regulation. Recent data indicate a modulatory role for the immune system on the circadian timing system. The authors investigated how the circadian timing system affects the hypothalamo-pituitary-adrenal (HPA) axis and glucose regulatory responses evoked by an immune challenge induced by lipopolysaccharide (LPS). LPS-induced increases in corticosterone were minimal during the trough of the daily corticosterone rhythm; in contrast, LPS effects on glucose, glucagon, and insulin did not vary across time-of-day. Complete ablation of the SCN resulted in increased corticosterone responses but did not affect LPS-induced hyperglycemia. The paraventricular nucleus (PVN) of the hypothalamus is an important neuroendocrine and autonomic output pathway for hypothalamic information, as well as one of the main target areas of the SCN. Silencing the neuronal activity in the PVN did not affect the LPS-induced corticosterone surge and only slightly delayed the LPS-induced plasma glucose and glucagon responses. Finally, surgical interruption of the neuronal connection between hypothalamus and liver did not affect the corticosterone response but slightly delayed the LPS-induced glucose response. Together, these data support the previously proposed circadian modulation of LPS-induced neuroendocrine responses, but they are at variance with the suggested major role for the hypothalamic pacemaker on the autonomic output of the hypothalamus, as reflected by the effects of LPS on glucose homeostasis. The latter effects are more likely due to direct interactions of LPS with peripheral tissues, such as the liver.     

Neuropeptide FF and neuropeptide VF inhibit GABAergic neurotransmission in parvocellular neurons of the rat hypothalamic paraventricular nucleus

Neuropeptide FF (NPFF) and neuropeptide VF (NPVF) are octapeptides belonging to the RFamide family of peptides that have been implicated in a wide variety of physiological functions in the brain, including central autonomic and neuroendocrine regulation. The effects of these peptides are mediated via NPFF1 and NPFF2 receptors that are abundantly expressed in the rat brain, including the hypothalamic paraventricular nucleus (PVN), an autonomic nucleus critical for the secretion of neurohormones and the regulation of sympathetic outflow. In this study, we examined, using whole cell patch-clamp recordings in the brain slice, the effects of NPFF and NPVF on inhibitory GABAergic synaptic input to parvocellular PVN neurons. Under voltage-clamp conditions, NPFF and NPVF reversibly and in a concentration-dependent manner reduced the evoked bicuculline-sensitive inhibitory postsynaptic currents (IPSCs) in parvocellular PVN neurons by 25 and 31%, respectively. RF9, a potent and selective NPFF receptor antagonist, blocked NPFF-induced reduction of IPSCs. Recordings of miniature IPSCs in these neurons following NPFF and NPVF applications showed a reduction in frequency but not amplitude, indicating a presynaptic locus of action for these peptides. Under current-clamp conditions, NPVF and NPFF caused depolarization (6-9 mV) of neurons that persisted in the presence of TTX but was abolished in the presence of bicuculline. Collectively, these data provide evidence for a disinhibitory role of NPFF and NPVF in the hypothalamic PVN via an attenuation of GABAergic inhibitory input to parvocellular neurons of this nucleus and explain the central autonomic effects of NPFF.     

Suprachiasmatic nucleus organization

The suprachiasmatic nucleus (SCN) of the hypothalamus is a dominant circadian pacemaker in the mammalian brain controlling the rest-activity cycle and a series of physiological and endocrine functions to provide a foundation for the successful elaboration of adaptive sleep and waking behavior. The SCN is anatomically and functionally organized into two subdivisions: (1) a core that lies adjacent to the optic chiasm, comprises predominantly neurons producing vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP) colocalized with GABA and receives dense visual and midbrain raphe afferents, and (2) a shell that surrounds the core, contains a large population of arginine vasopressin (AVP)-producing neurons in its dorsomedial portion, and a smaller population of calretinin (CAR)-producing neurons dorsally and laterally, colocalized with GABA, and receives input from non-visual cortical and subcortical regions. In this paper, we present a detailed quantitative analysis of the organization of the SCN core and shell in the rat and place this in the context of the functional significance of the subdivisions in the circadian control of regulatory systems.     

Circadian control of the daily plasma glucose rhythm: an interplay of GABA and glutamate

The mammalian biological clock, located in the hypothalamic suprachiasmatic nuclei (SCN), imposes its temporal structure on the organism via neural and endocrine outputs. To further investigate SCN control of the autonomic nervous system we focused in the present study on the daily rhythm in plasma glucose concentrations. The hypothalamic paraventricular nucleus (PVN) is an important target area of biological clock output and harbors the pre-autonomic neurons that control peripheral sympathetic and parasympathetic activity. Using local administration of GABA and glutamate receptor (ant)agonists in the PVN at different times of the light/dark-cycle we investigated whether daily changes in the activity of autonomic nervous system contribute to the control of plasma glucose and plasma insulin concentrations. Activation of neuronal activity in the PVN of non-feeding animals, either by administering a glutamatergic agonist or a GABAergic antagonist, induced hyperglycemia. The effect of the GABA-antagonist was time dependent, causing increased plasma glucose concentrations only when administered during the light period. The absence of a hyperglycemic effect of the GABA-antagonist in SCN-ablated animals provided further evidence for a daily change in GABAergic input from the SCN to the PVN. On the other hand, feeding-induced plasma glucose and insulin responses were suppressed by inhibition of PVN neuronal activity only during the dark period. These results indicate that the pre-autonomic neurons in the PVN are controlled by an interplay of inhibitory and excitatory inputs. Liver-dedicated sympathetic pre-autonomic neurons (responsible for hepatic glucose production) and pancreas-dedicated pre-autonomic parasympathetic neurons (responsible for insulin release) are controlled by inhibitory GABAergic contacts that are mainly active during the light period. Both sympathetic and parasympathetic pre-autonomic PVN neurons also receive excitatory inputs, either from the biological clock (sympathetic pre-autonomic neurons) or from non-clock areas (para-sympathetic pre-autonomic neurons), but the timing information is mainly provided by the GABAergic outputs of the biological clock.     

Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms

Converging lines of evidence have firmly established that the hypothalamic suprachiasmatic nucleus (SCN) is a light-entrainable circadian oscillator in mammals, critically important for the expression of behavioral and physiological circadian rhythms. Photic information essential for the daily phase resetting of the SCN circadian clock is conveyed directly to the SCN from retinal ganglion cells via the retinohypothalamic tract. The SCN also receives a dense serotonergic innervation arising from the mesencephalic raphe. The terminal fields of retinal and serotonergic afferents within the SCN are co-extensive, and serotonergic agonists can modify the response of the SCN circadian oscillator to light. However, the functional organization and subcellular localization of 5HT receptor subtypes in the SCN are just beginning to be clarified. This information is necessary to understand the role 5HT afferents play in modulating photic input to the SCN. In this paper, we review evidence suggesting that the serotonergic modulation of retinohypothalamic neurotransmission may be achieved via at least two different cellular mechanisms: 1) a postsynaptic mechanism mediated via 5HT_1A or 5ht₇ receptors located on SCN neurons; and 2) a presynaptic mechanism mediated via 5HT_1B receptors located on retinal axon terminals in the SCN. Activation of either of these 5HT receptor mechanisms in the SCN by specific 5HT agonists inhibits the effects of light on circadian function. We hypothesize that 5HT modulation of photic input to the SCN may serve to set the gain of the SCN circadian system to light.     

Neural interaction of gonadotropin-regulating hormone immunoreactive neurons and the suprachiasmatic nucleus with the paraventricular organ in the Japanese grass lizard (Takydromus tachydromoides)

Our previous study demonstrated that the paraventricular organ (PVO) in the hypothalamus of the Japanese grass lizard (Takydromus tachydromoides) showed immunoreactivity against the light signal-transducing G-protein, transducin. This finding suggested that the PVO was a candidate for the deep-brain photoreceptor in this species. To understand functions of the PVO, we investigated distributions of transducin, serotonin, gonadotropin-releasing hormone (GnRH), and gonadotropin-inhibitory hormone (GnIH) in the lizard's brain. We immunohistochemically confirmed co-localization of transducin and serotonin in PVO neurons that showed structural characteristics of cerebrospinal fluid (CSF)-contacting neurons. GnRH-immunoreactive (ir) cells were localized in the posterior commissure and lateral hypothalamic area. Some of the serotonin-ir fibers extending from the PVO to the lateral hypothalamic area contacted the GnRH-ir cell bodies. GnIH-ir cells were localized in the nucleus accumbens, paraventricular nucleus, and upper medulla, and GnIH-ir fibers from the paraventricular nucleus contacted the lateral processes of serotonin-ir neurons in the PVO. In addition, we found that serotonin-ir fibers from the PVO extended to the suprachiasmatic nucleus (SCN), and the retrograde transport method confirmed the PVO projections to the SCN. These findings suggest that the PVO, by means of innervation mediated by serotonin, plays an important role in the regulation of pituitary function and the biological clock in the Japanese grass lizard.     

Histamine Receptor Expression, Hippocampal Plasticity and Ammonia in Histidine Decarboxylase Knockout Mice

Genetic ablation of the histamine producing enzyme histidine decarboxylase (HDC) leads to alteration in exploratory behaviour and hippocampus-dependent learning. We investigated how brain histamine deficiency in HDC knockout mice (HDC KO) affects hippocampal excitability, synaptic plasticity, and the expression of histamine receptors. No significant alterations in: basal synaptic transmission, long-term potentiation (LTP) in the Schaffer collateral synapses, histamine-induced transient changes in the CA1 pyramidal cell excitability, and the expression of H1 and H2 receptor mRNAs were found in hippocampal slices from HDC KO mice. However, when compared to WT mice, HDC KO mice demonstrated: 1. a stronger enhancement of LTP by histamine, 2. a stronger impairment of LTP by ammonia, 3. no long-lasting potentiation of population spikes by histamine, 4. a decreased expression of H3 receptor mRNA, and 5. less potentiation of population spikes by H3 receptor agonism. Parallel measurements in the hypothalamic tuberomamillary nucleus, the origin of neuronal histamine, demonstrated an increased expression of H3 receptors in HDC KO mice without any changes in the spontaneous firing of “histaminergic” neurons without histamine and their responses to the H3 receptor agonist (R)-α-methylhistamine. We conclude that the absence of neuronal histamine results in subtle changes in hippocampal synaptic transmission and plasticity associated with alteration in the expression of H3 receptors.     

The biological clock: the bodyguard of temporal homeostasis

In order for any organism to function properly, it is crucial that it be table to control the timing of its biological functions. An internal biological clock, located, in mammals, in the suprachiasmatic nucleus of the hypothalamus (SCN), therefore carefully guards this temporal homeostasis by delivering its message of time throughout the body. In view of the large variety of body functions (behavioral, physiological, and endocrine) as well as the large variety in their preferred time of main activity along the light:dark cycle, it seems logical to envision different means of time distribution by the SCN. In the present review, we propose that even though it presents a unimodal circadian rhythm of general electrical and metabolic activity, the SCN seems to use several sorts of output connections that are active at different times along the light: dark cycle to control the rhythmic expression of different body functions. Although the SCN is suggested to use diffusion of synchronizing factors in the rhythmic control of behavioral functions, it also needs neuronal connections for the control of endocrine functions. The distribution of the time-of-day message to neuroendocrine systems is either directly onto endocrine neurons or via intermediate neurons located in specific SCN targets. In addition, the SCN uses its connections with the autonomic nervous system for spreading its time-of-day message, either by setting the sensitivity of endocrine glands (i.e., thyroid, adrenal, ovary) or by directly controlling an endocrine output (i.e., melatonin synthesis). Moreover, the SCN seems to use different neurotransmitters released at different times along the light: dark cycle for each of the different connection types presented. Clearly, the temporal homeostasis of endocrine functions results from a diverse set of biological clock outputs.