Neuronal nitric oxide synthase and gonadal steroid interaction in the MPOA of male rats: Co-localization and testosterone-induced restoration of copulation and nNOS-immunoreactivity

Sato, Satoru; Braham, Claudean S.; Putnam, Susan K.; Hull, Elaine M.

doi:10.1016/j.brainres.2005.02.074

Cited by 60 publications

(56 citation statements)

References 27 publications

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“…Accordingly, another recent study has demonstrated that an agonist of the NMDA-type glutamate receptor, which triggers puberty, ovulation, and GnRH secretion in both rodents (Urbanski and Ojeda, 1990;Brann and Mahesh, 1991) and primates (Plant et al, 1989;Claypool et al, 2000), is capable of activating the reproductive axis in both Kiss-and Gpr54-null mice, and that these effects may involve nNOS neurons (d'Anglemont de . Since most nNOS neurons of the preoptic region express the NMDA receptor (d'Anglemont de Tassigny et al, 2007a) and estrogen receptor ␣ (Scordalakes et al, 2002;Sato et al, 2005), both of which are critical for the estrogen positive-feedback effect on GnRH neurons (Brann and Mahesh, 1991;Wintermantel et al, 2006) and nNOS activity (d'Anglemont de Tassigny et al, 2007a, it is tempting to speculate that nNOS neurons may be involved in the cellular mechanisms underlying compensation in animals in which neurons mediating kisspeptin/GPR54 signaling are absent (Mayer and Boehm, 2011). Estrogens may indeed regulate Intriguingly, our immunofluorescence experiments demonstrated that the systemic administration of kisspeptin selectively induces nNOS phosphorylation in an area proximal to the OVLT, a brain area devoid of a blood-brain barrier (Broadwell and Brightman, 1976;Ciofi et al, 2009) and containing numerous kisspeptin fibers and nNOS neurons (present paper), and to which GnRH neurons have recently been shown to extend dendrites (Herde et al, 2011;Prevot, 2011).…”

Section: Discussionmentioning

confidence: 99%

Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation

Parkash²,

et al. 2012

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Reproduction is controlled in the brain by a neural network that drives the secretion of gonadotropin-releasing hormone (GnRH).Various permissive homeostatic signals must be integrated to achieve ovulation in mammals. However, the neural events controlling the timely activation of GnRH neurons are not completely understood. Here we show that kisspeptin, a potent activator of GnRH neuronal activity, directly communicates with neurons that synthesize the gaseous transmitter nitric oxide (NO) in the preoptic region to coordinate the progression of the ovarian cycle. Using a transgenic Gpr54-null IRES-LacZ knock-in mouse model, we demonstrate that neurons containing neuronal NO synthase (nNOS), which are morphologically associated with kisspeptin fibers, express the kisspeptin receptor GPR54 in the preoptic region, but not in the tuberal region of the hypothalamus. The activation of kisspeptin signaling in preoptic neurons promotes the activation of nNOS through its phosphorylation on serine 1412 via the AKT pathway and mimics the positive feedback effects of estrogens. Finally, we show that while NO release restrains the reproductive axis at stages of the ovarian cycle during which estrogens exert their inhibitory feedback, it is required for the kisspeptin-dependent preovulatory activation of GnRH neurons. Thus, interactions between kisspeptin and nNOS neurons may play a central role in regulating the hypothalamic-pituitary-gonadal axis in vivo.

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Section: Discussionmentioning

confidence: 99%

Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation

Parkash²,

et al. 2012

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“…In the preoptic region of the hypothalamus, most NMDA receptor-expressing neurons also contain estrogen receptor ␣ (Chakraborty et al, 2003), which is not only localized to cell nuclei but also found in perikaryal cy- toplasm and dendrites (Blaustein, 1992;Blaustein et al, 1992). In fact, up to 90% of nNOS neurons of the preoptic region were shown to express estrogen receptor ␣ (Scordalakes et al, 2002;Sato et al, 2005). Together with our results showing that virtually all nNOS neurons express NMDA receptor NR2B subunit, these studies suggest that most nNOS neurons in the preoptic region also contain estrogen receptors.…”

Section: Discussionmentioning

confidence: 99%

Coupling of Neuronal Nitric Oxide Synthase to NMDA Receptors via Postsynaptic Density-95 Depends on Estrogen and Contributes to the Central Control of Adult Female Reproduction

Tassigny

Campagne²,

Dehouck³

et al. 2007

Journal of Neuroscience

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Considerable research has been devoted to the understanding of how nitric oxide (NO) influences brain function. Few studies, however, have addressed how its production is physiologically regulated. Here, we report that protein-protein interactions between neuronal NO synthase (nNOS) and glutamate NMDA receptors via the scaffolding protein postsynaptic density-95 (PSD-95) in the hypothalamic preoptic region of adult female rats is sensitive to cyclic estrogen fluctuation. Coimmunoprecipitation experiments were used to assess the physical association between nNOS and NMDA receptor NR2B subunit in the preoptic region of the hypothalamus. We found that nNOS strongly interacts with NR2B at the onset of the preovulatory surge at proestrus (when estrogen levels are highest) compared with basal-stage diestrous rats. Consistently, estrogen treatment of gonadectomized female rats also increases nNOS/NR2B complex formation. Moreover, endogenous fluctuations in estrogen levels during the estrous cycle coincide with changes in the physical association of nNOS to PSD-95 and the magnitude of NO release in the preoptic region. Finally, temporary and local in vivo suppression of PSD-95 synthesis by using antisense oligodeoxynucleotides leads to inhibition of nNOS activity in the preoptic region and disrupted estrous cyclicity, a process requiring coordinated activation of neurons containing gonadotropin-releasing hormone (the neuropeptide controlling reproductive function). In conclusion, our findings identify a novel steroid-mediated molecular mechanism that enables the adult mammalian brain to control NO release under physiological conditions.

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“…Sixty minutes after the start of copulation sessions or control observations, animals were deeply anesthetized with sodium pentobarbital (100 mg/kg) and perfused with 0.1 M PBS, pH 7.4, and 4% paraformaldehyde in PBS. Brains were cryoprotected in 20% sucrose-PBS, and every other 40 m cryostat section (30 per animal) from the vicinity of the hypothalamic hcrt/orx cell population was immunolabeled for prepro-hcrt/orx (1:100; Millipore, Billerica, MA) and Fos (1: 10,000; EMD Biosciences, San Diego, CA) with 3Ј,3Ј-diaminobenzidine (DAB) and nickel-intensified DAB, respectively, according to immunohistochemistry procedures described previously (Espana et al, 2003;Sato et al, 2005). Cell counts were performed under high magnification using an Olympus (Tokyo, Japan) microscope and camera on a single section at a consistent rostrocaudal level (see Fig.…”

Section: Methodsmentioning

confidence: 99%

A Role for Hypocretin (Orexin) in Male Sexual Behavior

Muschamp¹,

Domínguez²,

Sato³

et al. 2007

J. Neurosci.

179

119

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The role of hypocretin (orexin; hcrt/orx) neurons in regulation of arousal is well established. Recently, hcrt/orx has been implicated in food reward and drug-seeking behavior. We report here that in male rats, Fos immunoreactivity (ir) in hcrt/orx neurons increases markedly during copulation, whereas castration produces decreases in hcrt/orx neuron cell counts and protein levels in a time course consistent with postcastration impairments in copulatory behavior. This effect was reversed by estradiol replacement. Immunolabeling for androgen (AR) and estrogen (ER␣) receptors revealed no colocalization of hcrt/orx with AR and few hcrt/orx neurons expressing ER␣, suggesting that hormonal regulation of hcrt/orx expression is via afferents from neurons containing those receptors. We also demonstrate that systemic administration of the orexin-1 receptor antagonist SB 334867 [N-(2-methyl-6-benzoxazolyl)-NЉ-1,5-naphthyridin-4-yl urea] impairs copulatory behavior. One locus for the prosexual effects of hcrt/orx may be the ventral tegmental area (VTA). We show here that hcrt-1/orx-A produces dose-dependent increases in firing rate and population activity of VTA dopamine (DA) neurons in vivo. Activation of hcrt/orx during copulation, and in turn, excitation of VTA DA neurons by hcrt/orx, may contribute to the robust increases in nucleus accumbens DA previously observed during male sexual behavior. Subsequent triple immunolabeling in anterior VTA showed that Fos-ir in tyrosine hydroxylase-positive neurons apposed to hcrt/orx fibers increases during copulation. Together, these data support the view that hcrt/orx peptides may act in a steroid-sensitive manner to facilitate the energized pursuit of natural rewards like sex via activation of the mesolimbic DA system.

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Neuronal nitric oxide synthase and gonadal steroid interaction in the MPOA of male rats: Co-localization and testosterone-induced restoration of copulation and nNOS-immunoreactivity

Cited by 60 publications

References 27 publications

Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation

Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation

Coupling of Neuronal Nitric Oxide Synthase to NMDA Receptors via Postsynaptic Density-95 Depends on Estrogen and Contributes to the Central Control of Adult Female Reproduction

A Role for Hypocretin (Orexin) in Male Sexual Behavior

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