Regular ArticleExcitatory Amino Acids: Function and Significance in Reproduction and Neuroendocrine Regulation
Abstract
Excitatory amino acid neurotransmission is an essential component of the neuroendocrine transmission line that regulates anterior pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Excitatory amino acids (EAAs), such as glutamate and aspartate, are found in largo concentrations in presynaptic boutons of a variety of important hypothalamic nuclei, including the arcuate nucleus, the suprachiasmatic nucleus, the supraoptic nucleus, the paraventricular nucleus, and the preoptic area. EAA receptors can be divided into two broad groups, namely, ionotropic and metabotropic receptors. Ionotropic receptors are subdivided into NMDA (N-methyl-D-aspartate), kainate, and AMPA (DL-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Their main mode of action is by the modulation of Na+, K+, and Ca2+ ion channels. Metabotropic receptors, on the other hand, act by a G-protein-stimulated release of intracellular Ca2+ or modulation of adenylate cyclase activity. The different EAA receptor subtypes are found in a variety of areas of the hypothalamus and the brain. In a variety of species, the administration of glutamate, NMDA, or kainate leads to LH release mediated through the stimulation of hypothalamic gonadotropin hormone-releasing hormone (GnRH) release. The major site of NMDA action appears to be the preoptic area—where GnRH cell bodies reside. AMPA and kainate appear to act primarily at the arcuate nucleus/median eminence, the site of GnRH nerve terminals. NMDA may also act upon noradrenergic neurons in the locus coeruleus to influence hypothalamic GnRH release. The steroid-induced LH surge in ovariectomized animals and the preovulatory surge of LH in cycling animals and in pregnant mare's serum gonadotropic-primed animals are blocked by the NMDA antagonist MK801 and the AMPA/kainate antagonist DNQX. MK801 also suppressed FSH surges in most instances, whereas DNQX had no effect on FSH surges. In the ovariectomized female rat, both the NMDA antagonist AP5 and the AMPA/kainate antagonist DNQX, lowered mean LH levels, LH pulse amplitude, and LH pulse frequency. Activation of NMDA receptors advanced the time of vaginal opening in the immature female rat, while kainate and DNQX were without effect. Gonadal steroid removal (castration) did not alter NMDA receptor levels or affinity in the hypothalamus of female or male rats. Likewise, steroid replacement to castrate rats did not affect hypothalamic NMDA receptor levels or NMDA R1 mRNA levels. Similarly, NMDA and kainate receptor levels in the hypothalamus did not change during the time of puberty in the female rat. In contrast, AMPA receptor (GluR1) immunoreactive levels in the magnocellular preoptic area (mPOA), the arcuate nucleus (ARC), and the suprachiasmatic nucleus (SCN) were found to be markedly elevated during the time of the LH surge in estradiol-progesterone-treated castrate rats compared to those of the vehicle-only-treated castrate rat. The release rates of glutamate and aspartate in the POA were found to be significantly elevated during the steroid-induced LH surge in the ovariectomized adult rat. Hence, the induction of the LH surge by steroids may involve enhanced EAA neurotransmission mediated by steroid-induced elevations in the release of glutamate and aspartate in the POA and AMPA receptors in the POA, the ARC, and the SCN. Evidence also exists supporting a role of EAAs in the release of other pituitary hormones, such as prolactin, ACTH, growth hormone, oxytocin, and vasopressin, as well as circadian rhythm induction and regulation. The above evidence points to a pivotal role of EAAs acting at the level of the hypothalamus in the neuroendocrine regulation of a variety of hormonal systems with the largest amount of data available on the control of gonadotropin secretion.
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Hypothalamic Regulation of Anterior Pituitary Function
2022, The PituitarySince their close interaction was recognized almost a century ago, there has been considerable progress in our knowledge of the anatomical, physiological, and pathophysiological aspects of hypothalamic regulation of the pituitary gland. Discovery of pituitary hormones was followed by isolation of hypothalamic neuropeptides that regulate their respective synthesis, their cognate receptors, and multiple intrapituitary signaling pathways. Extensive feedback mechanisms, essential for appropriate neuroendocrine hormonal regulation and brain networking, act to control hypothalamic neuropeptide action on pituitary and ultimately target gland responses. This chapter focuses on the hypothalamic–pituitary unit, including anatomy and histology, and the hypothalamic hormones regulating pituitary function including thyrotrophin-releasing hormone, corticotrophin-releasing hormone, growth-hormone-releasing hormone, gonadotrophin-releasing hormone, and somatostatin- and prolactin-regulating hormones. Mechanisms underlying hypothalamic hormone production, localization, and regulation and their effect on cognate pituitary receptors are described. These functions are geared toward the integration of metabolic and trophic hormone homeostasis.
Coilia nasus (C. nasus) is an important anadromous fish species that resides in the Yangtze River in China. However, wild C. nasus have suffered serious damage as a result of overfishing and environmental pollution. We performed comparative liver and brain transcriptome analyses of C. nasus from the Jingjiang (JJ) and Dangtu (DT) sections of the Yangtze River. The results indicate that, during migration, most signal pathways in C. nasus livers were downregulated, indicating that the liver has a function in energy conservation. The brain assumes more of a regulatory role, and the signal transduction pathways and relevant genes were upregulated. This study provides genetic information for screening the key regulatory genes of gonad development of C. nasus, which can be applied in the artificial breeding of C. nasus, providing high-quality fish fry for proliferation and release and may also contribute to efforts towards the restoration of wild C. nasus.
Alterations of estradiol-induced histone H3 acetylation in the preoptic area and anteroventral periventricular nucleus of middle-aged female rats
2019, Biochemical and Biophysical Research CommunicationsCitation Excerpt :This is especially apparent in cells located in the anterior hypothalamus, including preoptic area (POA) [11,12] and anteroventral periventricular nucleus (AVPV) [6,7]. Changes in E2-responsive gene expression have been linked to insufficient production of neurotransmitters such as kisspeptin [7,8] and glutamate (Glu) [9,10,13], resulting in diminished excitatory drive to GnRH neurons. Proper regulation of gene expression depends upon the binding of various transcription factors and certain epigenetic modifications.
In this study we investigated the characteristics of histone H3 acetylation in the anterior hypothalamus under E2 positive feedback to gain a better understanding of the mechanism underlying reduced GnRH neuron activation and altered gene expression in female reproductive aging. Young and middle-aged female rats were ovariectomized (OVX) and treated with estradiol (E2) or oil. C-Fos expression, the number of GnRH neurons co-localized with c-Fos in the preoptic area (POA), and the number of acetylated histone H3 cells in the POA and anteroventral periventricular nucleus (AVPV) were quantified at the time of the expected GnRH neuron activation. We used real-time PCR to evaluate the expression of Esr1 target genes including Kiss1 and VGluT2 and genes known as Esr1 coregulators in the anterior hypothalamus. Our results show that in the young females, E2 markedly increased histone H3 acetylation in the POA and AVPV, coincident with increased c-Fos and GnRH neuron activation in the POA. In middle-aged females, E2-induced histone H3 acetylation was reduced in the POA but was not significantly altered in the AVPV. This occurred in association with a reduction of c-Fos expression and the number of GnRH cells expressing c-Fos in the POA as well as a down-regulation of Kiss1 and VGluT2 mRNA expression in the anterior hypothalamus of the animals. E2 caused significant decreases in Ncoa2 and Crebbp mRNA expression in the anterior hypothalamus of young, but not middle-aged females. Taken together, these data suggest that alterations of histone H3 acetylation in the POA and AVPV and the inability of Ncoa2 and Crebbp to respond to E2 in the middle-aged anterior hypothalamus partially contribute to the decline of GnRH neuron activation and E2 target gene expression changes that occur in female along with reproductive aging.
Effect of Progesterone on Cerebral Vasospasm and Neurobehavioral Outcomes in a Rodent Model of Subarachnoid Hemorrhage
2018, World NeurosurgeryCitation Excerpt :PROG receptors are colocalized with GluR1 in different parts of the brain.36 GluR1 expression is significantly increased during luteinizing hormone surge, suggesting that PROG may be involved in modulating GluR1 expression.23 AMPA receptor trafficking can be modulated by proinflammatory cytokines, with tumor necrosis factor-α rapidly increasing synaptic GluR1 within minutes.37
Subarachnoid hemorrhage (SAH) induces widespread inflammation leading to cellular injury, vasospasm, and ischemia. Evidence suggests that progesterone (PROG) can improve functional recovery in acute brain injury owing to its anti-inflammatory and neuroprotective properties, which could also be beneficial in SAH. We hypothesized that PROG treatment attenuates inflammation-mediated cerebral vasospasm and microglial activation, improves synaptic connectivity, and ameliorates functional recovery after SAH.
We investigated the effect of PROG in a cisternal SAH model in adult male C57BL/6 mice. Neurobehavioral outcomes were evaluated using rotarod latency and grip strength tests. Basilar artery perimeter, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor 1 (GluR1)/synaptophysin colocalization, and Iba-1 immunoreactivity were quantified histologically.
PROG (8 mg/kg) significantly improved rotarod latency at day 6 and grip strength at day 9. PROG-treated mice had significantly reduced basilar artery vasospasm at 24 hours. GluR1/synaptophysin colocalization, indicative of synaptic GluR1, was significantly reduced in the SAH+Vehicle group at 24 hours, and PROG treatment significantly attenuated this reduction. PROG treatment significantly reduced microglial cell activation and proliferation in cerebellum and cortex but not in the brainstem at 10 days.
PROG treatment ameliorated cerebral vasospasm, reduced microglial activation, restored synaptic GluR1 localization, and improved neurobehavioral performance in a murine model of SAH. These results provide a rationale for further translational testing of PROG therapy in SAH.
Hypothalamic Regulation of Anterior Pituitary Function
2017, The Pituitary: Fourth EditionSince their close interaction was recognized almost a century ago, there has been considerable progress in our knowledge of the anatomical, physiological, and pathophysiological aspects of hypothalamic regulation of the pituitary gland. Discovery of pituitary hormones was followed by isolation of hypothalamic neuropeptides that regulate their respective synthesis, their cognate receptors, and multiple intrapituitary signaling pathways. Extensive feedback mechanisms, essential for appropriate neuroendocrine hormonal regulation and brain networking, act to control hypothalamic neuropeptide action on pituitary and ultimately target gland responses.
This chapter focuses on the hypothalamic–pituitary unit, including anatomy and histology, and the hypothalamic hormones regulating pituitary function including thyrotrophin-releasing hormone, corticotrophin-releasing hormone, growth hormone-releasing hormone, gonadotrophin-releasing hormone, and somatostatin- and prolactin-regulating hormones. Mechanisms underlying hypothalamic hormone production, localization, and regulation and their effect on cognate pituitary receptors are described. These functions are geared towards integration of metabolic and trophic hormone homeostasis.
The onset of puberty is the result of the increased secretion of hypothalamic luteinizing hormone-releasing hormone (LHRH). The pubertal process can be altered by substances that can affect the prepubertal secretion of this peptide. Alcohol is one such substance known to diminish LHRH secretion and delay the initiation of puberty. The increased secretion of LHRH that normally occurs at the time of puberty is due to a decrease of inhibitory tone that prevails prior to the onset of puberty, as well as an enhanced development of excitatory inputs to the LHRH secretory system. Additionally, it has become increasingly clear that glial-neuronal communications are important for pubertal development because they play an integral role in facilitating the pubertal rise in LHRH secretion. Thus, in recent years attempts have been made to identify specific glial-derived components that contribute to the development of coordinated communication networks between glia and LHRH cell bodies, as well as their nerve terminals. Transforming growth factor-α and transforming growth factor-β1 are two such glial substances that have received attention in this regard. This review summarizes the use of multiple neuroendocrine research techniques employed to assess these glial-neuronal communication pathways involved in regulating prepubertal LHRH secretion and the effects that alcohol can have on their respective functions.