Three-Dimensional Representation of the Neurotransmitter Systems of the Human Hypothalamus: Inputs of the Gonadotrophin Hormone-Releasing Hormone Neuronal System (original) (raw)
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Ultrastructural characterization of gonadotropin-releasing hormone (GnRH)-producing neurons
The Journal of Comparative Neurology, 1985
By means of preembedding immunohistochemistry, two types of gonadotropin-releasing hormone (GnRH) positive neurons in the rat could be identified and characterized in the preoptic region and in the diagonal band: (1) a "smooth" GnRH neuron with relatively even cytoplasmic contours, and (2) a "spiny" GnRH neuron with thorn-like protrusions of the perikaryon and cell processes. Both cell types contain the same organelles in similar number and distribution, but they differ in the number of synaptic contacts. In general, GnRH cell bodies have a large round or ovoid nucleus, welldeveloped rough endoplasmic reticulum arranged in multilayered stacks or as individual cisternae, and several Golgi complexes. Lysosomes are not numerous under the conditions studied. Specializations include kinocilia, nematosomes, and lamellar whorls. Throughout the cytoplasm, scattered dense core vesicles with a diameter of 100 nm and clear vesicles with a diameter of 30-40 nm can be seen with a preferential localization close to the cell membrane. The cell processes of smooth GnRH cells close to the perikaryal appear as extensions of the perikaryal cytoplasm with all organelles except the nucleus. The two neurites originate from the perikaryon as tapering cones over a distance of 200-300 pm, until they reach a diameter of 0.5-3 pm. Cell processes of spiny GnRH cells show bifurcations, protrusions, or invaginations and contain clear and dense core vesicles in their spines. In areas distant from the perikaryon, immunoreactive fibers with a large number of dense core and clear vesicles can occasionally be seen to terminate synaptically or asynaptically on other neurons. The GnRH neurons show postsynaptic specializations at the level of the perikaryon and at cell processes, when apposed by a presynaptic terminal. Such synaptic contacts are seen less frequently on smooth cells than on spiny cells. Large areas of the GnRH cell may be covered by a thin glial lamella, which separates the cell body from the surrounding neuropil. The results indicate the existence of two populations of GnRH cell bodies with different patterns of innervation, which suggest different integrative capacities.
Gonadotropin releasing hormone (GnRH) released into the hypophysial portal vasculature is the major stimulus for gonadotropin secretion. These hormones in turn regulate gonadal function. The GnRH neurosecretory cells receive a sparse but chemically diverse innervation. Double-label immunocytochemical experiments at the ultrastructural level have demonstrated GABA-(Leranth et al., 1985), serotonin- , and proopiomelanocortin- (Chen et al., in press; Leranth et al., 1988) containing inputs. Previous light microscopic studies suggested that GNRH cells were also contacted by numerous tyrosine hyroxylase (TH)- and/or dopamine beta hydroxylase (DBHbpositive terminals . As all three catecholamines have been implicated in regulation of GnRH secretion , we have applied immunocytochemical techniques at the ultrastructural level to determine if TH-containing terminals synapse onto GnRH neurons.
In vitro paradigms for the study of GnRH neuron function and estrogen effects
Annals of the New York Academy of Sciences, 2003
The elaboration of in vitro paradigms has enabled direct study of GnRH secretion and the regulation of this process. Common findings using different models are the pulsatile nature and calcium-dependency of GnRH secretion, the excitatory effect of glutamate, and the inhibitory or excitatory effect of GABA. Among the different paradigms, the fetal olfactory placode cultures exhibit the unique property of migration in vitro and may retain the capacity to undergo maturational changes in vitro. The short-term incubation of hypothalamic explants obtained at different ages enables one to study developmental changes as well. Estrogens may have important roles in the regulation of GnRH function and can act indirectly via the neighboring neuronal/glial apparatus and directly on GnRH neurons at the cell body and terminal levels. A direct effect is supported by the recent localization of ERalpha and ERbeta transcripts in GnRH neurons using most paradigms. Discrepant effects of estrogens on GnR...
The Journal of Comparative Neurology, 1997
The timing and occurrence of the preovulatory luteinizing hormone (LH) surge in the female rodent are critically dependent on the integrity of the suprachiasmatic nucleus (SCN). Destruction of the SCN leads to a cessation of the ovarian cycle, whereas implantation of estrogen in ovariectomized rats results in daily LH surges. The anatomical substrate for these effects is not known. Previous studies involving lesions of the SCN have suggested the presence of a direct vasoactive intestinal polypeptide (VIP)-containing pathway to gonadotropin-releasing hormone (GnRH) neurons. To further investigate the direct connection between the SCN and the GnRH system, we have used tract-tracing with the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PhaL) in combination with an immunocytochemical staining for GnRH in light and electron microscopic studies. Small, unilateral PhaL deposits, especially when they were placed in the rostral ventrolateral portion of the SCN, revealed a bilateral projection to the preoptic area, where PhaL-immunoreactive fibers were regularly found in close apposition to GnRH neurons. Ultrastructural studies showed synaptic interaction of PhaL-containing fibers with GnRH-immunoreactive (IR) cell bodies, thus demonstrating a direct SCN-GnRH connection. Taken together, these data provide evidence for the existence of a monosynaptic pathway from the SCN to the GnRH system in the hypothalamus of the female rat. We suggest that this pathway may contain at least VIP as a putative transmitter and may play a role in the circadian regulation of the estrous cycle in the female rat.
Glutamatergic and GABAergic Innervation of Human Gonadotropin-Releasing Hormone-I Neurons
Amino acid (aa) neurotransmitters in synaptic afferents to hypothalamic GnRH-I neurons are critically involved in the neuroendocrine control of reproduction. Although in rodents the major aa neurotransmitter in these afferents is γ-aminobutyric acid (GABA), glutamatergic axons also innervate GnRH neurons directly. Our aim with the present study was to address the relative contribution of GABAergic and glutamatergic axons to the afferent control of human GnRH neurons. Formalin-fixed hypothalamic samples were obtained from adult male individuals (n = 8) at autopsies, and their coronal sections processed for dual-label immunohistochemical studies. GABAergic axons were labeled with vesicular inhibitory aa transporter antibodies, whereas glutamatergic axons were detected with antisera against the major vesicular glutamate transporter (VGLUT) isoforms, VGLUT1 and VGLUT2. The relative incidences of GABAergic and glutamatergic axonal appositions to GnRH-immunoreactive neurons were compared quantitatively in two regions, the infundibular and paraventricular nuclei. Results showed that GABAergic axons established the most frequently encountered type of axo-somatic apposition. Glutamatergic contacts occurred in significantly lower numbers, with similar contributions by their VGLUT1 and VGLUT2 subclasses. The innervation pattern was different on GnRH dendrites where the combined incidence of glutamatergic (VGLUT1 + VGLUT2) contacts slightly exceeded that of the GABAergic appositions. We conclude that GABA represents the major aa neurotransmitter in axo-somatic afferents to human GnRH neurons, whereas glutamatergic inputs occur somewhat more frequently than GABAergic inputs on GnRH dendrites. Unlike in rats, the GnRH system of the human receives innervation from the VGLUT1, in addition to the VGLUT2, subclass of glutamatergic neurons.
Immunoreactive GnRH type I receptors in the mouse and sheep brain
Journal of Chemical Neuroanatomy, 2008
GnRH has been implicated in an array of functions outside the neuroendocrine reproductive axis. Previous investigations have reported extensive GnRH binding in numerous sites and this has been supported by in situ hybridization studies reporting GnRH receptor mRNA distribution. The present study on mice and sheep supports and extends these earlier investigations by revealing the distribution of cells immunoreactive for the GnRH receptor. In addition to sites previously shown to express GnRH receptors such as the hippocampus, amygdala and the arcuate nucleus, the improved resolution afforded by immunocytochemistry detected cells in the mitral cell lay of the olfactory bulb as well as the central grey of the mesencephalon. In addition, GnRH receptor immunoreactive neurons in the hippocampus and mesencephalon of the sheep were shown to colocalize with estrogen receptor β. Although GnRH may act at some of these sites to regulate reproductive processes, evidence is accumulating to support an extra-reproductive role for this hypothalamic decapeptide.
Neuroscience Letters, 1997
In urethane-anesthetized ovariectomized rats, estrogen-sensitive descending neurons were identified in the midbrain ventral tegmental area (VTA), based on estrogen-induced changes in the excitability in antidromic responses to midbrain central gray stimulation. Estrogen increased the threshold and decreased the firing rate of the identified neurons. Responses of the identified neurons to the microiontophoresis of gonadotropin-releasing hormone (GnRH) or d-Phe 2 , d-Ala 6-GnRH, a behaviorally active analog, but not to glutamate or g-aminobutyric acid (GABA), depended on estrogen. In the ovariectomized rat, GnRH excited a few neurons; the analog had no effect. GnRH suppressed spontaneous or glutamate-induced firing in almost all neurons in the estrogen-primed rat. The analog had mixed effects. The facilitation of female rat sexual behavior induced by infusion of GnRH in the VTA is due to the inhibition of VTA neurons.
Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals
Proceedings of The National Academy of Sciences, 2006
Successful reproduction requires maintenance of the reproductive axis within fine operating limits through negative feedback actions of sex steroids. Despite the importance of this homeostatic process, our understanding of the neural loci, pathways, and neurochemicals responsible remain incomplete. Here, we reveal a neuropeptidergic pathway that directly links gonadal steroid actions to regulation of the reproductive system. An RFamide (Arg-Phe-NH 2) peptide that inhibits gonadotropin release from quail pituitary was recently identified and named gonadotropin-inhibitory hormone (GnIH). Birds are known to have specialized adaptations associated with gonadotropin-releasing hormone (GnRH) regulation to optimize reproduction (e.g., encephalic photoreceptors), and the existence of a hypothalamic peptide inhibiting gonadotropins may or may not be another such specialization. To determine whether GnIH serves as a signaling pathway for sex steroid regulation of the reproductive axis, we used immunohistochemistry and in situ hybridization to characterize the distribution and functional role of this peptide in hamsters, rats, and mice. GnIH-immunoreactive (GnIH-ir) cell bodies are clustered in the mediobasal hypothalamus with pronounced projections and terminals throughout the CNS. In vivo GnIH administration rapidly inhibits luteinizing hormone secretion. Additionally, GnIH-ir neurons form close appositions with GnRH cells, suggesting a direct means of GnRH modulation. Finally, GnIH-ir cells express estrogen receptor-␣ and exhibit robust immediate early gene expression after gonadal hormone stimulation. Taken together, the distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIH-ir nuclei, and GnIH inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.