Abstract
Human reproduction is controlled by ~2000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here, we report the discovery and characterization of additional ~150,000-200,000 GnRH-synthesizing cells in the human basal ganglia and basal forebrain. Nearly all extrahypothalamic GnRH neurons expressed the cholinergic marker enzyme choline acetyltransferase. Similarly, hypothalamic GnRH neurons were also cholinergic both in embryonic and adult human brains. Whole-transcriptome analysis of cholinergic interneurons and medium spiny projection neurons laser-microdissected from the human putamen showed selective expression of GNRH1 and GNRHR1 autoreceptors in the cholinergic cell population and uncovered the detailed transcriptome profile and molecular connectome of these two cell types. Higher-order non-reproductive functions regulated by GnRH under physiological conditions in the human basal ganglia and basal forebrain require clarification. The role and changes of GnRH/GnRHR1 signaling in neurodegenerative disorders affecting cholinergic neurocircuitries, including Parkinson's and Alzheimer's diseases, need to be explored.
Highlights
Mammalian reproduction is controlled by a few hundred/thousand preoptic/hypothalamic neurons, which release the decapeptide neurohormone gonadotropin-releasing hormone (GnRH) into the hypophysial portal circulation
Labeled neurons were scattered in the globus pallidus (GP), the ventral pallidum (VP), and the bed nucleus of the stria terminalis (BnST)
To investigate the possibility that GnRH neurons in the basal ganglia and the basal forebrain of the adult human brain use GnRH1-5, rather than GnRH decapeptide for signaling, we first tested a series of polyclonal antibodies against human GnRH-associated peptide or GnRH decapeptide (Supplementary file 2) for their reactivity with GnRH neurons of the human Pu (N = 10; #5, 6, and 12–19)
Summary
Mammalian reproduction is controlled by a few hundred/thousand preoptic/hypothalamic neurons, which release the decapeptide neurohormone gonadotropin-releasing hormone (GnRH) into the hypophysial portal circulation. Unlike other neurons of the central nervous system, GnRH neurons are born in the olfactory placodes and migrate into the forebrain prenatally 2000 neurons were observed along a ventral migratory path whereby GnRH neurons reach the hypothalamus to regulate reproduction after puberty. A previously unknown dorsal migratory route has been identified whereby ~8000 GnRH neurons migrated towards pallial and/or subpallial structures. The fate of these neurons at later stages of pre- and postnatal development has been unexplored so far
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