Different dendritic domains of the GnRH neuron underlie the pulse and surge modes of GnRH secretion in female mice

Wang, Li; Guo, Wei; Shen, Xi; Yeo, Shel Hwa; Long, Hui; Wang, Zhexuan; Lyu, Qifeng; Herbison, Allan E.; Kuang, Yanping

doi:10.7554/elife.53945

Cited by 59 publications

(60 citation statements)

References 48 publications

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“…The proximal GnRH neuron dendrite was the focus of this study, as GABAergic remodeling is restricted to this region [ 14 , 16 ]. However, we cannot rule out changes at the more distal GnRH neuron dendron, the region known to be critical in driving pulsatile LH secretion [ 59 ]. In any case, the present finding stands in contrast to the plasticity that has been observed in the GABA ARN -to-GnRH neuron circuit, despite NPY ARN neurons composing a large proportion of this circuit [ 14 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Investigating the NPY/AgRP/GABA to GnRH Neuron Circuit in Prenatally Androgenized PCOS-Like Mice

Marshall

Prescott

Campbell

2020

Journal of the Endocrine Society

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Polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility, is associated with altered signalling within the hormone-sensitive neuronal network that regulates gonadotropin-releasing hormone (GnRH) neurons, leading to a pathological increase in GnRH secretion. Circuit remodelling is evident between GABAergic neurons in the arcuate nucleus (ARN) and GnRH neurons in a murine model of PCOS. One third of ARN GABA neurons co-express neuropeptide Y (NPY), which has a known yet complex role in regulating GnRH neurons and reproductive function. Here, we investigated whether the NPY-expressing subpopulation (NPY ARN) of ARN GABA neurons (GABA ARN) is also affected in prenatally androgenized (PNA) PCOS-like NPY ARN reporter mice [Agouti-related protein (AgRP)-Cre;τGFP]. PCOS-like mice and controls were generated by exposure to di-hydrotestosterone or vehicle (VEH) in late gestation. τGFP-expressing NPY ARN neuron fiber appositions with GnRH neurons and gonadal steroid hormone receptor expression in τGFP-expressing NPY ARN neurons were assessed using confocal microscopy. Although GnRH neurons received abundant close contacts from τGFP-expressing NPY ARN neuron fibers, the number and density of putative inputs was not affected by prenatal androgen excess. NPY ARN neurons did not co-express progesterone receptor or estrogen receptor α in either PNA or VEH mice. However, the proportion of NPY ARN neurons co-expressing the androgen receptor was significantly elevated in PNA mice. Therefore, NPY ARN neurons are not remodelled like the wider GABA ARN population by prenatal androgen excess, indicating GABA-to-GnRH neuron circuit remodelling occurs in a presently unidentified non-NPY/AgRP population of GABA ARN neurons. NPY ARN neurons do, however, show independent changes in the form of elevated androgen sensitivity

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Section: Discussionmentioning

confidence: 99%

Investigating the NPY/AgRP/GABA to GnRH Neuron Circuit in Prenatally Androgenized PCOS-Like Mice

Marshall

Prescott

Campbell

2020

Journal of the Endocrine Society

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“…The functional difficulties imposed by this topography appear to be solved, in part, by GnRH neurons focusing their blended dendritic/axonal projections on the median eminence where they can be regulated in a concerted manner by the KNDy pulse generator (Herbison 2018). While it is clear that classic synaptic inputs exist on the GnRH neuron dendron (Moore, Prescott et al 2018, Wang, Guo et al 2020, we note that this is not the case for the KNDy neuron innervation. Although many close appositions were identified with regular confocal analysis, no evidence was found with ExM for these to be synaptic inputs between KNDy fibers and GnRH neuron dendrons.…”

Section: Kisspeptin In Kndy Neurons Is Essential For Episodic Activatmentioning

confidence: 87%

“…Expansion microscopy (ExM) uses isotropic swelling of the tissue specimen to provide ~70 nm spatial resolution that can reliably image synapses in the brain (Wassie, Zhao et al 2019). We have previously demonstrated using ExM that a "sideplane" overlap of >0.23 μm (0.95 μm post-expansion) or face-plane (z stack) overlap >0.42 μm (1.75 μm post-expansion) between a synaptophysin-immunoreactive bouton and the GFP of a GnRH neuron represents a bona fide synapse (Wang, Guo et al 2020). The presence of kisspeptin synapses on distal dendrons was examined by assessing synaptophysin-containing kisspeptin boutons opposed to GFP-expressing dendrons.…”

Section: Kndy Neurons Signal Through Volume Transmission To the Gnrh mentioning

confidence: 99%

“…For the face-view orientation, a 2 µm x 2 µm (width x length) box was drawn on each of the synaptophysin-kisspeptin boutons to measure the relative intensity of Alexa488 and ATTO647 in z-stack through scan. An apposition was considered a synapse where the signals overlapped by >0.95 μm (0.23 μm preexpansion) in the side-on plane or >1.75 μm (0.42 μm pre-expansion) in the z-stack through/face-view (Wang, Guo et al 2020). The same method was used to establish the relationship between synaptophysin-kisspeptin profiles and the distal dendron using 60 μm (15 μm pre-expansion) contiguous lengths of dendron located in the ventrolateral ARN.…”

Section: Immunohistochemistry For Expansion Microscopymentioning

confidence: 99%

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Highly redundant neuropeptide volume co-transmission underlying episodic activation of the GnRH neuron dendron

Liu

Yeo

McQuillan

et al. 2020

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The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic KNDy neurons co-express kisspeptin, neurokinin B (NKB) and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close but non-synaptic appositions with the GnRH neuron dendron. Confocal GCaMP6 calcium imaging demonstrated that, of the neurotransmitters co-expressed by KNDy neurons, only kisspeptin was able to activate the GnRH neuron dendron. The selective deletion of kisspeptin from KNDy neurons resulted in mice in which the synchronized behavior of the KNDy neurons was maintained but their ability to drive episodic hormone secretion was abolished. This indicates that KNDy neurons drive episodic hormone secretion through converse modes of highly redundant neuropeptide co-transmission orchestrated by differential postsynaptic neuropeptide receptor expression at their two target sites.

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“…It has previously been shown that proximal segments of GnRH dendrites have a pivotal role in the physiology of the cells. They express active ion conductances, generate action potentials and contribute-via synaptic inputs-to the surge release of the hormone (Iremonger and Herbison 2015;Wang et al 2020;Norberg et al 2013).…”

Section: Quantification Of the Neuronal Glp-1 Input To Hypophysiotropmentioning

confidence: 99%

Networking of glucagon-like peptide-1 axons with GnRH neurons in the basal forebrain of male mice revealed by 3DISCO-based immunocytochemistry and optogenetics

et al. 2020

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Glucagon-like peptide-1 (GLP-1) regulates reproduction centrally, although, the neuroanatomical basis of the process is unknown. Therefore, the putative networking of the central GLP-1 and gonadotropin-releasing hormone (GnRH) systems was addressed in male mice using whole mount immunocytochemistry and optogenetics. Enhanced antibody penetration and optical clearing procedures applied to 500–1000 µm thick basal forebrain slices allowed the simultaneous visualization of the two distinct systems in the basal forebrain. Beaded GLP-1-IR axons innervated about a quarter of GnRH neurons (23.2 ± 1.4%) forming either single or multiple contacts. GnRH dendrites received a more intense GLP-1 innervation (64.6 ± 0.03%) than perikarya (35.4 ± 0.03%). The physiological significance of the innervation was examined by optogenetic activation of channelrhodopsin-2 (ChR2)-expressing axons of preproglucagon (GCG) neurons upon the firing of GnRH neurons by patch clamp electrophysiology in acute brain slices of triple transgenic mice (Gcg-cre/ChR2/GFP-GnRH). High-frequency laser beam stimulation (20 Hz, 10 ms pulse width, 3 mW laser power) of ChR2-expressing GCG axons in the mPOA increased the firing rate of GnRH neurons (by 75 ± 17.3%, p = 0.0007). Application of the GLP-1 receptor antagonist, Exendin-3-(9-39) (1 μM), prior to the photo-stimulation, abolished the facilitatory effect. In contrast, low-frequency trains of laser pulses (0.2 Hz, 60 pulses) had no effect on the spontaneous postsynaptic currents of GnRH neurons. The findings indicate a direct wiring of GLP-1 neurons with GnRH cells which route is excitatory for the GnRH system. The pathway may relay metabolic signals to GnRH neurons and synchronize metabolism with reproduction.

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Different dendritic domains of the GnRH neuron underlie the pulse and surge modes of GnRH secretion in female mice

Cited by 59 publications

References 48 publications

Investigating the NPY/AgRP/GABA to GnRH Neuron Circuit in Prenatally Androgenized PCOS-Like Mice

Investigating the NPY/AgRP/GABA to GnRH Neuron Circuit in Prenatally Androgenized PCOS-Like Mice

Highly redundant neuropeptide volume co-transmission underlying episodic activation of the GnRH neuron dendron

Networking of glucagon-like peptide-1 axons with GnRH neurons in the basal forebrain of male mice revealed by 3DISCO-based immunocytochemistry and optogenetics

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