Abstract
The endocannabinoids have been shown to target the afferents of hypothalamic neurons via cannabinoid 1 receptor (CB1) and thereby to influence their excitability at various physiological and/or pathological processes. Kisspeptin (KP) neurons form afferents of multiple neuroendocrine cells and influence their activity via signaling through a variation of co-expressed classical neurotransmitters and neuropeptides. The differential potency of endocannabinoids to influence the release of classical transmitters or neuropeptides, and the ovarian cycle-dependent functioning of the endocannabinoid signaling in the gonadotropin-releasing hormone (GnRH) neurons initiated us to study whether (a) the different subpopulations of KP neurons express CB1 mRNAs, (b) the expression is influenced by estrogen, and (c) CB1-immunoreactivity is present in the KP afferents to GnRH neurons. The aim of the study was to investigate the site- and cell-specific expression of CB1 in female mice using multiple labeling in situ hybridization and immunofluorescent histochemical techniques. The results support that CB1 mRNAs are expressed by both the GABAergic and glutamatergic subpopulations of KP neurons, the receptor protein is detectable in two-thirds of the KP afferents to GnRH neurons, and the expression of CB1 mRNA shows an estrogen-dependency. The applied estrogen-treatment, known to induce proestrus, reduced the level of CB1 transcripts in the rostral periventricular area of the third ventricle and arcuate nucleus, and differently influenced its co-localization with vesicular GABA transporter or vesicular glutamate transporter-2 in KP neurons. This indicates a gonadal cycle-dependent role of endocannabinoid signaling in the neuronal circuits involving KP neurons.
Highlights
Evidence increases for a broad involvement of the endocannabinoid signaling employed by preoptic/hypothalamic neurons/e.g., for corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), oxytocin (OT), and vasopressin (VP)—see (Di et al 2003); for proopiomelanocortin (POMC)—see (Hentges et al 2005); for gonadotropin-releasing hormone (GnRH)—see (Farkas et al 2010) to regulate the activity of their afferents and thereby to influence their own excitability at various physiological and/or pathological processes
The RNAscope in situ hybridization technique detected mRNA signals for KP, cannabinoid 1 receptor (CB1), VGLUT2, and vesicular GABA transporter (VGAT) concurrently in ovariectomized mouse models treated for 2 days either with EB or oil vehicle
While EBtreatment significantly increased the mRNA levels for KP in the RPRV region, the same treatment reduced it in the arcuate nucleus (ARC)
Summary
Evidence increases for a broad involvement of the endocannabinoid signaling employed by preoptic/hypothalamic neurons/e.g., for corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), oxytocin (OT), and vasopressin (VP)—see (Di et al 2003); for proopiomelanocortin (POMC)—see (Hentges et al 2005); for gonadotropin-releasing hormone (GnRH)—see (Farkas et al 2010) to regulate the activity of their afferents and thereby to influence their own excitability at various physiological and/or pathological processes. They are located in three major sites, i.e., the preoptic area (POA), the arcuate nucleus (ARC), and the medial amygdaloid nucleus (ME) (Clarkson et al 2009; Lehman et al 2013), where they establish local connections (Comninos et al 2016; Stephens and Kauffman 2017; Krajewski et al 2010; Qiu et al 2018), as well as project to distant target areas including the POA (Qiu et al 2018), supraoptic (SON), and paraventricular (PVH) nuclei of the hypothalamus (Yeo et al 2016) Their processes play a key role in mediating the positive and negative estrogen feedback to GnRH neurons (Ohkura et al 2009), which is based on their direct genomic and non-genomic (Mittelman–Smith et al 2012) responses to estrogen, and direct connections to GnRH neurons. They provide a rich innervation of OT (Seymour et al 2017; Liu and Herbison 2016; Scott and Brown 2013), VP neurons (Liu and Herbison 2016) in the SON and PVH, and POMC (Higo et al 2017; Qiu et al 2018), and tyrosine hydroxylase (TH) neurons (Sawai et al 2012) in the ARC, and the functional significance of these neuronal connections, is incompletely understood
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