A Glial-Neuronal Circuit in the Median Eminence Regulates Thyrotropin-Releasing Hormone-Release via the Endocannabinoid System

Abstract

Based on the type-I cannabinoid receptor (CB1) content of hypophysiotropic axons and the involvement of tanycytes in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis, we hypothesized that endocannabinoids are involved in the tanycyte-induced regulation of TRH release in the median eminence (ME). We demonstrated that CB1-immunoreactive TRH axons were associated to DAGLa-immunoreactive tanycyte processes in the external zone of ME and showed that endocannabinoids tonically inhibit the TRH release in this tissue. We showed that glutamate depolarizes the tanycytes, increases their intracellular Ca 2+ level and the 2-AG level of the ME via AMPA and kainite receptors and glutamate transport. Using optogenetics, we demonstrated that glutamate released from TRH neurons influences the tanycytes in the ME. In summary, tanycytes regulate TRH secretion in the ME via endocannabinoid release, whereas TRH axons regulate tanycytes by glutamate, suggesting the existence of a reciprocal microcircuit between tanycytes and TRH terminals that controls TRH release.

SARS-CoV-2 infects human GnRH neurons and tanycytes, disrupting hypothalamic-pituitary hormonal axes

“…Surprisingly however, given previous reports of a correlation between the intensity of the in ammatory response and low testosterone levels 13 , the level of C-reactive protein (CRP), an indicator of in ammation, was also not found to be a confounding factor for hypogonadism (Supplementary gure 1d). Interestingly, COVID-19 patients with low LH/FSH levels (Groups 1 and 2) also displayed low levels of thyroid stimulating hormone, TSH (Supplementary gure 1e), whose releasing hormone, TRH, is secreted by hypothalamic neuroendocrine terminals in the median eminence similarly to GnRH 14,15 . Together, these results suggest that the severely low total testosterone levels seen in the majority of COVID-19 patients in intensive care are not just a re ection of gonadal insu ciency but of impaired hypothalamic function, or hypogonadotropic hypogonadism.…”

“…However, while Nprotein was often colocalized with tanycytic processes, dsRNA labeling was fainter in tanycytic cell bodies lining the ventricular wall than in the nuclei of non-tanycytic cells morphologically associated with vimentin-immunoreactive tanycytic processes (Figure 3c,d). Interestingly, immunolabeling for S-protein, which mediates host-cell entry 23 , was extremely high in ACE2-and TMPRSS2-coexpressing tanycytic end-feet, which contact fenestrated capillaries at the external pial surface of the median eminence (Figure 3e,f) and where they are known to interact morphologically with GnRH and TRH axon terminals 3,14,15 . In addition, despite the extreme paucity of GnRH neurons and their scattered distribution in the hypothalamus, we identi ed NRP1-or ACE2-positive GnRH neurons (Figure 4a,b), including several positive for the viral S-protein, in all COVID-19 patient brains (Figure 4b).…”

“…While an alteration of GnRH secretion due to the infection of either the neurons themselves or of tanycytes could cause transient hypogonadotropic hypogonadism, in the worst-case scenario, the death of GnRH neurons that we observed in this normally stable population and the dramatic decrease in GnRH transcripts in the hypothalamus of COVID-19 patient brains, may have long-lasting effects on fertility in patients who survive infection. In addition, since tanycytes also tightly control the release of other neurohormones such as TRH into the pituitary portal circulation 14,15 , and the external zone of the median eminence also harbors the neurosecretory terminals of TRH neurons, the infection of tanycytes or these other neurons associated with them may durably impact other physiological processes, and lead to endocrine-triggered neurological or psychiatric disorders. For instance, depression is known to occur in at least 33% of patients diagnosed with COVID-19 46 and in up to 80% of hospitalized COVID-19 patients 47 .…”

The neural cell adhesion molecule NrCAM regulates development of hypothalamic tanycytes

“…Further, in rodents, different tanycyte subsets have been classified according to function. Distinct tanycyte subsets have been shown to regulate hormone levels, act as nutrient and hormone sensors, and regulate body content -all of which support acute physiological changes (Samms et al, 2015;Lazutkaite et al, 2017;Müller-Fielitz et al, 2017;Farkas et al, 2020;Yoo et al, 2020;Rohrbach et al, 2021).…”

International Neuroendocrine Federation: Year 2020 in Review

“…Together, under the influence of photoperiod‐specific pineal melatonin secretion, these increase or decrease thyrotropin expression in the pars tuberalis of the pituitary under the influence of the transcriptional co‐activator EYA3. Also with regard to the thyrotropic axis, Farkas et al 7 of the Hungarian Neuroendocrine Section demonstrate that the release of thyrotropin releasing hormone (TRH) into the pituitary portal circulation at neuroendocrine terminals in the external zone of the hypothalamic median eminence is controlled by a reciprocal neuron–tanycyte interaction. In short, tanycytic end‐feet take up glutamate released by TRH neuronal terminals through AMPA/kainite receptors and glutamate transporters and, in return, surprisingly synthesize endocannabinoids, a typical neuronal signal, to repress TRH neuronal activity through the CB1 receptor.…”