The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice

Abstract

BackgroundThe suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level rhythms and hormone release. Specific subpopulations of SCN neurons, defined by their peptide expression, regulate defined SCN output. Here we focus on the vasoactive intestinal peptide (VIP) expressing neurons of the SCN. SCN VIP neurons are known to regulate circadian rhythms and reproductive function. MethodsTo specifically study SCN VIP neurons, we generated a novel knock out mouse line by conditionally deleting the SCN enriched transcription factor, Ventral Anterior Homeobox 1 (Vax1), in VIP neurons (Vax1Vip; Vax1fl/fl:VipCre).ResultsWe found that Vax1Vip females presented with lengthened estrous cycles, reduced circulating estrogen, and increased depressive-like behavior. Further, Vax1Vip males and females presented with a shortened circadian period in locomotor activity and ex vivo SCN circadian period. On a molecular level, the shortening of the SCN period was driven, at least partially, by a direct regulatory role of VAX1 on the circadian clock genes Bmal1 and Per2. Interestingly, Vax1Vip females presented with increased expression of arginine vasopressin (Avp) in the paraventricular nucleus, which resulted in increased circulating corticosterone. SCN VIP and AVP neurons regulate the reproductive gonadotropin-releasing hormone (GnRH) and kisspeptin neurons. To determine how the reproductive neuroendocrine network was impacted in Vax1Vip mice, we assessed GnRH sensitivity to a kisspeptin challenge in vivo. We found that GnRH neurons in Vax1Vip females, but not males, had an increased sensitivity to kisspeptin, leading to increased luteinizing hormone release. Interestingly, Vax1Vip males showed a small, but significant increase in total sperm and a modest delay in pubertal onset. Both male and female Vax1Vip mice were fertile and generated litters comparable in size and frequency to controls.ConclusionTogether, these data identify VAX1 in SCN VIP neurons as a neurological overlap between circadian timekeeping, female reproduction, and depressive-like symptoms in mice, and provide novel insight into the role of SCN VIP neurons.

Vasoactive intestinal peptide excites GnRH neurons via KCa3.1, a potential player in the slow afterhyperpolarization current

“…Therefore, VIP inputs from the SCN directly onto GnRH neurons, long ago identified (Beek et al, 1993), remain a candidate for gating kisspeptin responsiveness and onset of the LH surge. A recent study showing greater GnRH sensitivity to kisspeptin when VIP expression is abnormal, further supports this hypothesis (Van Loh et al, 2023).…”

“…Functionally, GnRH neurons in females contacted by VIP preferentially expressed c-fos at the time of the GnRH/LH surge ( Beek et al, 1994 ) and infusion of VIP antisense in SCN impairs c-fos expression in these GnRH neurons ( Gerhold et al, 2005 ; Kahan et al, 2023 ). In addition, a recent study showed that the loss of the VAX1 transcription factor required for normal VIP expression, delays puberty onset, alters females estrous cycle length and potentiates the GnRH response to kisspeptin stimulation ( Van Loh et al, 2023 ). Together, the experimental evidence highlights the importance of VIP signaling, from cells in the SCN to GnRH neurons, for maintenance of normal reproductive function.…”

Association between bedtime and female infertility: a secondary analysis from a cross-sectional study

“…In mammals, these coordinated oscillations are mediated by the SCN ( 23 ). The SCN is closely related to the secretion of gonadotropin-releasing hormone (GnRH) neurons and a variety of reproductive hormones ( 24 ). One pathway comprises direct innervation of GnRH neurons by the SCN ( 25 , 26 ), while the other involves an indirect circuitry where the SCN communicates with the HPG axis via Kisspeptin neurons ( 27 , 28 ).…”

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“…coordinated oscillations are mediated by the SCN (23). The SCN is closely related to the secretion of gonadotropin-releasing hormone (GnRH) neurons and a variety of reproductive hormones (24). One pathway comprises direct innervation of GnRH neurons by the SCN (25, 26), while the other involves an indirect circuitry where the SCN communicates with the HPG axis via Kisspeptin neurons (27,28).…”