Sex‐ and sub region‐dependent modulation of arcuate kisspeptin neurons by vasopressin and vasoactive intestinal peptide

Abstract

A population of kisspeptin neurons located in the hypothalamic arcuate nucleus (ARN) very likely represent the gonadotrophin‐releasing hormone pulse generator responsible for driving pulsatile luteinizing hormone secretion in mammals. As such, it has become important to understand the neural inputs that modulate the activity of ARN kisspeptin (ARN^KISS) neurons. Using a transgenic GCaMP6 mouse model allowing the intracellular calcium levels (i[Ca²⁺]) of individual ARN^KISS neurons to be assessed simultaneously, we examined whether the circadian neuropeptides vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP) modulated the activity of ARN^KISS neurons directly. To validate this methodology, we initially evaluated the effects of neurokinin B (NKB) on i[Ca²⁺] in kisspeptin neurons residing within the rostral, middle and caudal ARN subregions of adult male and female mice. All experiments were undertaken in the presence of tetrodotoxin and ionotropic amino acid antagonists. NKB was found to evoke an abrupt increase in i[Ca²⁺] in 95‐100% of kisspeptin neurons throughout the ARN of both sexes. In marked contrast, both VIP and AVP were found to primarily activate kisspeptin neurons located in the caudal ARN of female mice. Whereas 58 and 59% of caudal ARN kisspeptin neurons responded to AVP and VIP, respectively, in female mice, only 0‐8% of kisspeptin neurons located in other ARN subregions responded in females and 0‐12% of cells in any subregion in males (p<0.05). These observations demonstrate unexpected sex differences and marked heterogeneity in functional neuropeptide receptor expression amongst ARN^KISS neurons organized on a rostro‐caudal basis. The functional significance of this unexpected influence of VIP and AVP on ARN^KISS neurons remains to be established.

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