Sexually dimorphic neuronal inputs to the neuroendocrine dopaminergic system governing prolactin release

Abstract

Prolactin (PRL) is a pleiotropic hormone that was identified in the context of maternal care and its release from the anterior pituitary is primarily controlled by neuroendocrine dopaminergic (NEDA) neurones of the arcuate nucleus of the hypothalamus. The sexually dimorphic nature of PRL physiology and associated behaviours is evident in mammals, even though the number and density of NEDA neurones is reported as not being sexually dimorphic in rats. However, the underlying circuits controlling NEDA neuronal activity and subsequent PRL release are largely uncharacterised. Thus, we mapped whole‐brain monosynaptic NEDA inputs in male and female mice. Accordingly, we employed a rabies virus based monosynaptic tracing system capable of retrogradely mapping inputs into genetically defined neuronal populations. To gain genetic access to NEDA neurones, we used the dopamine transporter promoter. Here, we unravel 59 brain regions that synapse onto NEDA neurones and reveal that male and female mice, despite monomorphic distribution of NEDA neurones in the arcuate nucleus of the hypothalamus, receive sexually dimorphic amount of inputs from the anterior hypothalamic nucleus, anteroventral periventricular nucleus, medial preoptic nucleus, paraventricular hypothalamic nucleus, posterior periventricular nucleus, supraoptic nucleus, suprachiasmatic nucleus, lateral supramammillary nucleus, tuberal nucleus and periaqueductal grey. Beyond highlighting the importance of considering sex as a biological variable when evaluating connectivity in the brain, these results illustrate a case where a neuronal population with similar anatomical distribution has a subjacent sexually dimorphic connectivity pattern, potentially capable of contributing to the sexually dimorphic nature of PRL release and function.

Neural circuits of social behaviors: Innate yet flexible

“…Consistent with this, activating MPOA Gal projection to the PAG, VTA, and MeA elicits grooming, pup seeking, and suppression of infanticide, respectively, whereas activating MPOA Esr1+ projection to the VTA elicits pup approach and retrieval (Fang et al, 2018;. In addition to direct behavioral control, the MPOA also modulates neuroendocrine responses related to parental behaviors through its projection to vasopressin-, oxytocin-, and corticotropinreleasing hormone (CRH)-expressing cells in the paraventricular nucleus (PVN) Scott et al, 2015) as well as neuroendocrine dopaminergic (NEDA) neurons in the arcuate nucleus (ARC) (Esteves et al, 2019). NEDA cells are essential for parental behaviors because it controls release of prolactin, which directly activates MPOA cells and promotes parental behaviors (Brown et al, 2017;Gudelsky, 1981;Stagkourakis et al, 2020a).…”

No evidence for prolactin’s involvement in the post-ejaculatory refractory period

“…PRL is primarily produced and released into the bloodstream from the anterior pituitary 11,28 , reaching the central nervous system either via circumventricular regions lacking a blood-brain barrier 29 or via receptor-mediated mechanisms 30 , binding its receptor which has widespread distribution, including in the social brain network 31 . Hence, circulating PRL can impact the activity of neuronal circuits involved in the processing of socio-sexual relevant cues and in principle alter the detection of opposite-sex conspecific cues and thus sexual arousal 32,33 . Circulating PRL reaches the central nervous system on a timescale that supports the rapid behavioral alterations that are observed immediately after ejaculation (in less than 2 minutes) 34 .…”

Dopamine-inhibited POMCDrd2+ neurons in the ARC acutely regulate feeding and body temperature

“…Given the sex differences for POMC expression ( 22 ) and the sex-specific regulation of synaptic inputs in dopaminergic ARC neurons ( 23 ), we compared the dopamine responses in POMC neurons of male and female mice. This analysis revealed an overall similar response pattern between both sexes; however, there was a higher proportion of POMC neurons that underwent inhibition upon incubation with 10 μM dopamine in female compared with male mice ( Supplemental Figure 1 , A and B).…”