Abstract
Estrogens are critical in driving sex-typical social behaviours that are ethologically relevant in mammals. This is due to both production of local estrogens and signaling by these ligands, particularly in an interconnected set of nuclei called the social behavioural network (SBN). The SBN is a sexually dimorphic network studied predominantly in rodents that is thought to underlie the display of social behaviour in mammals. Signalling by the predominant endogenous estrogen, 17β-estradiol, can be either via the classical genomic or non-classical rapid pathway. In the classical genomic pathway, 17β-estradiol binds the intracellular estrogen receptors (ER) α and β which act as ligand-dependent transcription factors to regulate transcription. In the non-genomic pathway, 17β-estradiol binds a putative plasma membrane ER (mER) such as GPR30/GPER1 to rapidly signal via kinases or calcium flux. Though GPER1’s role in sexual dimorphism has been explored to a greater extent in cardiovascular physiology, less is known about its role in the brain. In the last decade, activation of GPER1 has been shown to be important for lordosis and social cognition in females. In this review we will focus on several mechanisms that may contribute to sexually dimorphic behaviors including the colocalization of these estrogen receptors in the SBN, interplay between the signaling pathways activated by these different estrogen receptors, and the role of these receptors in development and the maintenance of the SBN, all of which remain underexplored.
Highlights
The steroid hormone 17b-estradiol (E2) is the most physiologically relevant estrogen, with a myriad of effects that is dependent on signaling from a receptor
Neurodegenerative diseases disproportionately affect women [68], whereas learning difficulties such as those associated with autism spectrum disorder and dyslexia are more commonly observed in males [69]
Chronic administration of G-1 was anxiolytic in the open field test (OFT), but not the elevated plus maze (EPM) [74] in females while acute administration of G1 was anxiolytic in the EPM within 30 min of administration in males but not females [75]
Summary
The steroid hormone 17b-estradiol (E2) is the most physiologically relevant estrogen, with a myriad of effects that is dependent on signaling from a receptor. The classical genomic mode of estrogen signaling is via nuclear estrogen receptors (ER) a and b, which translocate to the nucleus upon ligand binding to act as transcription factors, regulating transcription over hours to days [1]. E2 acts via both signaling mechanisms to facilitate spinogenesis and dendrite growth [2, 3], cell survival [4], and neuroprotection [5]. All these processes contribute to the sexual differentiation of the brain, a process that is restricted to critical periods of development in conserved nuclei of the brain referred to as the social behavior network [SBN; [6]]. We detail the contribution of the various ERs to the formation of the sexually dimorphic SBN and to the local production of estrogens, with areas of future exploration highlighted
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