Cognitive effects of SRY inhibition in the brain

Summary

The male sex determination gene SRY is widely expressed in the male brain, in the ventral tegmental area (VTA), the substantia nigra (SN), and the medial mammillary bodies (MMB). We are interested in assessing the effect of SRY knockdown in these brain regions on cognitive function. This project will provide novel insights into the molecular neurobiology of sexually dimorphic behaviours.

Description

SRY (Sex-determining Region on the Y chromosome) is the key male sex-determination gene that directs embryonic gonads to develop as testes, rather than ovaries. SRY is passed from father to son on the Y chromosome and is therefore not present in females.

A number of studies have demonstrated that SRY is persistently expressed in the male brain into adulthood. Brain mapping studies in male rats demonstrated that SRY protein is abundant in areas such as the substantia nigra (SN), ventral tegmental area (VTA), and medial mammillary bodies (MMB). These brain regions contain either dopamine producing cells or nerve terminals and show differences between genders (ie., size, number of cells, neurotransmitter levels).

Thus, in addition to its role as a central mediator of male sex-determination, SRY may exert its influence directly on the male brain. The aim of the proposed project is to determine the role of SRY in other brain regions such as the VTA (involved in reward and addiction) and MMB (involved in recognition and spatial memory) in male rats.

We will address this aim by stereotaxic injection of SRY antisense or sense control oligonucleotide directly into these brain regions and assess their performance on various behavioural paradigms (e.g., Conditioned place preference, Morris water maze, Y-maze, male sexual behaviour). The efficacy of the SRY knockdown will be determined by in situ hybridisation and immunohistochemistry.

The proposed project will provide entirely novel insights into the neurogenetic mechanisms of sexually dimorphic behaviour in mammals.

Funding

National Institutes of Health (USA)
Rebecca L. Cooper Medical Research Foundation

Outcomes

Established rodent stereotaxic surgery, including site-specific injections and intracerebral cannulations of brain structures

Selected Publications

Dewing P, Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, Vilain E. Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol. 2006 Feb 21;16(4):415-20

Lee, J. and Harley, V. Sex differences in catecholamine regulation. Bioessays. Accepted 24/1/12

PHI Research Team