Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation assessment of the Four Core Genotype mouse model

Abstract

Males and females exhibit several differences in brain structure and function. To examine the basis for these sex differences, we investigated the influences of sex hormones and sex chromosomes on brain structure and function in mice. We used the Four Core Genotype (4CG) mice, which can generate both male and female mice with XX or XY sex chromosome complement, allowing the decoupling of sex chromosomes from hormonal milieu. To examine whole brain structure, high-resolution ex vivo MRI was performed, and to assess differences in cognitive function, mice were trained on a radial arm maze. Voxel-wise and volumetric analyses of MRI data uncovered a striking independence of hormonal versus chromosomal influences in 30 sexually dimorphic brain regions. For example, the bed nucleus of the stria terminalis and the parieto-temporal lobe of the cerebral cortex displayed steroid-dependence while the cerebellar cortex, corpus callosum, and olfactory bulbs were influenced by sex chromosomes. Spatial learning and memory demonstrated strict hormone-dependency with no apparent influence of sex chromosomes. Understanding the influences of chromosomes and hormones on brain structure and function is important for understanding sex differences in brain structure and function, an endeavor that has eventual implications for understanding sex biases observed in the prevalence of psychiatric disorders.

An Allometric Analysis of Sex and Sex Chromosome Dosage Effects on Subcortical Anatomy in Humans

“…Moreover: (1) studies in transgenic mice have established the presence of gonad-independent SCD effects on both cortical and subcortical anatomy (Corre et al, 2014;Raznahan et al, 2014), and (2) neuroimaging studies in human sex-chromosome aneuploidy (SCA) have established that changes in X-and Y-chromosome count can modify the anatomy of cortical regions with known subcortical projections (Bryant et al, 2011(Bryant et al, , 2012Hong et al, 2014;Raznahan et al, 2016). To date however, it is not known whether and how SCD influences subcortical morphology in humans.…”

Allometric Analysis Detects Brain Size-Independent Effects of Sex and Sex Chromosome Complement on Human Cerebellar Organization

“…Sex chromosome effects represent a priority for further study in this regard given that (1) sex chromosome complement can modify cerebellar anatomy in mice independently of sex differences in circulating sex steroids (Corre et al, 2016) and (2) sex chromosome aneuploidies (SCAs) such as XXY and XYY syndrome are associated with impairments in several cerebellar-dependent cognitive domains, including motor control, language, and executive functioning (Hong and Reiss, 2014). To date, however, it remains unknown whether and how X-and Y-chromosome aneuploidy affects cerebellar anatomy in humans.…”

Animal models for Alzheimer’s disease: a focused review of transgenic rodent models and behavioral assessment methods

“…Compared with MWM, RAM is suitable for the assessment of STM concluding working memory and reference memory. The RAM is a hippocampal-dependent task, where food-deprived mice must learn to locate maze arms baited with food rewards [73]. During this task, mice have to enter the arms to find food.…”

“…During this task, mice have to enter the arms to find food. Then, each visit (entry of the full body, excluding the tail, into an arm) is scored as a correct visit or a wrong visit [73]. A correct visit was defined as an entry into a baited arm that had not been visited earlier in the same trial [73].…”

“…Then, each visit (entry of the full body, excluding the tail, into an arm) is scored as a correct visit or a wrong visit [73]. A correct visit was defined as an entry into a baited arm that had not been visited earlier in the same trial [73]. Finally, the "wrong visits" were analysed as working memory errors and reference memory errors to determinate the basis of learning.…”