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Mapping mouse brains shows gender differences

Despite male brains being larger, female mice brains have more inhibitory neurons than males...


Neuroscientists at Cold Spring Harbor Laboratory (CSHL) are counting cell types throughout the mouse brain using advanced imaging and math. Published in Cell, they report two surprising findings so far.

Contrary to expectation, the numbers and ratios of three major inhibitory cell types in the mouse cortex vary in a fairly stereotypical way. It also appears these cognition cortical areas, when compared to the brain's sensory perception area, evolved circuits tailored to specific functions.

While male and female brains have the same number of cells in their cortical regions, there are 11 subcortical areas with gender-specific differences. Despite male brains tending to be larger in size, female mouse brains have 10 regions with more inhibitory neurons than males.
female mouse brains have more inhibitory neurons than male brains

Pavel Osten's CSHL team used qBrain mapping technology to discover female mouse brains despite their smaller size, on average have more inhibitory neurons (7 types and subtypes) than male brains in most subcortical regions.

"This implies there are more cells that modulate signals and exert temporal control in areas regulating reproduction, social and parenting behaviors in females — than in males.

With one exception so far. A small area in the hypothalamus, called posterodorsal preoptic nucleus, that is believed to control ejaculation — a single male-specific reproductive function."


Pavel Osten PhD, Associate Professor, CSHL and team leader.
Inhibitory cells exert influence on excitatory neurons which are neurons that trigger a positive change in the membrane of post synaptic neurons to which they are connected. An inhibitory neuron triggers a negative change on the membrane of a post synaptic neuron. So far, qBrain technology has counted cells expressing the proteins: (1) parvalbumin (PV+), (2) somatostatin, (3) (SST+), (4) vasoactive intestinal peptide (VIP+) plus four other subtypes of these — where each protein flags a distinct cell type.

Over the next 5 years, the brain mapping project will build an online database for scientists with distribution maps and morphologies of over 100 distinct cell types in the mouse brain. It is the first step in the "BRAIN Initiative Cell Census Network (BICCN)" for the National Institute of Health, a project conducted by CSHL and collaborators.
"Even our first results show that it really matters knowing the composition of the brain in a precise, quantitative way.

"The brain is like a very complicated Lego puzzle, with pieces that come in all sorts of shapes and sizes. If you want to understand how brain circuits work, you first need to know how many pieces there are, of what types, and how they are distributed.

"It's still not known, but there are thought to be at least 500 cell types in the mammalian brain, and possibly thousands. We still lack a basic parts list."


Pavel Osten PhD, Associate Professor, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

Each mouse brain was scanned by computers and precisely registered in a 600-region grid to a master file, at the rate of one brain per day. The ~200 GB of data for each brain was then analyzed with machine learning algorithms that identify individual neurons by type, according to parameters "learned" from human experts. CSHL Professors Z. Josh Huang and Partha Mitra collaborated on the qBrain Cell paper.

qBrain is built on an automated technology platform that will be used to perform similar analyses of other mammalian brains, from prairie voles to marmoset monkeys as well as humans, enabling unprecedented cross-species comparisons. Hopefully, to provide models of psychiatric, neurodevelopmental and neurodegenerative disorders - from depression and schizophrenia to autism and Alzheimer's diseases.

Highlights
• Quantitative maps reveal cell-type-based structural organization of the brain
• PV+ and SST+ interneuron distribution defines cortical hierarchies
• Circuit architectures differ in frontal/ associational and sensorimotor cortices
• SST+ and VIP+ distribution identifies sexually dimorphic subcortical circuits

Summary
The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in 10 out of 11 sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions.

Authors are Yongsoo Kim, Guangyu Robert Yang, Kith Pradhan, Kannan Umadevi Venkataraju, Mihail Bota, Luis Carlos Garcνa del Molino, Greg Fitzgerald, Keerthi Ram, Miao He, Jesse Maurica Levine, Partha Mitra, Z. Josh Huang, Xiao-Jing Wang, Pavel Osten

Conceptualization, Y.K. and P.O.; Computational modeling, G.R.Y, L.C.G.d.M, and X.-J.W; Sample preparation and Data collection, Y.K., G.F., and J.M.L.; Software and statistical analysis tools, K.P. and K.U.V; Transgenic mice, M.H., and Z.J.H.; Web visualization, K.R. and P.M; Anatomical expression analysis, M.B; Manuscript preparation, Y.K., G.R.Y., X.-J.W., and P.O. with the assistance of other authors.


Acknowledgments: We thank Kristin Baldwin for discussions and critical reading and editing the manuscript, Adam Kepecs, Colin Barnstable and Brett Mensh for discussions and critical reading the manuscript. This work was supported by NIH grants U01MH105971 (P.O.) and R01MH062349 (X.J.W.), Simons Foundation Autism Research Initiative (P.O. and P. M.), STCSM grants 14JC1404900 and 15JC1400104 (X.J.W), the Pennsylvania Department of Health Tobacco CURE Funds SAP#4100062216 (Y.K.), Samuel J. and Joan B. Williamson Fellowship (G.R.Y.), Mathers Charitable Foundation H N Mahabala Chair Professorship (P.M.), and IIT Madras (K.R. and P.M).

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Oct 11, 2017   Fetal Timeline   Maternal Timeline   News   News Archive




Osten's team uses qBrain brain-mapping platform to visualize and count inhibitory neurons in the mouse brain. Brainwide distribution of the 3 major inhibitory cell types, expressing neuropeptides called (RED) SST, (GREEN) PV and (BLUE) VIP, is shown in this color-coded composite pic. The image reveals an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating (GREEN) PV+ interneurons, while association areas are dominated by input-modulating (RED) SST+ interneurons. Despite smaller size, in most subcortical areas female brains had more interneurons than male brains. Image Credit: Osten Lab, CSHL



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