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Lateralized change in cortical neural networks in autism spectrum disorders

自闭症谱系障碍中皮质神经网络的偏侧变化

基本信息

批准号：
10816075
负责人：
Tara Deemyad
金额：
$ 8.19万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10816075
关键词：
Address Adult Affect Age Animals Behavior Behavioral Biotinylation Brain Buffers Calcium Cells Cerebral Dominance Cerebral cortex Characteristics Defect Development Electric Stimulation Electrophysiology (science)Equilibrium Exhibits Extracellular Matrix Functional disorder Future Human Hyperactivity Hypersensitivity Image Immunohistochemistry In Vitro Knowledge Label Language Development Lectin Link Maintenance Measures Mechanics Methods Movement Mus Myoepithelial cell Neurodevelopmental Disorder Neurologic Neurons Output Parvalbumins Pattern Play Population Property Pyramidal Cells Reporting Role Sensory Side Social Behavior Somatosensory Cortex Structure Synapses Time Vibrissae Vicia Viral autism spectrum disorder barrel cortex cognitive process critical period experimental study hippocampal pyramidal neuron imaging study in vivo calcium imaging individuals with autism spectrum disorder interdisciplinary approach learned behavior mouse model neural circuit neural network novel novel therapeutic intervention patch clamp postnatal period response risk variant targeted treatment

项目摘要

Project summary Aberrant lateralization in brain structure and function is linked to the neurodevelopmental disorders such as autism spectrum disorders (ASD). We have recently reported a lateralized decrease in the number of parvalbumin expressing (PV+) basket cells (BCs) in L2/3 of the somatosensory cortex in the dominant hemisphere of adult Shank3-/- mouse model of ASD. The dominant hemisphere was identified by a reaching task to define each animal’s dominant forepaw. We further used a marker to recognize the specific extracellular matrix enwrapping BCs and found that the number of BCs was not different between the two hemispheres, but rather, some BCs did not express detectable levels of PV (PV- BCs). Remarkably, we showed a mechanical hypersensitivity in the dominant paw correlated with the decrease in the number of PV+ BCs in the corresponding cortex. However, almost nothing is known regarding the developmental trajectory of the observed lateralization in BCs and the impact of a reduction in PV expression on the properties of BCs or pyramidal neurons in local neural circuits. In the present proposal, we will first characterize interhemispheric differences in BC – pyramidal cell network properties in L2/3 of the somatosensory cortex in the Shank3-/- mouse by a combination of in vivo calcium (Ca2+) imaging during whisker stimulation and in vitro patch clamp recording. We investigate differences in the activity and electrophysiological properties of PV+ BCs and the atypical PV- BCs present in Shank3-/- mice. Next, we will evaluate changes in the output of the somatosensory cortex by in vivo Ca2+ imaging of L2/3 pyramidal cells in the barrel cortex during whisker stimulation in Shank3-/- mice. Furthermore, to determine the excitation / inhibition ratio directly, we will use patch clamp recording to study the synaptic inputs to L2/3 pyramidal cells during electrical stimulation of L4. Finally, we will identify the developmental trajectory of interhemispheric differences in the number of L2/3 PV+ and PV- BCs in the somatosensory cortex of the Shank3-/- mouse using immunohistochemistry. Results of the immunohistochemistry, electrophysiology and calcium imaging studies proposed here will significantly increase our knowledge about the role of lateralized changes in the dominant hemisphere in the pathophysiology of ASD and could provide the means for new therapeutic approaches.

项目总结