Normal brain function requires proper neuronal connections. Layer 2/3 cortical pyramidal neurons in a mammalian brain have similar morphological and functional characteristics, but they tend to form functionally distinct microcircuits by making specialized connections. The cellular and molecular mechanisms by which one neuron finds specific target neurons and eventually forms functional subnetworks are not fully understood. A growing body of evidence indicates that the functional microcircuit formation is largely influenced by the activity pattern arising in local circuits. Presumably, the exact timing of action potential firing, the degree of excitability, and the level of inhibition ar important, but how these factors are operated together and are expressed at the level of multiple neurons have not yet been precisely defined. We propose to address these questions by using electrophysiological and optical approaches to visualize and manipulate neuronal activities at individual cell level. In the Aim 1, we seek to determine how spikes generated in multiple neurons within a short time window influence circuit reorganization by varying three factors: spike timing and number, distance between neurons, and the number of neurons.
In Aim 2, cellular mechanisms such as neuronal excitability and the involvement of disinhibition will be examined. Lastly, Aim 3 is designed to test whether circuit assembly can be manipulated in awake behaving animals. Completion of the proposed work will provide mechanistic insight during cortical circuit plasticity and would establish experimental evidence for non-random features of neural connectivity in the mammalian brain. Abnormal neuronal connectivity has been implicated in various neuropsychiatric diseases such as schizophrenia, epilepsy, and autism spectrum diseases, and can directly influence the symptoms of other brain disorders or injuries. Thus, understanding cellular mechanisms of activity-dependent redistribution of local circuits could also help inform the development of novel strategies for circuit dysfunction.

Public Health Relevance

We do not understand fundamental abnormalities that cause many brain diseases. Abnormal neuronal connectivity has been implicated in various neuropsychiatric diseases such as schizophrenia, epilepsy, and autism spectrum diseases. Understanding cellular mechanisms of activity-dependent modification of local neuronal connectivity will be essential basis of understanding the pathogenesis of each disorder, and ultimately it will promote the development of novel treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH107460-04
Application #
9433682
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Panchision, David M
Project Start
2015-05-18
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Max Planck Florida Corporation
Department
Type
DUNS #
022946007
City
Jupiter
State
FL
Country
United States
Zip Code
33458
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