We propose an experimental program aimed at determining basic cellular/synaptic mechanisms of local synaptic circuit organization in mouse primary motor cortex (M1). We present a multidisciplinary approach using laser scanning photostimulation (LSPS), pair recording, and related techniques for quantitative analysis of neocortical synaptic circuits. Our guiding hypothesis, based on preliminary data, is that local circuits in M1 - unlike sensory cortex - are adapted for `top down'control of motor output signals, in the form of massively convergent excitatory circuits from upper layers (layer 2/3) onto deeper layers (layers 5A, 5B, 6), and that this descending projection is composed of parallel intracortical pathways that are functionally specialized to integrate synaptic signals for corticospinal, corticostriatal, and other major M1 outputs.
Our specific aims, testing different aspects of this general hypothesis, are as follows. First, because cortical layering is a primary determinant of cortical `wiring', in brain slice experiments we will record individually from pyramidal neurons located in all cortical layers in M1, and map the laminar and horizontal sources of excitatory synaptic input. This unique connectivity matrix data set will allow us to determine (for the first time for any cortical area) the average overall excitatory circuit organization in terms of the laminar locations of its neurons. Second, because cortical layers contain functionally distinct subclasses of neurons, we will determine the local circuit organization of major M1 neuronal subclasses. We will use retrograde tracers to identify corticospinal, corticocortical, and corticostriatal neurons for LSPS analysis. We will extend this analysis to determine circuit phenotypes for genetically labeled subclasses as well. Third, because the specific circuits identified above are likely to be functionally specialized, we will analyze their synaptic physiology using pair recording methods to measure unitary connection properties, including the amplitude, time course, and short term plasticity of synaptic signals. We will extend this analysis to the level of single-synapse properties through a novel combination of LSPS mapping and strontium treatment to isolate uniquantal events. Fourth, we will develop and use random access photostimulation to examine the efficacy and timing of feedforward synaptic excitation and inhibition within the M1 local circuit. This will reveal mechanisms of synaptic integration and coincidence detection in identified M1 synaptic pathways. The results will provide radically new insights for understanding the synaptic organization of M1 in wild type mice, providing a quantitative, mechanistic framework for future investigations of synaptic circuit pathophysiology in epilepsy, paralysis, and other disorders of voluntary motor control.

Public Health Relevance

Voluntary movements depend on synaptic circuits in the motor area of the neocortex (cortical gray matter) in the cerebral hemispheres. Here we propose a systematic, quantitative experimental approach that will elucidate fundamental synaptic signaling mechanisms and pathways in mammalian motor neocortex at the cellular level. The results will provide a much needed quantitative framework for understanding cortical circuit pathophysiology in epilepsy, paralysis, and related motor disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061963-02
Application #
7614166
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Chen, Daofen
Project Start
2008-08-01
Project End
2013-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$314,694
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Guo, KuangHua; Yamawaki, Naoki; Svoboda, Karel et al. (2018) Anterolateral Motor Cortex Connects with a Medial Subdivision of Ventromedial Thalamus through Cell Type-Specific Circuits, Forming an Excitatory Thalamo-Cortico-Thalamic Loop via Layer 1 Apical Tuft Dendrites of Layer 5B Pyramidal Tract Type Neurons. J Neurosci 38:8787-8797
Li, Xiaojian; Yamawaki, Naoki; Barrett, John M et al. (2018) Corrigendum: Scaling of Optogenetically Evoked Signaling in a Higher-Order Corticocortical Pathway in the Anesthetized Mouse. Front Syst Neurosci 12:50
Li, Xiaojian; Yamawaki, Naoki; Barrett, John M et al. (2018) Scaling of Optogenetically Evoked Signaling in a Higher-Order Corticocortical Pathway in the Anesthetized Mouse. Front Syst Neurosci 12:16
Neymotin, Samuel A; Suter, Benjamin A; Dura-Bernal, Salvador et al. (2017) Optimizing computer models of corticospinal neurons to replicate in vitro dynamics. J Neurophysiol 117:148-162
Yamawaki, Naoki; Suter, Benjamin A; Wickersham, Ian R et al. (2016) Combining Optogenetics and Electrophysiology to Analyze Projection Neuron Circuits. Cold Spring Harb Protoc 2016:pdb.prot090084
Heuermann, Robert J; Jaramillo, Thomas C; Ying, Shui-Wang et al. (2016) Reduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy. Neurobiol Dis 85:81-92
Yamawaki, Naoki; Radulovic, Jelena; Shepherd, Gordon M G (2016) A Corticocortical Circuit Directly Links Retrosplenial Cortex to M2 in the Mouse. J Neurosci 36:9365-74
Jovasevic, Vladimir; Corcoran, Kevin A; Leaderbrand, Katherine et al. (2015) GABAergic mechanisms regulated by miR-33 encode state-dependent fear. Nat Neurosci 18:1265-71
Suter, Benjamin A; Shepherd, Gordon M G (2015) Reciprocal interareal connections to corticospinal neurons in mouse M1 and S2. J Neurosci 35:2959-74
Yamawaki, Naoki; Shepherd, Gordon M G (2015) Synaptic circuit organization of motor corticothalamic neurons. J Neurosci 35:2293-307

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