Neurons of the cerebral cortex are embedded in a highly interconnected network, allowing them to participate in a nearly infinite variety of neural circuits. The activity of a single neuron is determined by the flow of activity within this flexibl and powerful circuit. We hypothesize that neurons receive two broad categories of synaptic inputs that determine their action potential discharge: a slow, and sometimes, maintained component that strongly influences neuronal excitability and provides the cell with context;and a more rapid, temporally precise component that determines exactly when a cell discharges. The broad component is mediated by a proportional or balanced interaction of recurrent excitatory and inhibitory interactions in the cortex. The more rapid component appears to be mediated by temporally precise interactions of specific excitatory and inhibitory networks. Who are the interneurons that contribute to these two components and how are they achieving their task? Here we will address this important question through advanced in vitro and in vivo imaging and recording techniques. Using a recently developed in vitro mouse entorhinal cortical slice preparation that robustly generates spontaneous rhythmic Up and Down states, we will address the activity of several subclasses of neuron, including two excitatory cell types (Pyramidal and Stellate) and several inhibitory neuronal subtypes (PV/FS, SOM, NPY, 5HT3a, CR, VIP). This preparation not only generates the slow oscillation between Up and Down states, but also robust gamma-frequency oscillations during the Up state. Thus, we will also utilize this preparation to investigate the interneuronal cell types robustly involved in the generation of not only the general balance of recurrent excitation and inhibition that underlies persistent activity n the cortex, but also the generation of higher frequency network oscillations and the fast synaptic events that trigger action potentials on a precise time scale. These experiments will involve whole cell patch clamp and local field/MU recordings, as well as the selective inactivation/activation of known interneuronal cell populations with light activation of virally expressed archaerhodopsin, halorhodopsin, or channelrhodopsin. We will extend these investigations in vivo by studying the activity of identified subpopulations of interneurons in the mouse somatosensory cortex through patch clamp recording in a custom-built two-photon microscope. In a separate, but related, study, we will also investigate the possibility that local electrical fields may make a contribution to the synchronization and timing of higher frequency network oscillations. These investigations will help determine and define how the cerebral cortex operates, how it achieves a relative balance of recurrent excitation and inhibition, and how deviations from this balance may be critical in the generation of precisely timed action potential generation. The balanced operation of recurrent excitation and inhibition in the cortex is essential to the normal operation of the cerebral cortex and the breakdown of this balance readily results in the generation of epileptic seizures as well as psychiatric disorders.

Public Health Relevance

The cerebral cortex is the most important structure of the human brain, yet is only partially understood. We will examine the basic operating principles of the neocortex and how this arises from the properties of excitatory-inhibitory neuronal interaction. Our studies will give fundamental information relevant to understanding not only normal cortical operation, but also potential cortical dysfunction during epileptic seizures and psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS026143-26
Application #
8290628
Study Section
Special Emphasis Panel (SPC)
Program Officer
Chen, Daofen
Project Start
1988-04-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
26
Fiscal Year
2012
Total Cost
$385,782
Indirect Cost
$153,208
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ferrante, Michele; Tahvildari, Babak; Duque, Alvaro et al. (2017) Distinct Functional Groups Emerge from the Intrinsic Properties of Molecularly Identified Entorhinal Interneurons and Principal Cells. Cereb Cortex 27:3186-3207
Reimer, Jacob; McGinley, Matthew J; Liu, Yang et al. (2016) Pupil fluctuations track rapid changes in adrenergic and cholinergic activity in cortex. Nat Commun 7:13289
Zagha, Edward; Murray, John D; McCormick, David A (2016) Simulating Cortical Feedback Modulation as Changes in Excitation and Inhibition in a Cortical Circuit Model. eNeuro 3:
Castellucci, Gregg A; McGinley, Matthew J; McCormick, David A (2016) Knockout of Foxp2 disrupts vocal development in mice. Sci Rep 6:23305
Hadzipasic, Muhamed; Ni, Weiming; Nagy, Maria et al. (2016) Reduced high-frequency motor neuron firing, EMG fractionation, and gait variability in awake walking ALS mice. Proc Natl Acad Sci U S A 113:E7600-E7609
Casale, Amanda E; Foust, Amanda J; Bal, Thierry et al. (2015) Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties. J Neurosci 35:15555-67
Salkoff, David B; Zagha, Edward; Yüzgeç, Özge et al. (2015) Synaptic Mechanisms of Tight Spike Synchrony at Gamma Frequency in Cerebral Cortex. J Neurosci 35:10236-51
McCormick, David A; McGinley, Matthew J; Salkoff, David B (2015) Brain state dependent activity in the cortex and thalamus. Curr Opin Neurobiol 31:133-40
McGinley, Matthew J; David, Stephen V; McCormick, David A (2015) Cortical Membrane Potential Signature of Optimal States for Sensory Signal Detection. Neuron 87:179-92
Zagha, Edward; Ge, Xinxin; McCormick, David A (2015) Competing Neural Ensembles in Motor Cortex Gate Goal-Directed Motor Output. Neuron 88:565-77

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