Neuroscientists monitor extracellular brain signals to infer the underlying neural mechanisms of computation and cognition. While intracellular and transmembrane processes have monopolized the interest of researchers, much less attention has been paid to extracellular eld eects. Yet, the quality and quantity of information retrieved from extracellular recording sessions critically depends on our understanding of the transfer function between intracellular activity and the ex- tracellular space. Moreover, it has been shown that endogenous extracellular elds do aect the state and function of individual neurons through ephaptic coupling. This provides a continuous non-synaptic feedback mechanism between the eld and individual neurons. In a collaborative eort, the laboratories of C. Koch and G. Buzsaki propose to unravel the origin and functionality of extracellular eld eects in the hippocampal CA1 region during theta and sharp waves activity by using a modeling/experimental approach. Computationally, by modeling a large number of biophysical realistic pyramidal and inhibitory interneurons making up the rat CA1 hippocampus subeld. These, in conjunction with glia cells, will be arranged in a 3-D resistive cytoplasm, and their extracellular contributions will be summed to yield the nal extracellular electrical potential associated with electrical activity in individual neurons. Patch-clamp experiments from individ- ual hippocampal neurons will shed light onto the intracellular and extracellular correlates of CA1 pattern activity. Recordings from anesthetized rats will be used to constrain these models and to test their accuracy. Simultaneous optical stimulation (in CA3 using ChR2 and related optogenetic techniques) and extracellular recording experiments in CA1 will be performed to manipulate ex- tracellular brain activity to answer a series of questions: (i) what is the detailed makeup of the extracellular eld in the hippocampus, (ii) what are its contributors (pre- versus post-synaptic ac- tivity, spiking currents, glia), and (iii) how does the eld serve to synchronize the underlying sub- and suprathreshold activity of CA1 neurons - even in the absence of direct synaptic coupling. This research will also bear on our understanding of a number of pathologies and their treatment, in particular on the initiation and spread of pathological hypersynchronziation, such as in epilepsy, and the short- and long-range eect of direct brain stimulation via electrical current, as in deep brain stimulation. Here, therapy ecacy crucially depends on a solid understanding of the eect of extracellular elds on neurons and neural circuits.

Public Health Relevance

Project Narrative The aim of this project is to analyze the origin of the electric eld measured inside the brain and how changes in this eld aect brain processes. This electrical eld is most likely important in propagating hyper-synchronous electrical discharges during epileptic seizures. Deep brain stimula- tion, as frequently used to treat Parkinsons disease and some forms of depression, will also directly aect this electrical eld with ill-understood consequences. It is thus essential to study the direct and indirect biophysical eects of electrical elds, either endogenous or imposed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074015-02
Application #
8215823
Study Section
Special Emphasis Panel (ZRG1-NT-B (09))
Program Officer
Liu, Yuan
Project Start
2011-02-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$307,514
Indirect Cost
$87,014
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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Peyrache, Adrien; Lacroix, Marie M; Petersen, Peter C et al. (2015) Internally organized mechanisms of the head direction sense. Nat Neurosci 18:569-75
Stark, Eran; Roux, Lisa; Eichler, Ronny et al. (2015) Local generation of multineuronal spike sequences in the hippocampal CA1 region. Proc Natl Acad Sci U S A 112:10521-6
Schaub, Michael T; Billeh, Yazan N; Anastassiou, Costas A et al. (2015) Emergence of Slow-Switching Assemblies in Structured Neuronal Networks. PLoS Comput Biol 11:e1004196
Khodagholy, Dion; Gelinas, Jennifer N; Thesen, Thomas et al. (2015) NeuroGrid: recording action potentials from the surface of the brain. Nat Neurosci 18:310-5
Buzsáki, György; Stark, Eran; Berényi, Antal et al. (2015) Tools for probing local circuits: high-density silicon probes combined with optogenetics. Neuron 86:92-105
Anastassiou, Costas A; Koch, Christof (2015) Ephaptic coupling to endogenous electric field activity: why bother? Curr Opin Neurobiol 31:95-103
Krook-Magnuson, Esther; Gelinas, Jennifer N; Soltesz, Ivan et al. (2015) Neuroelectronics and Biooptics: Closed-Loop Technologies in Neurological Disorders. JAMA Neurol 72:823-9
Roux, Lisa; Buzsáki, György (2015) Tasks for inhibitory interneurons in intact brain circuits. Neuropharmacology 88:10-23
Buzsáki, György; Peyrache, Adrien; Kubie, John (2014) Emergence of Cognition from Action. Cold Spring Harb Symp Quant Biol 79:41-50

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