Numerous recent experiments in humans and other animals demonstrate impaired temporal coordination of neuronal activity in many psychiatric diseases. A prevalent hypothesis is that temporal coordination in high associational areas of the brain, critical for cognition, is brought about by the multiple hierarchies of rhythms the brain generates. Since most brain rhythms are based on inhibition, the goal of this proposal is to examine the contribution of the variety of interneuron classes to the different oscillations and temporal coordination of principal cell assemblies. Inhibition, both oscillatory and non-oscillator, can flexibly congregate and segregate neuronal populations to support fundamental cortical operations. However, the exact contribution of the different classes of interneurons and their cooperation in these flexible operations are poorly understood. The goal of this proposal is to uncover these mechanisms. Our target is the hippocampus because the mechanisms of several oscillations (theta, gamma, sharp wave ripples) and their contribution to navigation and memory have been extensively studied in this brain region. We will follow two strategies to explore and explain the mechanisms of interneuron-controlled grouping and segregation of principal cells. First, we will quantify the firing rate and phase correlations of the various interneuron types uniquely embeddedness in the various network patterns, using optogenetic identification and large scale recording of the neurons in mice. Second, a closed-loop optogenetic activation and silencing of the identified interneurons will be performed to interfere with native network pattern locally. These combined experiments will therefore identify the causal role of the specific interneuron classes in the organization of cell assemblies supporting spatial navigation and memory. The findings will have important implications for mental disease associated with impaired temporal coordination.

Public Health Relevance

Temporal coordination of neuronal activity within and across brain regions is among the most fundamental neuronal operations and impairment of time management is an underlying mechanism of a variety of mental disorders. Our aim is to explain the role of different interneuron classes in the hippocampus in brain state dependent oscillations and the flexible formation of cell assemblies that support spatial navigation and memory. To achieve this goal we combine optogenetic and large-scale recording methods in behaving mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH054671-14
Application #
8581939
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (57))
Program Officer
Osborn, Bettina D
Project Start
1997-09-30
Project End
2018-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2013
Total Cost
$423,750
Indirect Cost
$173,750
Name
New York University
Department
Physiology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Buzsáki, György; Tingley, David (2018) Space and Time: The Hippocampus as a Sequence Generator. Trends Cogn Sci 22:853-869
Oliva, Azahara; Fernández-Ruiz, Antonio; Fermino de Oliveira, Eliezyer et al. (2018) Origin of Gamma Frequency Power during Hippocampal Sharp-Wave Ripples. Cell Rep 25:1693-1700.e4
Watson, Brendon O; Ding, Mingxin; Buzsáki, György (2018) Temporal coupling of field potentials and action potentials in the neocortex. Eur J Neurosci 48:2482-2497
Lisman, John; Buzsáki, György; Eichenbaum, Howard et al. (2017) Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci 20:1434-1447
English, Daniel Fine; McKenzie, Sam; Evans, Talfan et al. (2017) Pyramidal Cell-Interneuron Circuit Architecture and Dynamics in Hippocampal Networks. Neuron 96:505-520.e7
Levenstein, Daniel; Watson, Brendon O; Rinzel, John et al. (2017) Sleep regulation of the distribution of cortical firing rates. Curr Opin Neurobiol 44:34-42
Fernández-Ruiz, Antonio; Oliva, Azahara; Nagy, Gerg? A et al. (2017) Entorhinal-CA3 Dual-Input Control of Spike Timing in the Hippocampus by Theta-Gamma Coupling. Neuron 93:1213-1226.e5
Khodagholy, Dion; Gelinas, Jennifer N; Buzsáki, György (2017) Learning-enhanced coupling between ripple oscillations in association cortices and hippocampus. Science 358:369-372
Roux, Lisa; Hu, Bo; Eichler, Ronny et al. (2017) Sharp wave ripples during learning stabilize the hippocampal spatial map. Nat Neurosci 20:845-853
Peyrache, Adrien; Schieferstein, Natalie; Buzsáki, Gyorgy (2017) Transformation of the head-direction signal into a spatial code. Nat Commun 8:1752

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