High-level neural functions, including perception, cognition, and memory, rely on the coordinated activity of at least thousands of cortical neurons. The synchronized neuronal activity of large cortical cell assemblies results in electrical oscillations in electroencephalographic records and in local field potentials. Psychiatric, neurological, and neurodegenerative diseases, including schizophrenia, epilepsy, and Alzheimer's disease are characterized by a change in oscillatory timing and patterns. However, it is currently not known which therapeutic interventions could restore temporal control of neural circuits to achieve improvements in cognitive function. It has been suggested that the hippocampal theta rhythm provides temporal control for neuronal firing patterns that support memory processes, but this can only be tested if theta oscillations can be controlled with high temporal precision. We therefore propose to use the temporal precision of optogenetic inactivation techniques in neural circuits for theta generation to test the hypothesis that theta oscillations provide temporal coordination for hippocampal neurons during memory encoding and retrieval. We will test this hypothesis in two aims.
The first aim i s to attain precise tempora control of the theta rhythm and the second aim is to use temporally precise disruption to determine whether the coordination of hippocampal spike timing by theta oscillations is required during memory acquisition, retention, or retrieval. For both aims, we will infuse AAV9-Arch3.0-EYFP or AAV9-ArchT3.0-EYFP into medial septum and place recording electrodes in the hippocampus and/or the medial entorhinal cortex of rats. AAV9 was selected as a viral vector because it provides widespread infection of brain tissue, and Arch3.0 and ArchT3.0 were selected as opsins because they are effective light-induced inhibitors of neuronal activity. After recovery from surgery, rats will, for aim 1, be trained to continuously run on a track or randomly forage. Behaviorally relevant illumination protocols will be used to determine the effects of oscillating and discrete light pulses in the septal area on hippocampal theta oscillations. For all protocols, the analysis will focus on changes in the amplitude and frequency of theta oscillations and also on the effect of theta/gamma coupling.
For aim 2, rats will be trained on a figure-eight delayed spatial alternation task with distinct encoding, retrieval, and retention phases. On separate days, light pulses will be delivered during one of these phases to determine when theta oscillations are required. For light- stimulation protocols that disrupt behavioral performance, we will examine the changes in the spike timing of hippocampal cells during decreased memory performance. By using temporally precise inactivation of a pacemaker for oscillations, the proposed aims will determine which phases of a memory task require oscillatory neural activity and to what extent the precisely timed neural activity in hippocampus is required for memory processes. Because electrical stimulation paradigms can also be effective by inhibiting ongoing neuronal activity, these experiments will provide new insight for the therapeutic use of deep brain stimulation.

Public Health Relevance

High-level neural functions, including perception, cognition, and memory, rely on the coordinated activity of at least thousands of neurons. Many studies have now demonstrated that brain oscillations emerge when the spike timing of cell assemblies in high-level cortical areas becomes synchronized. Psychiatric, neurological, and neurodegenerative diseases are characterized by a change in oscillatory timing and patterns. Success in treating the underlying dysfunction might be coupled to the extent to which healthy oscillatory activity, and thus the function of large cell assemblies, can be restored. An understanding of mechanisms that generate oscillations and of how they support cognitive function is therefore needed. By using temporally precise inactivation of a pacemaker for oscillations, the proposed aims will determine which phases of a memory task require oscillatory neural activity and to what extent the precisely timed neural activity in hippocampus is required for memory processes. Because standard electrical stimulation paradigms can also be effective by inhibiting ongoing neuronal activity, these experiments will provide new insight for the therapeutic use of deep brain stimulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH100354-02
Application #
8641434
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Osborn, Bettina D
Project Start
2013-04-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$181,969
Indirect Cost
$56,969
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sasaki, Takuya; Leutgeb, Stefan; Leutgeb, Jill K (2015) Spatial and memory circuits in the medial entorhinal cortex. Curr Opin Neurobiol 32:16-23
Brandon, Mark P; Koenig, Julie; Leutgeb, Jill K et al. (2014) New and distinct hippocampal place codes are generated in a new environment during septal inactivation. Neuron 82:789-96
Brandon, Mark P; Koenig, Julie; Leutgeb, Stefan (2014) Parallel and convergent processing in grid cell, head-direction cell, boundary cell, and place cell networks. Wiley Interdiscip Rev Cogn Sci 5:207-219