Oscillatory network dynamics provide an intermediate phenotype that, in some human imaging studies, has proven to be a more fruitful correlation target than behavioral measures for identifying genetic biomarkers of psychiatric disorders. Using rodent models, we propose to study oscillatory long-range synchronization and its alterations in schizophrenia, as well as disturbances in developmental trajectories of oscillatory networks from adolescence to adulthood. The primary focus is the impaired rhythmic coordination between activities in the hippocampus (HC) and prefrontal cortex (PFC) which is particularly important for specific cognitive functions in the adult and was also shown to play an important role in early neurodevelopment. Abnormal functional connectivity between HC and PFC has been demonstrated in schizophrenic patients and in chronic animal models of schizophrenia. Since pathological alterations of the key elements of neuronal oscillatory networks are present in both HC and PFC, impaired cortico-hippocampal synchronization can originate from the pathology of either or both structures. We propose to examine this issue using a novel approach that can precisely define the spatial distribution of rhythmic generators and quantify their interactions, including the essential directional influences. We will systematically investigate the spectral structure, the anatomy, physiology, and pharmacology of these interactions in normal rats and in pharmacological models of schizophrenia. We further hypothesize that impaired oscillations also adversely affect the maturation of cortical networks and their long-range connections. Understanding the ontogeny of temporal dynamics and their control is a severe gap area in the field, because oscillations are critical for normal cognition ad seem to be impaired not just in schizophrenia, but also in autism, and other mental illnesses. Thus we will also investigate the normal development of HC-PFC relationship through adolescence and early adulthood and its pathological alterations in a neurodevelopmental model of schizophrenia using daily electrophysiological recordings; such a longitudinal design has not been attempted in prior studies.
Specific Aim 1 is to establish the pattern of PFC- HC interactions including directional information. We propose that long-range influences synchronizing neuronal activity and gamma oscillations between HC and PFC are active in both directions, with an overall HC dominance. We will investigate the anatomical substrate of these bidirectional interactions and their role in a cognitive task which requires dynamic PFC-HC coupling.
Specific Aim 2 is to examine the impaired PFC-HC interactions in pharmacological models of schizophrenia using NMDA receptor antagonists and dopamine D4 receptor agonists which, besides schizophrenia-relevant symptoms, are known to significantly alter brain oscillations and to reduce performance on cognitive tasks requiring functional PFC and HC networks.
Specific Aim 3 is to define how oscillation networks develop through the periadolescent period in normal rats and in a neurodevelopmental model of schizophrenia. We propose a longitudinal study to investigate how the adult pattern of oscillatory synchronization develops and when and how the developmental trajectories in the schizophrenia model diverge from normal.

Public Health Relevance

Treatment-resistant cognitive impairment of schizophrenics is a major public health issue. Using recently developed innovative analysis techniques, this study will investigate the mechanism of how schizophrenia- relevant structural abnormalities in the cortical microcircuitry lead to deficits in long-range communication between different cortical and hippocampal regions. This research will also determine how this will affect cognition and neurodevelopment during adolescence and early adulthood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH100820-04
Application #
9261599
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Buhring, Bettina D
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
4
Fiscal Year
2017
Total Cost
$374,220
Indirect Cost
$113,220
Name
Beth Israel Deaconess Medical Center
Department
Type
Independent Hospitals
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Pittman-Polletta, Benjamin; Hu, Kun; Kocsis, Bernat (2018) Subunit-specific NMDAR antagonism dissociates schizophrenia subtype-relevant oscillopathies associated with frontal hypofunction and hippocampal hyperfunction. Sci Rep 8:11588
Dhamala, Mukesh; Liang, Hualou; Bressler, Steven L et al. (2018) Granger-Geweke causality: Estimation and interpretation. Neuroimage 175:460-463
Kocsis, Bernat; Pittman-Polletta, Benjamin R; Roy, Alexis (2018) Respiration-coupled rhythms in prefrontal cortex: beyond if, to when, how, and why. Brain Struct Funct 223:11-16
Kang, Daesung; Ding, Mingzhou; Topchiy, Irina et al. (2017) Reciprocal Interactions between Medial Septum and Hippocampus in Theta Generation: Granger Causality Decomposition of Mixed Spike-Field Recordings. Front Neuroanat 11:120
Roy, Alexis; Svensson, Frans Pettersson; Mazeh, Amna et al. (2017) Prefrontal-hippocampal coupling by theta rhythm and by 2-5 Hz oscillation in the delta band: The role of the nucleus reuniens of the thalamus. Brain Struct Funct 222:2819-2830
Kim, Bowon; Kocsis, Bernat; Hwang, Eunjin et al. (2017) Differential modulation of global and local neural oscillations in REM sleep by homeostatic sleep regulation. Proc Natl Acad Sci U S A 114:E1727-E1736
Kocsis, Bernat (2016) NEUROSCIENCE. REMembering what you learned. Science 352:770-1
Trongnetrpunya, Amy; Nandi, Bijurika; Kang, Daesung et al. (2015) Assessing Granger Causality in Electrophysiological Data: Removing the Adverse Effects of Common Signals via Bipolar Derivations. Front Syst Neurosci 9:189
Kim, Tae; Thankachan, Stephen; McKenna, James T et al. (2015) Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc Natl Acad Sci U S A 112:3535-40
Pittman-Polletta, Benjamin R; Kocsis, Bernat; Vijayan, Sujith et al. (2015) Brain rhythms connect impaired inhibition to altered cognition in schizophrenia. Biol Psychiatry 77:1020-30

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