2009 — 2010 |
Kocsis, Bernat |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Interneuron Circuits and Brain Oscillations in Rat Models of Schizophrenia @ Beth Israel Deaconess Medical Center
DESCRIPTION (provided by applicant): The recent shift in the conceptualization of schizophrenia from errors in dopamine neurotransmission to core deficits in information processing gave rise to a new generation of animal models focusing on the neurodevelopmental aspects and on the role of other systems, such as NMDA and GABA. Importantly, these models exhibit the animal equivalents of schizophrenia-related neurocognitive deficits and show characteristic abnormalities in the organization of the GABAergic interneuron networks, specifically in the hippocampus and prefrontal cortex, reminiscent of those in schizophrenic patients. GABAergic interneurons are involved in the generation of brain oscillations which in turn are known to be critical for cognitive processes. Their alterations in schizophrenic patients were proposed to significantly contribute to the neurocognitive impairments characteristic for this disease. The proposed project will examine the mechanisms of oscillatory synchronization in these models in an attempt of finding a link between the structural changes and neurocognitive deficits. We hypothesize that pathologic alterations in the neuronal circuitry in chronic neurodevelopmental animal models of schizophrenia will result in impaired oscillatory synchronization in the hippocampus and prefrontal cortex which in turn contribute to the neurocognitive deficits. We will test the specific hypothesis that this impairment correlates with the extent of damage to the local GABAergic interneuron network and in particular with the loss of parvalbumin positive basket and chandelier cells. Neuronal synchronization in the hippocampus and prefrontal cortex will be tested in two animal models each exhibiting abnormalities reminiscent of the neurocognitive deficits of human schizophrenia and each showing involvement of GABAergic mechanisms and a reduction of parvalbumin positive interneurons. The two models represent chronic conditions but are produced by different interventions;one is a neurodevelopmental model, the other is drug-induced in adult rats and is based on systemic NMDA antagonism. Electrophysiological signals will be processed for detection and analysis of their rhythmic components (power spectra, phase, and coherence). The brains will be processed for immunohistological examination of the hippocampus, prefrontal cortex, and medial septum and the results of electrophysiology will be compared with the extent of the reduction in parvalbumin expressing interneurons. This work will increase our neuronal level understanding of the mechanisms of cognitive deficits in schizophrenia and may lead to new strategies for drug development. PUBLIC HEALTH RELEVANCE: Contemporary views of schizophrenia regard cognitive dysfunction as the primary core deficit due to dysfunction of neuronal microcircuits. Brain oscillations are known to be critical for cognitive processes and their alterations in schizophrenic patients were proposed to significantly contribute to the neurocognitive impairments characteristic for this disease. This project will examine the functioning of neuronal networks involved in cortical oscillations in neurodevelopmental animal models of schizophrenia in an attempt of finding a link between the structural changes and neurocognitive deficits and will thus increase our neuronal level understanding of the mechanisms of cognitive deficits in schizophrenia and will facilitate the development of new strategies for drug development.
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0.922 |
2010 — 2011 |
Kocsis, Bernat |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Information Flow in the Limbic Theta Circuit Revealed by Granger Causality @ Beth Israel Deaconess Medical Center
DESCRIPTION (provided by applicant): Theta behaviors in the hippocampus fall in several categories, e.g. movement related (Type 1), immobility related (Type 2), and REM sleep theta, with distinct layer specific current source distributions, different pharmacological features, and characteristic frequencies. The mechanism of the generation of theta at different frequencies is poorly understood but its strong association with different aspects of behavior (sensory-motor integration, sleep, etc.) indicates that subcortical structures play an essential role. A number of subcortical nuclei exhibit theta rhythmic neuronal activity synchronized with hippocampal oscillations and our goal is to identify the functional relationship among these structures and rhythmic activity in the hippocampus. The commonly used symmetrical methods of signal analysis have limited utilities in this regard as they could not provide information on causal influences. Thus the goal of the present R21 is to test the effectiveness of a newly proposed method called Granger causality on two subcortical structures generating theta in the hippocampus: medial septum (MS) and supramammillary nucleus (SUM). First (Specific Aim 1), we will validate the method in the context of the hippocampal network in two experiments;one in which the causal direction is known (using stimulation of input pathways and recording field potentials in their target layers of the hippocampus) and the other in which the causal direction comes from prior knowledge of the information flow along the classic hippocampal "three-synaptic circuit". Then, in Specific Aim 2, we will address the causal influence and directional driving of hippocampal theta by subcortical theta generators (SUM and MS) and test whether Granger causality can be a tool in hypothesis-driven investigation of this system. We hypothesize, in particular, that SUM involvement is limited to specific states, and thus expect to find significant directional drive from SUM to hippocampus associated with fast theta during waking exploration and phasic episodes of REM sleep but not during slow theta of waking immobility, and tonic REM sleep. On the other hand, we hypothesize that MS, providing a final common pathway for ascending drives from different sources, will show significant directional drive to the hippocampus in all theta states. PUBLIC HEALTH RELEVANCE: The mechanism of the generation of theta at different frequencies is poorly understood but its strong association with different aspects of behavior indicates that subcortical structures play an essential role. The goal of the present R21 is to test the effectiveness of a newly proposed method called Granger causality on two subcortical structures: medial septum (MS) and supramammillary nucleus (SUM).
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0.922 |
2010 — 2014 |
Kocsis, Bernat |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neuronal Control Mechanisms of the Ascending Sleep Arousal Pathway @ Beth Israel Deaconess Medical Center
Obstructive sleep apnea (OSA) is a common sleep disorder that is characterized by frequent arousals from sleep caused by the collapse of the upper ainway and resulting hypercarbia/hypoxemia. Frequent arousals from sleep interfere with the architecture of normal sleep, reduce deep sleep, and impair the restorative/ cognitive benefits of sleep. Despite the importance of preventing arousals from sleep in order to improve sleep quality for millions of Americans with OSA, very little is known about the neural control mechanisms that mediate arousals during OSA. Recent work using anatomical methods suggests that the brainstem glutamatergic neurons of the parabrachial complex (PB/PC), which receive visceral and respiratory input, are important for arousal during OSA via their projections to the basal forebrain (BF), a region containing cortically projecting &wakefulness promoting neurons. However, these findings have not yet been complemented by an essential element, the recording of neurons in this circuit. This project addresses this need by using tetrode/multiple single unit recordings of PB/PC and BF neurons during natural sleep cycles and during arousals from both slow wave sleep (non-REM sleep) and REM sleep provoked by hypercarbia, thus mimicking the stimuli from OSA. To model the arousals of sleep apnea, rats will be exposed to 10% carbon dioxide to awaken them from sleep. We hypothesize that the cortical activation seen in the arousals of sleep apnea is mediated by the projection from PB/PC to BF. Since PB neurons receive input about levels of carbon dioxide and respiratory effort, we predict that PB/PC neurons will exhibit an increase in discharge activity that precedes cortical activation when the arousals from sleep are produced by carbon dioxide, but not when the arousals are spontaneous, or induced by acoustic stimulation. Reversible muscimol inactivation of PB/PC will further test the role of PB/PC in arousals. We predict that all types of arousals from sleep &the accompanying cortical activation will correlate with the elevated discharge of BF wakefulness promoting neurons. This project's precise information on the timing of neuronal activation relative to hypercarbia will complement and enhance the other projects of this program project grant.
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0.922 |
2014 — 2018 |
Ding, Mingzhou Kocsis, Bernat |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Spatiotemporal Network Dynamics in a Rat Model of Schizophrenia @ Beth Israel Deaconess Medical Center
DESCRIPTION (provided by applicant): 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.
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0.922 |