1997 — 2012 |
O'donnell, Patricio |
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. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Electrophysiology of the Prefrontal Cortex
DESCRIPTION (Adapted from applicant's abstract): The interactions among the prefrontal cortex, hippocampus and dopaminergic systems are thought to play a role in schizophrenia. However, the nature of such interactions from a physiological perspective are not yet fully understood. Establishing how a hippocampal deficit impacts on physiological measures of prefrontal neuron activity and how dopamine modulates these interactions may provide a significant contribution towards establishing a comprehensive animal model of this devastating disorder. In this proposal, plans are presented to assess the impact of a number of manipulations in the hippocampal afferents to prefrontal cortical neurons intracellularly recorded in vivo: 1) determining the input responsible for the transitions to the active periods in prefrontal cortical neurons exhibiting a slow oscillation in their membrane potential and cell firing; 2) establishing the role of hippocampal afferents on such oscillations and their source input by assessing the effects of hippocampal stimulation and by performing similar experiments in animals with a hippocampal lesion; 3) assessing the effects of a neonatal hippocampal lesion on these interactions in adult animals as an initial attempt of testing the hypothesis of a developmental hippocampal disturbance resulting in hypofrontality; 4) testing the effects of rearing animals in social isolation on these interactions, with the aim to determine the actions of an environmentally-induced brain deficit that in many respects exhibits alterations resembling schizophrenia; and, 5) determining the glutamate receptor subtype involved in hippocampal-prefrontal interactions by studying the actions of glutamate receptor agonists and antagonists on synaptic responses in prefrontal cortical cells recorded in vivo.
|
0.972 |
2001 — 2005 |
O'donnell, Patricio |
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. |
Electrophysiology of Behavioral Sensitization
DESCRIPTION (provided by applicant): The dopaminergic projection to the nucleus accumbens and prefrontal cortex has been implicated in the mechanisms leading to drug abuse. Upon repeated administration of psychostimulants (i.e., cocaine, d-amphetamine, methamphetamine), animals typically exhibit increased behavioral activation when given a challenge stimulant dose; this phenomenon has been termed "behavioral sensitization" and it has been related to the increased responses addicted subjects exhibit upon repeated drug intake, particularly to the craving for drug upon withdrawal. Our plan is to explore the brain regions involved in the establishment and expression of such sensitization using electrophysiological techniques. The current views on the mechanisms evoking and expressing sensitization have been built upon several separate studies. The expression of behavioral sensitization, for example, involves the activation of dopamine projections to the nucleus accumbens. On the other hand, the glutamatergic projection from the prefrontal cortex to the ventral tegmental area (the group of cells from which the dopamine projection to the accumbens originates) is required to elicit sensitization. We have been studying the interactions among the prefrontal cortex, nucleus accumbens and ventral tegmental area from a physiological perspective. These regions exhibit mutual interactions that control their information processing; therefore, we hypothesize that such interactions would be altered in sensitized animals. Recording the electrical activity of these neurons simultaneously is an optimal means to address the role of such interactions in the induction and/or expression of behavioral sensitization. In vivo intracellular recordings will be employed to assess changes upon repeated administration of methamphetamine. Methamphetamine was chosen as the sensitizing agent given its recent growth as an abused substance in the U.S.
|
0.906 |
2001 — 2012 |
O'donnell, Patricio |
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. |
Information Processing in the Nucleus Accumbens @ University of Maryland Baltimore
DESCRIPTION (provided by applicant): The nucleus accumbens is a brain region with an important role in processing reward information and the selection of behaviors appropriate to the context. It has been proposed that one mechanism by which context guides response selection in the nucleus accumbens is via a synaptic interaction that has been characterized as a gating mechanism; hippocampal inputs are believed to be necessary for other inputs to drive action potential firing in the nucleus accumbens. Although the gating hypothesis has received further support from several studies, novel data indicate that the nucleus accumbens could disengage from its hippocampal inputs and follow prefrontal activity during epochs in which selection of a behavior is required. We proposed that the nucleus accumbens can behave a switchboard where response selection takes place by the interactions among multiple afferents. Here we will test whether the integration of information in the nucleus accumbens is critical for decision-making and selection of the appropriate behavioral response to a given context using multichannel recordings (simultaneously from the prefrontal cortex, hippocampus and nucleus accumbens) in two different operant tasks. Furthermore, we will explore the synaptic mechanisms underlying these interactions with in vivo intracellular recordings and whole cell recordings in accumbens slices, aimed at testing whether strong prefrontal afferent activation can attenuate the impact of hippocampal afferents and whether this interaction is dependent on local GABA or dopamine. Unveiling the cellular and synaptic processes responsible for response selection in the nucleus accumbens would advance our understanding of this critical function and pave the way to novel views on the pathophysiology of neuropsychiatric disorders, including schizophrenia, and perhaps eventually seek novel therapeutic approaches. PUBLIC HEALTH RELEVANCE: This project will test whether the integration of information in the nucleus accumbens is critical for decision-making and selection of the appropriate behavioral response to a given context. In particular, we will assess the manner activity in the prefrontal cortex affects the influence exerted by the hippocampus on nucleus accumbens electrical activity and the behaviors that depend on it. Such integration of information in this critical brain region is important for understanding decision making and response selection and gaining an understanding of its mechanism will helps us develop better models to explain mental disorders.
|
0.972 |
2003 — 2005 |
O'donnell, Patricio |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Cortical Control of Striatal Cell Activity @ University of Maryland Baltimore
DESCRIPTION (provided by applicant) Schizophrenia, Parkinson's disease, Tourette's syndrome, obsessive-compulsive disorder and drug addiction, are only some of the relevant clinical conditions that have been related to dysfunction of brain dopamine systems and abnormal processing of cortical input in the striatum. The robust membrane potential depolarizations ("up states") during which striatal neurons become responsive to the fine structure of cortical input, are synaptically-driven events invoked by the cortex itself and probably shaped by dopamine-regulated membrane currents. The suggestion that the striatum behaves as an "action selection" network, raised interest in understanding how dynamic patterns of cortical activity are represented in the striatum and how this representation is modified by changes in dopamine neurotransmission. By simultaneously recording the population activity of cortical neurons and the membrane potential of striatal neurons, we have recently clarified some aspects of the temporal dynamics of up states. In this proposal, we plan to analyze the representation of spatial variations of cortical activity on striatal neurons by recording field potentials and multiunit activity from multiple cortical sites together with the membrane potential of striatal neurons in anesthetized rats. Our main goal is to understand how spatially-distributed and dynamically-changing patterns of cortical activity are reflected in the membrane potential (as an index of synaptic input) and firing pattern (as an index of neuronal output) of striatal neurons. Furthermore, we will investigate the impact of cortical activity on striatal neurons in genetically-modified mice lacking functional D1 or D2 dopamine receptors. This research will be done primarily in Argentina, at the Buenos Aires University School of Medicine, in collaboration with M. Gustavo Murer, as an extension of NIH grant # R01MH060131.
|
0.972 |
2004 — 2007 |
O'donnell, Patricio |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Us-France Cooperative Research: Electrophysiological Studies of Dopamine in the Dorsal and Ventral Striatum @ Albany Medical College of Union University
0340577 O'Donnell
This three-year award supports U.S.-France cooperative research in neurosciences between Patricio O'Donnell of Albany Medical College and Francois Gonon of the Universite de Bordeaux II. The objective of their research is to study, under experimental conditions, the electrophysiological effects of endogenously released dopamine on striatal neurons and try to identify those neurons that are dopamine sensitive. The investigators will utilize electrophysiological recordings on identified striatal neurons and investigate in vivo the effects of endogenously released dopamine. The experimental conditions will attempt to mimic the physiological conditions.
The project will advance understanding of the natural processes involved in dopamine release, its impact on processes involved in physiological behavior. The U.S. and French investigators will share their complementary expertise in electrophysiological techniques (O'Donnell's group), electrochemical monitoring of dopamine release (Gonon's group) and anatomofunctional techniques (Gonon's group).
This project is jointly supported by the National Science Foundation (NSF) and the Centre National de la Recherche Scientifique (CNRS). NSF will cover the costs of visits to France by the U.S. investigator and his team. The CNRS provides support to the French team for visits to the United States.
|
0.966 |
2008 — 2012 |
O'donnell, Patricio |
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. |
Animal Model of Dual Diagnosis @ University of Maryland Baltimore
[unreadable] DESCRIPTION (provided by applicant): Dual-diagnosis in psychiatry refers to the co-existence of drug abuse with a psychiatric condition. This is quite prevalent in schizophrenia, where more than 50% of the patients abuse some type of drug. There is no agreement in the field regarding whether this is another symptom of the disease, due to a common involvement of the brain systems that are dysfunctional in schizophrenia, or an attempt at self-medication. As animal models of schizophrenia have become more refined, incorporating a developmental origin and environmental factors, it has become apparent that many of those animals have also enhanced liability for addictive behaviors. Animals with a neonatal ventral hippocampal lesion do exhibit increased self-administration of cocaine and methamphetamine. We will use this model to explore whether those animals' increased addiction can be described as self-medication or another manifestation of their condition. Also, we will use lesioned and sham animals to explore the cellular and synaptic mechanisms associated with the increased drive for cocaine these animals exhibit, combining behavioral assessments with electrophysiological studies in slices, in anesthetized animals and in awake, freely moving animals. The experiments are expected to shed some light onto why there is propensity for addictive behaviors when mesocorticolimbic circuits are dysfunctional (as likely occurring in schizophrenia and in animals with a neonatal hippocampal lesion), and may open avenues for newer therapeutic approaches for this extremely difficult to treat dual condition This project has the potential for unveiling mechanisms by underlying the increased drive for substance abuse that exists in patients with schizophrenia. It is widely known that schizophrenia patients have increased liability for drug abuse, and this is likely to emerge from an involvement of the reward brain circuits in the disorder or alternatively as an attempt at self-medication. We will conduct a series of experiments aimed at distinguishing these two possibilities in a well-established developmental animal model of schizophrenia. To understand the cellular and synaptic mechanisms in corticolimbic circuits that could contribute to an enhanced craving for drugs in brains with a developmental alteration in these circuits would advance our understanding of why there is a strong comorbidity between drug abuse and schizophrenia, and may result in the identification of potential targets for new therapeutic approaches. [unreadable] [unreadable] [unreadable]
|
0.972 |
2012 — 2013 |
Feldman, Ricardo A (co-PI) [⬀] Hong, L Elliot [⬀] O'donnell, Patricio |
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.) |
Cellular Electrophysiology of Nicotine Addiction Clinical Phenotypes @ University of Maryland Baltimore
DESCRIPTION (provided by applicant): Smoking remains the leading cause of preventable diseases and death in the US, and is known to be heritable. This application aims to develop a set of nicotine addiction cell lines based on clinically defined imaging phenotype and genotype. Our goal is to test that neuronal electrophysiological response to nicotinic agonists will be associated with the strength of the clinical imaging based circuit phenotype in patients with severe nicotine addiction and carry smoking related risk alleles. Our innovation here is to closely link these cell lines with state-of-the art clinical measures of nicotine addiction, so that we coud iteratively test electrophysiological phenotypes of the cells that are likely underlying key clinicl nicotine addiction measures. PUBLIC HEALTH RELEVANCE: Smoking remains the leading cause of preventable diseases and death in the US. This application aims to develop nicotine addiction cell lines based on clinically defined imaging phenotype and genotype. Our goal is to identify electrophysiological mechanisms underlying clinical nicotine addiction.
|
0.972 |