1992 — 2012 |
Moghaddam, Bita |
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. R29Activity Code Description: Undocumented code - click on the grant title for more information. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Neurochemical Effects of Antipsychotic Drugs @ University of Pittsburgh At Pittsburgh
The overarching aim of thisgrant is to examine the role of glutamatergic neurotransmission,in particular that ofjgiutamatergic efferents rom the prefrontal cortex (RFC), in the functional abnormalities that may be ¿elated to schizophrenia.One of our key findings during the past funding period has been that NMDA receptor hypofunction in b having animals increases the firing of RFC pyramidal cells consistent with the idea that cortical GABAint irneurons have a high level of NMDA tonic activation that drives the pyramidal neurons. Based on this progress, it is hypothesized that NMDA receptor hypofunction reduces the inhibitory influence of GABA interneurons on cortical pyramidal cells producing a tonic state of disinhibition at these neurons. We predict that tr is reduced inhibitory control (1) diminishes the capacity of RFC neurons to fire appropriately to task relevant stimuli, and (2) exaggeratesthe phasic impact of glutamate afferentson some pyramidal neurons leading to abnormal activity of RFC projections to dopamine cells resulting in excess dopamine release.The first prediction assumes a constant state of aberration, consistentwithsustained cognitive deficits in schizof: hrenia. The second prediction assumes interrupted changes in dopamine release th^t occur in response to p lasic activationof afferents from regions such as the thalamus and habenula consistent with episodic incidents of psychosis in schizophrenia. We further hypothesize that events at the excitatory afferent-GABAsynapse in the RFC are key for discovering drug targetsthat normalize the impact of jthe reduced inhibitory central on RFC efferents and, hence, may be useful for treatment of schizophrenia. We propose to test these hypotheses using ensemble recording and mierodialysis in behaving rodents. Public health relevance schizophrenia is a major public health concern. This project seeks to develop anew understanding of the pathophysiology of schizophrenia and evaluate novel treatment options for treatment of this disorder.
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1998 — 2002 |
Moghaddam, Bita |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Glutamatergic Mechanisms in Cognition and Psychosis |
0.97 |
1999 — 2003 |
Moghaddam, Bita |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Glutamate and Prefrontal Cortex Function
A plethora of evidence has implicated the improper functioning of the prefrontal cortex in the pathophysiology of schizophrenia. While numerous findings have described a role for monoaminergic and cholinergic projections to the prefrontal cortex in the cognitive functions associated with this region, the extent of the involvement of the most prevalent prefrontal cortex afferents, namely those projections that contain glutamate as their neurotransmitter, in mnemonic, attentional, and other associative functions of the prefrontal cortex has not been well characterized. Considering that a number of recent findings are suggestive of glutamatergic abnormalities in schizophrenia, it is imperative that more be learned about the role of glutamate receptors in cognitive functions that are relevant to schizophrenic symptomatology. The research proposed in this request for an Independent Scientist Award (K02) involves characterizing the contribution of glutamate receptors in regulating those associative functions of the prefrontal cortex that are relevant to the pathophysiology of schizophrenia. This award will allow the applicant to devote maximal effort to the above research objectives which entails receiving appropriate training in order to establish in her laboratory behavioral paradigms that have direct relevance to different aspects of the cognitive dysfunctions associated with schizophrenia and that are analogous to clinical tests at which patients with schizophrenia show an impairment. Considering that the present mode of therapy for schizophrenia, i.e., treatment with antidopaminergic drugs, does not effectively treat cognitive deficits associated with this disorder, an understanding of the neurochemical basis of associative functions of the prefrontal cortex will help in the development of novel pharmacotherapeutic strategies for the treatment of schizophrenia.
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1999 |
Moghaddam, Bita |
F33Activity Code Description: To provide opportunities for experienced scientists to make major changes in the direction of research careers, to broaden scientific background, to acquire new research capabilities, to enlarge command of an allied research field, or to take time from regular professional responsibilities for the purpose of increasing capabilities to engage in health-related research. |
Glutamate Neurotransmission and Attention @ University of Cambridge
behavioral /social science research tag; prefrontal lobe /cortex
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0.958 |
2001 — 2003 |
Moghaddam, Bita |
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.) |
Translational Studies On Cognitive Flexibility
DESCRIPTION (provided by applicant): Cognitive disorganization is a fundamental aspect of the psychopathology of schizophrenia, contributing to the overall morbidity of the disease process and greatly impacting outcome. Current antipsychotic medications have minimal beneficial effects on cognitive deficits of schizophrenia, and design of novel treatments is contingent upon translational research that will lead to a better understanding of the neural basis of these deficits. However, feasibility of such translational studies has been limited, primarily because of the scarcity of cognitive tasks for laboratory animals that assess similar cognitive constructs as those assessed in the routinely used clinical test paradigms. One such construct is "behavioral flexibility" or attentional set-shifting, which is assessed commonly in patients with schizophrenia using the Wisconsin Card Sort Test (WCST). While the limited cognitive capacity of laboratory animals, in particular rodents, hinders the design of cognitive tasks that would be considered entirely "analogous" to complex tasks such as the WCST, it is possible to design behavioral paradigms that can evaluate cognitive constructs that are "comparable" to those measured in many clinical test paradigms. However, while studies with laboratory animals have primarily relied on validating a task based on "theoretical homology" with human tasks, to carry out clinically relevant mechanistic studies, we believe, it is crucial that "functional homology" also be established. The principal aim of this application is to initiate collaborations between basic and clinical researchers and work toward standardizing quantitative measures that can be used to establish functional homology between human and animal cognitive tasks that are relevant to schizophrenia. The initial aspect of this collaboration will involve the use of parallel basic and clinical quantitative measures to establish the construct validity of a newly developed rodent task that has theoretical homology with WCST. Specific aims are designed to characterize the structural and neurochemical homology between these tasks.
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2003 |
Moghaddam, Bita |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Glumate and Disorders of Cognition and Motivation @ New York Academy of Sciences
DESCRIPTION (provided by applicant): Although glutamate-mediated neurotransmission has long been implicated in neurodegenerative disorders, the major focus of research on cognitive, affective and addictive disorders has been on monoamine(dopamine, serotonin, norepinephrine) systems in the brain. Because of glutamate's importance in cortical function, and because glutamatergic projections govern the activity of monoaminergic neurons, studies on the possible role of glutamate in affective and addictive disorders began 10-15 years and have led to significant advances in our understanding of glutamatergic involvement in these disorders. The New York Academy of Sciences is sponsoring a 2.5 day conference, scheduled for April 13-15, 2003, in New Haven, CT, titled "Glutamate and Disorders of Cognition and Motivation" The objective is to bring together diverse groups of basic and clinical researchers who study the role of glutamate in cognitive disorders such as schizophrenia, and disorders relating to motivation and affect, such as depression and addiction. This conference will provide a venue for presentation of cutting edge research in both basic and clinical fields. By facilitating interactions between basic scientists and clinicians, it may accelerate the rate at which advances in our knowledge of basic mechanisms can be translated into development of new pharmacotherapies. The conference will be organized in six sessions. The first session will review recent advances in basic aspects of glutamate-mediated signaling and present anatomical, electrophysiological and signal transduction perspectives on interactions between monoamine systems, long the focus of research on psychiatric disorders, and glutamate systems. The next four sessions will be organized around specific disorders. The meeting will close with a session on glutamate-based pharmacotherapies for disorders ranging from schizophrenia to addiction. In addition to the plenary sessions, poster sessions will be held on two afternoons.
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0.925 |
2008 — 2009 |
Moghaddam, Bita |
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.) |
Cannabinoid Approaches For Treatment of Tourette's Syndrome @ University of Pittsburgh At Pittsburgh
[unreadable] DESCRIPTION (provided by applicant): Neuroleptics remain the primary mode of treatment for Tourette's syndrome (TS). However, these drugs have profound side effects including dysphoria, cognitive deficits, and tardive dyskinesia. Recent randomized double- blind placebo-controlled clinical trials have shown that delta-9-tetrahdrocannabinol (THC) reduces symptoms of TS. These findings substantiate numerous anecdotal reports in the last several decades indicating that cannabis ameliorates some symptoms of TS and suggest that activation of cannabinoid neurotransmission is a plausible treatment strategy for treatment of TS. Treatment of TS with THC, however, is not a feasible option because of abuse-related concerns. Other pharmacological approaches that directly activate cannabinoid receptors in the brain are also problematic because the CB1 receptor, the primary cannabinoid receptor in the brain, becomes desensitized by direct exogenous agonist activation. Another foreseeable problem with targeting cannabinoid neurotransmission for treatment of TS is that this disorder is manifested during adolescence. Exposure to cannabis during this period has been linked to long-term adverse cognitive effects and increased propensity to develop other psychiatric disorders. The aim of this proposal is to explore the feasibility of an alternative approach to enhance cannabinoid neurotransmission for treatment of TS which may not be associated with the aforementioned shortcomings. The approach involves manipulating levels of endogenous cannabinoids (eCB) anandemide and 2-AG by either reducing their hydrolysis or rate of uptake. Several brain permeable compounds have been recently described as effective pharmacological tools for blocking eCB transporter and anandamide hydrolysis. We propose to (1) explore the effectiveness of these agents in reversing tic-like behaviors in several animal models of TS in both adult and adolescent rats and, (2) determine the effect of repeated exposure to these compounds in early adolescent rats on cognitive and affective functioning in late adolescent and adult rats. It is anticipated that the results of these studies will, in addition to exploring the feasibly of a novel treatment approach for TS, provide the basis for future mechanistic studies on the role of eCB in regulating motor and cognitive functions during normal development and in disease states. Relevance to public health: Drugs used presently to treat Tourette's syndrome are minimally effective or have profound side effects. This preclinical proposal aims to complete exploratory studies to determine the feasibility and safety of a novel treatment option for this childhood neuropsychiatric disorder. [unreadable] [unreadable] [unreadable]
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2009 — 2017 |
Moghaddam, Bita |
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. |
Inhibitory Control of Prefrontal Cortex @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): Prefrontal cortex (PFC) dysfunction is a fundamental aspect of the pathophysiology of schizophrenia. Understanding the mechanisms that contribute to this dysfunction has been hindered by the scarcity of animal models that study the relationship between specific clinical features of the illness and PFC pathology in dynamic and behaviorally relevant contexts. Many studies of this relationship in humans have focused on altered metabolic activation of dorsal regions of prefrontal cortex (PFC) which provide mechanistically vague measures because they primarily provide an index of presynaptic activity, independent of whether this presynaptic activity results in postsynaptic excitation, inhibition, or modulation. Thus, translating the findings of human imaging studies to electrophysiological and other mechanistic studies in laboratory animals has been difficult. In the past few years, two separate lines of evidence have begun to provide clues about the mechanisms that may contribute to the dysfunction of PFC in schizophrenia. These include static measures in postmortem tissue showing reductions in the markers of GABA synthesis and dynamic measures in behaving individuals that report abnormal oscillatory neuronal activity during behavioral engagement in individuals with schizophrenia. Although these findings have been theoretically linked, there is no clear evidence that reduced GABA synthesis in the PFC is a potential cause of impaired oscillatory activity and cortical dysfunction. The overarching aim of this project is to establish a relationship between reduced GABA synthesis in the PFC, disruptions in oscillatory activity of PFC neurons, and cognitive functioning. Using ensemble recordings and pharmacological manipulations in rats engaged in cognitive tasks dependent on the functional integrity of PFC we will address two specific hypotheses: (1) that reduced GABA synthesis in the PFC impairs cognitive functioning and disrupts the dynamics of neuronal activity in this region by reducing GABA availability and (2) that this disruption occurs at multi- scale levels meaning that we will observe changes in single neuron and neuron-pair interactions, local field potential (LFP) oscillations, and phase synchrony between single units and LFP oscillations.
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2012 — 2013 |
Moghaddam, Bita |
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.) |
Fatty Acids and Preclinical Models of Psychiatric Disorders @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): Deficiency in dietary intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) negatively impacts cognitive and affective functioning. A plethora of psychopathology literature also implicates n-3 PUFA deficiency in psychiatric disorders, including mood disorders and schizophrenia. Thus, defining potential neuronal mechanisms that link n-3 PUFA levels to behavioral deficits has important implications for basic neuroscience, as well as for public health, given that the trend of the modern diet has been toward reduced n-3 PUFA intake. The overarching objective of this exploratory R21 application is to move a field, which is becoming increasingly relevant to mental health, forward from the phenomenological stage to delineating brain mechanisms. We propose to use a rodent model to gain mechanistic understanding of the impact of n-3 PUFA deficiency and supplementation on coordinated neuronal activity of the prefrontal cortex (PFC) and ventral striatum (vStr) of adolescent rats. We have found subtle behavioral impairments in n-3 PUFA deficient adolescent rats, suggestive of disrupted motivational and attentional processing. Electrophysiological recordings of single unit activity and local field potentials (LFPs) in PFC subregions and vStr of behaviorally engaged adolescent rats will be made during a reward driven learning task to address two hypotheses: (1) n-3 PUFA deficiency disrupts the dynamics of neuronal activity in the PFC and ventral striatum in response to salient task relevant events, (2) These cellular disruptions are ameliorated with n-3 PUFA supplementation. It is anticipated that the results of these studies will increase our mechanistic understanding of the functional circuitry that influences the behavioral effects of n-3 PUFA deficiency and supplementation. PUBLIC HEALTH RELEVANCE: Through the use of animal models and innovative methodology, this project will increase our mechanistic understanding of how omega -3 supplementation may serve as protective intervention in individuals with psychiatric disease vulnerability.
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2013 — 2017 |
Moghaddam, Bita |
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. |
Neurochemical Basis of Antipsychotic Drugs @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): The overarching aim of this grant from its inception in 1990 has been to use animal models to gain a better understanding of neuronal systems that may be dysfunctional in schizophrenia. The neuronal networks that we have focused on have included dopamine innervated regions, and the glutamatergic regulation of these regions. While studies supported by this grant and work by others have provided a number of potential novel targets for treating schizophrenia, the enthusiasm that we will discover treatments that will cure or even provide far more superior efficacy than current antipsychotic medications has been dampened by our increased appreciation of the complexity of genetic and non-genetic causes of schizophrenia. It is increasingly evident that, by the time the illness presents itself, he damage (the miswiring resulting in functional lesions) may be irreversible. Thus, one of our best chances for treating this illness is to prevent its progression. Specifically, the clinical fild has advanced toward identifying individuals at the prodromal phase of the illness who are at high risk for psychosis, the great majority of whom are adolescents or young adults, with the hope that appropriate interventions in these individuals will prevent transition to the psychotic illness. The efforts to design safe and mechanistically driven interventions, however, are hampered seriously by our poor knowledge of the neurobiology of the adolescent brain. The overarching aim of this application is to gain a better functional understanding of neuronal systems that may be relevant to adolescent vulnerability to develop schizophrenia. The experimental design is guided by complementary clinical findings in individuals at-risk (AR) for schizophrenia and our own basic findings in adolescent rats. Human imaging findings in AR individuals report that the onset of psychosis is preceded by abnormal presynaptic dopamine activity in the associational as opposed to ventral regions of striatum, and that this measure correlates with altered prefrontal cortex (PFC) function. Our animal studies identify key differences in presynaptic dopamine activity in the dorsal striatum, and in the processing of salient information in the dorsal striatum and PFC of adolescent compared to adult rats. Collectively, these parallel findings suggest that the disruption of cortical networks that regulat dopamine projections to cortical and dorsal regions of the striatum may be relevant to increased vulnerability to transition to psychosis. Given this, we propose the working hypothesis that midbrain dopamine systems, and their interactions with striatal and PFC areas, are regulated differently in adolescents compared to adults. We address this hypothesis at multiple levels of analysis by using state-of-the-art methods to compare local and global functions of dopamine neurons in adolescents and adult rats. Regardless of the outcome, the data generated by the proposed experiments will inform us about brain circuits that subserve affective and cognitive behaviors in adolescents, and will provide a platform for future investigations toward intervention strategies in AR individuals.
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2018 — 2021 |
Moghaddam, Bita |
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. |
Reward Encoding and Anxiety @ Oregon Health & Science University
PROJECT SUMMARY/ABSTRACT Anxiety is a debilitating symptom of most psychiatric disorders including PTSD, major depression, schizophrenia, autism and addiction. Treatment of anxiety is mostly limited to benzodiazepines, which have abuse potential and produce multiple cognitive and behavioral side effects, including increased propensity to develop dementia. Design of alternative treatments or prevention strategies is contingent upon a better understanding of the neuronal basis of anxiety. While animal studies have so far informed us about the functional neuroanatomy of fear and anxiety, the negative impact of real-life anxiety extends beyond aversive feelings and involves disruptions in ongoing goal-directed behaviors. For example, anxiety is associated with deficits in flexible control of reward-driven actions and expression of motivated behavior when it is subject to the risk of an aversive outcome. The neural basis of these behavioral deficits is largely unknown. Thus, the overarching research question that drives the experimental aims of this application is: How does anxiety affect neuronal encoding of goal-directed behaviors? To address this question, a major challenge of the experimental approach is to create a background state of anxiety that does not prohibit animals to perform goal-oriented and rewarded tasks during electrophysiological recordings from multiple regions. With this in mind, we propose to use two complementary experimental models of anxiety in combination with innovative and clinically relevant behavioral tasks while measuring dynamic coordination between neurons of two regions implicated in reward processing and flexible control of behavior: ventral tegmental area (VTA) and dorsomedial prefrontal cortex (dmPFC). Specific aims are designed based on a computational-style model with assumptions that are supported by preliminary data: (1) behavioral differences (between control and anxiety states) are specific to conditions that involve action selection under conflict or the risk of an aversive outcome; (2) differences (between control and anxiety states) in neuronal activity are observed during conflict/aversive outcomes and involve diminished recruitment of action encoding neurons in dmPFC and disrupted coordination between dmPFC neural activity and VTA dopamine neurons. This approach is novel and significant because a neurocomputational understanding of aberrant neural activity relevant to symptoms such as anxiety can help identify biological markers and clinical measures that delineate etiology and physiology of those symptoms.
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