2010 |
Chang, Wei-Li |
F30Activity Code Description: Individual fellowships for predoctoral training which leads to the combined M.D./Ph.D. degrees. |
D3 Dopamine Receptor Signaling in the Regulation of Startle Gating @ University of California San Diego
DESCRIPTION (provided by applicant): Virtually all approved medications for schizophrenia are mixed dopamine (DA) D2-family (D2, 3 and 4) receptor antagonists or partial agonists with limited - if any - preference for specific subtypes of D2-family receptors. Selective D3 antagonists may represent a novel class of antipsychotics that lack the major side effects of non- selective antagonists. One valuable, translational and predictive model for antipsychotic action is prepulse inhibition (PPI), an operational measure of sensorimotor gating, that is impaired in unmedicated schizophrenia patients. The long term goals of this application are to identify molecular targets for drug discovery and link in vivo and ex vivo assays of pharmacological treatments by characterizing the intracellular signaling pathways of D3 receptor activation that regulate sensorimotor gating. The first aim is to determine the behavioral effects of D3 receptor activation in the rat. Preferential D3 agonists such as pramipexole (PRA) PD128907, or 7-OH- DPAT will be administered alone or after either SB277,011, a D3-selective antagonist, or L741,626, a D2- selective antagonist. Agonist-induced changes in PPI and other behaviors will be measured, and the role of D2 vs. D3 receptors will be determined by their blockade with selective antagonists, and by comparison with the D2-selective agonist, sumanirole. Based on these data, the most D3-specific agonist and dose will be used for subsequent studies in Aim 2. The second aim is to determine the intracellular effects of D3 receptor activation in the rat. DA-linked signal transduction molecules in the nucleus accumbens (NAC) will be assayed for: GTP3S binding, adenylate cyclase activity, PKA activity, CREB phosporylation, c-fos expression, ERK1/2 activity, MSK1 activity, and Elk-1 levels. The order of assays will permit the most efficient assessment of the the targeted signal pathways. Signaling molecule levels will also be measured in the dorsal striatum for comparison. The third aim is to test the role of signaling molecules identified in Aim 2 in D3-mediated behavioral effects identified in Aim 1 by altering signaling cascade activity via intracerebral infusion of inhibitors or activators of the relevant pathways. An example appropriate for the cAMP/PKA pathway would involve intra- NAC infusion of Rp-cAMPS (a competitive inhibitor of cAMP binding) prior to PPI testing. An intervention "downstream" of either the cAMP/PKA or MAPK/ERK pathways would be involve intra-NAC infusion of CREB antisense oligonucleotide. Clarifying the divergence in signaling pathways that control D2- and D3-regulation of PPI has translational potential for guiding the development of novel inference-based antipsychotics. Furthermore, signaling molecules that mediate PPI deficits might be linked to the pathophysiology of schizophrenia and related disorders, and thus the proposed study would provide a physiological context for genes identified in neuropsychiatric genetic linkage studies. PUBLIC HEALTH RELEVANCE: Project Narrative Schizophrenia is a chronic, severe, debilitating brain disorder that affects about 1% of the population in the U.S. and worldwide, with symptoms usually beginning in early adulthood. We still have much to learn about this disorder, but promising new research linking changes in brain chemistry with severe symptoms may lead to improvements in care for schizophrenia patients, through the development of new medications with greater efficacy and fewer side effects. Through our studies, we hope to expand our understanding of biological systems related to schizophrenia and to apply these advancements directly towards improving the treatment options for patients.
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2020 — 2021 |
Chang, Wei-Li |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Early Life Stress Effects On Ventral Hippocampal Microcircuitry During Emotional Behaviors @ New York State Psychiatric Institute
I am a physician-scientist in psychiatry studying neural circuits involved in psychiatric illness using animal models that enable us to record and manipulate real-time neuronal activity with single-cell resolution. My career goal is to become an expert on developmental risk factors, microcircuit physiology, and emotional processing. This career development award will support my work to determine the impact of early life stress on ventral hippocampal microcircuitry and how this influences anxiety- and anhedonia-related behaviors in adulthood. Early life stress (ELS) increases the risk of adult psychiatric illnesses, so understanding how ELS affects the neural circuits controlling emotional behaviors would provide a mechanism for this increased vulnerability and point towards therapeutic targets. We can model ELS in rodents by inducing fragmented maternal care in the early postnatal period and then examine neural activity during anxiety-like and reward- seeking behaviors in adulthood. The ventral portion of the hippocampus is directly connected to both fear and reward circuits, and heavily involved in emotional processing. The balance between excitatory pyramidal cells and inhibitory interneurons in the hippocampus is important for controlling the flow of information to and from other regions of these circuits. ELS alters the development of interneurons and decreases excitatory and inhibitory synaptic density in the hippocampus. We do not yet know how ELS affects hippocampal excitatory and inhibitory cell activity in vivo and how these changes relate to observed behavioral differences. This proposal will address these questions through three Specific Aims. In Aim 1, I will test the hypothesis that altered anxiety-like behavior and decreased reward-seeking in adult mice after ELS are correlated with increased pyramidal cell activity in the CA1 output region of the ventral hippocampus (vCA1). In Aim 2, I will determine the effects of ELS on PV neurons in the vCA1 during development and adulthood. First, I will test the hypothesis that ELS decreases vCA1 PV cell activity during anxiety-like and reward behaviors. Then, I will test the hypothesis that precocious expression of PV in the hippocampus after ELS is associated with changes in global hippocampal neural activity in response to positive and negative stimuli. In Aim 3, I will test the hypothesis that inhibition of vCA1 PV cell activity in normally-reared adult mice can alter anxiety- and anhedonia-like behaviors. I will conduct this work within the New York State Psychiatric Institute and Columbia University under the mentorship of Drs. René Hen and Kevin Bath. The training objectives of this K08 are to become an expert in in vivo calcium imaging and optogenetic manipulations in freely moving mice, animal models for ELS and neurodevelopment, computational techniques for examining task-related representations in neural firing, and volume microscopy imaging with immunostaining. Upon completing these scientific aims and training objectives, I will be prepared to transition to the next phase of my career as an independent investigator directing a research group at an academic medical center.
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