Area:
Dopamine, Prefrontal Cortex, Working Memory
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High-probability grants
According to our matching algorithm, Jeremy K. Seamans is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2002 — 2006 |
Seamans, Jeremy K |
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. |
Fast and Slow Dopamine Signaling in Prefrontal Cortex @ Medical University of South Carolina
DESCRIPTION (provided by applicant): Dopamine (DA) neurons in the ventral tegmental area (VTA) are thought to encode an error prediction signal, in that the firing of DA neurons and release of DA may encode errors in predictions about rewards. In order for this to occur, DA release must be temporally precise to ensure that the errors in reward prediction provide information about the reward and the associated events that had just occurred. This theory assumes the VTA DA signal is fast acting and brief. This simple assumption has not been adequately tested, and evidence for fast DA signaling is in fact lacking. Within the prefrontal cortex (PFC) at least, both pre-and postsynaptic indicies of DA function in vivo or in vitro, suggest that DA signaling is slow in onset and slow to recover, and is therefore inconsistent with the properties required for an error prediction signal. On the other hand, although DA receptors are typically not ionotropic, in vivo intracellular recordings show that PFC neurons respond to VTA stimulation with a fast EPSP. Preliminary data suggest this EPSP has properties similar to glutamate mediated EPSPs, is blocked by destruction of DA cells in the VTA and peripheral administration of a glutamate antagonist. These findings suggest that VTA DA cells may encode a fast signal in the PFC via co-release of another transmitter, possibly glutamate. This idea has a long and controversial history but co-release of glutamate by VTA DA neurons would remove the burden of concurrently encoding fast and slow signals by postsynaptic DA receptors. Moreover, glutamate release due to VTA firing could produce fast changes in the membrane potential of PFC neurons that would provide the temporally precise signal required for the error prediction theory. The first part of this proposal will test the hypothesis that the EPSP in the VTA-PFC pathway is mediated by glutamate. The second part will test the temporal limits of DA signaling in the PFC. Part 1 will involve in vivo intracellular recordings from PFC neurons in combination with administration of pharmacological agents (either applied peripherially or via a dialysis probe in PFC) that block DA, glutamate or GABA receptors in an attempt to block the EPSP in the VTA-PFC pathway. Additional experiments will be performed in VTA-PFC organotypic slice co-cultures to test the properties of the EPSP in a more rigorous manner. These experiments will also determine the validity of the organotypic slice co-culture as a means of studying the VTA-PFC pathway based on its similarities to the in vivo preparation. Part 2 will involve simultaneous measurements of DA release in PFC and the electrophysiological response of PFC neurons to VTA stimulation in an attempt to determine the parameters of this release and how quickly it can alter the properties of PFC neurons. A new theory will be proposed that incorporates fast and slow signaling from VTA neurons and that explains the existing literature while providing a new way to think about normal and pathological states involving PFC DA.
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1 |
2003 — 2005 |
Seamans, Jeremy K |
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. |
Dopamine &Ach Regulation of Inhibition in Pfc @ Medical University of South Carolina
[unreadable] DESCRIPTION (provided by applicant): The prefrontal cortex (PFC) is involved in the ability to use previously acquired information to guide forthcoming action, termed working memory. The cellular processes underlying working memory are regulated by both inhibitory neurons and dopamine (DA). Dysfunction of inhibitory and DA systems in the PFC is also thought to underlie aspects of schizophrenia, yet the manner in which these systems interact, is relatively unknown. The main goal of the proposed research is to study the mechanisms of dopamine (DA) modulation of inhibition in the prefrontal cortex (PFC). Preliminary data showed that dopamine has temporally biphasic effects on inhibitory postsynaptic potentials (IPSCs) onto pyramidal neurons in the PFC, producing an initial D2-mediated reduction in IPSC amplitude, followed some minutes later by a D1- mediated increase in IPSC amplitude. Based on preliminary data it was hypothesized that the D1 mediated increase in IPSCs was due to increased excitability of interneurons and their axons. Proposed experiments will test this hypothesis by investigating the direct effect of D1 agonists on ionic currents in subtypes of interneurons as well as potential D1 receptor effects on synaptic inputs to interneurons in PFC brain slices. In addition, we will test whether the signaling cascades mediating the D1 effects involve adenylate cyclase and protein kinase A, as in other brain regions, by using selective agents which either inhibit or activate these molecules. Preliminary data also showed an interesting interaction between acetylcholine (Ach) and D2 receptors. Specifically, Ach muscarinic antagonists eliminated the D2-mediated reduction in IPSCs while muscarinic agonists mimicked the D2 effect. Based on these data, it was hypothesized that D2 receptors released Ach that acted through muscarinic receptors to reduce GABA release. A number of experiments will test aspects of this hypothesis, including, depletion of vesicular Ach and lesions of the Ach terminals in the PFC, in order to eliminate Ach release and thus D2 mediated effects on IPSCs. These studies will provide a more comprehensive understanding of DA regulation in inhibition in the PFC, and how it might regulate cellular processes involved in working memory. [unreadable] [unreadable]
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