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Area:
GABA receptors, adult neurogenesis
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High-probability grants
According to our matching algorithm, Linda S. Overstreet-Wadiche is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2009 — 2021 |
Overstreet-Wadiche, Linda S |
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. |
Newborn Neurons in the Adult Hippocampal Network @ University of Alabama At Birmingham
? DESCRIPTION (provided by applicant): Neurogenesis persists in the dentate gyrus of all adult mammals, including humans. Neural production is perturbed by many physiological and pathological conditions, and selective manipulation of neurogenesis suggests that adult born neurons contribute to hippocampal-dependent behaviors. Despite growing knowledge of the cell biological processes directing neurogenesis, less is known about the physiological properties that may endow the small population of adult born neurons to contribute to hippocampal function. One possibility is that the continually renewing population of immature neurons exhibits distinct properties from the larger population of pre-existing neurons, resulting in unique functionality. Although considerable attention has focused on transient differences in intrinsic excitability, the potential consequences of distinct circuitry have not been explored. The goal of this project is to determine how changes in synaptic connectivity across maturation affect activation of dentate neurons, potentially allowing immature and mature neurons to process distinct components of hippocampal network activity. Dentate neurons receive two main excitatory afferent projections; the perforant path originating from the entorhinal cortex and the associational/commissural pathway arising from hilar mossy cells within the hippocampus itself. We will use in vitro slice physiology, a variety of transgenic mouse models and optogenetics to address how changing synaptic connectivity and intrinsic properties control recruitment at progressive stages of maturation. First we will focus on understanding the mechanisms controlling excitatory drive and synaptic integration of the perforant path and associational/commissural pathways (Aims 1 & 2).These single cell studies will be extended to test functional consequences of selective pathway stimulation at the synaptic and circuit level (Aim 3). We will go beyond circuit mapping to understand how stage-specific synaptic properties interact with intrinsic excitability to dictate integration of cortical and hippocampal afferent activity. Together the results of these Aims will reveal how synaptic connectivity contributes to the participation of immature neurons in dentate circuitry and provide insight into the potential for adult neurogenesis to produce a heterogeneous population of dentate neurons that can play diverse roles in hippocampal function. Understanding the physiological function of adult born neurons is an essential component of dissecting the significance and purpose of adult neurogenesis, a dramatic form of brain plasticity that may be a therapeutic target for numerous brain disorders.
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1 |
2018 — 2021 |
Overstreet-Wadiche, Linda |
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. |
Inhibitory Neural Circuits in Dentate Function @ University of Alabama At Birmingham
The dentate gyrus contributes to hippocampal memory encoding by transforming dense cortical patterns of sensory and spatial information into sparse neural representations of specific contexts. Diverse local inhibitory circuits are essential for this process, maintaining low levels of neural activity wherein only small fractions of principal neurons are active at any given time. The dentate gyrus also continually generates new neurons throughout life, providing a substrate for adult brain plasticity through experience-dependent construction of new circuits. It is well established that GABA receptor-mediated mechanisms tightly regulate proliferation and functional integration of adult-born neurons. Thus, GABAergic interneurons provide both inhibitory control of mature dentate neurons and regulate the production of adult-born neurons. The goal of this project is to determine how a highly abundant subtype of GABAergic interneuron contributes to both inhibitory and neurogenic functions in the dentate gyrus. This family of interneurons called Ivy/Neurogliaform cells (INGs) has been relatively neglected due to the inability to selectively target them using genetic approaches. We will address this roadblock by validating new tools to identify and manipulate INGs, and compare their functions with the highly-studied parvalbumin (PV)- expressing fast-spiking interneurons. These fast and slow-spiking interneuron subtypes have highly divergent anatomical, intrinsic and synaptic properties, suggesting that they play distinct roles in dentate inhibition and neurogenesis. Based on our preliminary data, we hypothesize that slow-spiking INGs use GABAA and GABAB receptor activation to enforce sparse yet high-fidelity spiking of mature GCs as well as regulate early stages of dentate neurogenesis. We will combine cellular and circuit level analysis with optogenetic approaches to assess the role of slow spiking interneurons in both inhibition and neurogenesis. After understanding the cellular properties of slow-spiking interneurons subtypes, we will dissect their role in controlling GC inhibition and spike timing, comparing with results from fast-spiking interneurons. We will use optogenetic silencing to determine the respective interneuron contributions to dentate excitability with a focus on GABAB mediated-inhibition and interactions between slow and fast-spiking subtypes. Finally, we will test the role of slow-spiking interneurons in stem cell proliferation, and the contribution of GABAB receptor-mediating inhibition in differential excitability of young and mature GCs. The results of these studies will provide fundamental insight into the function of slow-spiking interneurons in dentate excitability and neurogenesis.
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