The dentate gyrus is a critical contributor in the cognitive functions of the hippocampus. The principal cells of the dentate gyrus, dentate granule cells, exhibit firing in small subpopulations during execution of cognitive tasks, consistent with the process of sparse coding. Sparse coding is a stochastic process. This may not apply to the dentate gyrus, since small populations of cells exhibit preferential activation in multiple environments, while others remain persistently silent, a deterministic firing pattern. The mechanisms responsible for this are entirely unknown, but the birth of new granule cells in the adult brain may contribute. The dentate gyrus also regulates pathological activation of the limbic system. This function, when compromised, may contribute to epilepsy development. In patients with epilepsy, in addition to seizures, there are cognitive deficits that arise associated with damage to the dentate gyrus and other hippocampal structures. In this proposal, we will utilize advanced imaging, patch clamp, optogenetic, and transgenic techniques to test the hypothesis that sparse, deterministic firing of granule cells emerges as a specific consequence of tailored inhibitory function within the dentate gyrus, and this exhibits significant erosion in animals with epilepsy. We propose to characterize network firing in the dentate gyrus, determine the contributions of adult born granule cells to these firing properties, and examine dentate network activation in animals with epilepsy. Little is known about the mechanisms mediating cellular activation in the dentate gyrus, and how epilepsy development may erode these processes. In addition to seizures, patients with epilepsy exhibit severe cognitive co-morbidities, including deficits in emotion, mood, and learning and memory, typically thought of as limbic system functions. Understanding how epilepsy development alters limbic circuit properties is important both in targeting new therapies for seizure amelioration, and in developing treatments to reduce co-morbid conditions associated with seizure disorders.

Public Health Relevance

Despite the fact that the dentate gyrus is a critical regulator of the cognitive functions of the hippocampus, we know little about the mechanisms determining its activation properties, either in normal, healthy individuals or in patients with epilepsy. This proposal will examine these mechanisms using advanced imaging, patch clamp recording, gene targeting, and optogenetic techniques, focusing on how individual neurons within the dentate gyrus make the decision to activate or remain silent, both in normal animals, and in animal models of epilepsy. Insight derived from these studies should facilitate the development of better, more effective treatments for both epilepsy, and associated co-morbidities accompanying epilepsy development.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS082046-03
Application #
8712585
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Goldberg, Ethan M; Coulter, Douglas A (2013) Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat Rev Neurosci 14:337-49