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.

Public Health Relevance

Neurogenesis persists in the adult hippocampus of all mammals but it is not known how newly generated neurons contribute to hippocampal functions. The goal of this project is to determine how distinct synaptic connectivity endows newly generated neurons with capabilities that are different from the much larger population of mature neurons. The results of these studies will help determine how adult neurogenesis contributes to normal and pathological brain function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS064025-06A1
Application #
8853630
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lavaute, Timothy M
Project Start
2008-12-01
Project End
2019-02-28
Budget Start
2015-04-01
Budget End
2016-02-29
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Nietz, Angela K; Vaden, Jada H; Coddington, Luke T et al. (2017) Non-synaptic signaling from cerebellar climbing fibers modulates Golgi cell activity. Elife 6:
Laszczyk, Ann M; Fox-Quick, Stephanie; Vo, Hai T et al. (2017) Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss. Neurobiol Aging 59:41-54
Dieni, Cristina V; Panichi, Roberto; Aimone, James B et al. (2016) Low excitatory innervation balances high intrinsic excitability of immature dentate neurons. Nat Commun 7:11313
Enikolopov, Grigori; Overstreet-Wadiche, Linda; Ge, Shaoyu (2015) Viral and transgenic reporters and genetic analysis of adult neurogenesis. Cold Spring Harb Perspect Biol 7:a018804
Overstreet-Wadiche, Linda; McBain, Chris J (2015) Neurogliaform cells in cortical circuits. Nat Rev Neurosci 16:458-68
Wadiche, Jacques I; Overstreet-Wadiche, Linda (2015) New neurons don't talk back. Neuron 85:3-5
Hallengren, Jada J; Vaden, Ryan J (2014) Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice. J Neurophysiol 112:5-8
Chancey, Jessica H; Poulsen, David J; Wadiche, Jacques I et al. (2014) Hilar mossy cells provide the first glutamatergic synapses to adult-born dentate granule cells. J Neurosci 34:2349-54
Overstreet-Wadiche, Linda; Wadiche, Jacques I (2014) Good housekeeping. Neuron 81:715-7

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