The dentate gyrus of adult hippocampus continuously generates new granule cells. New granule cells integrate into the existing neural circuits and regulate hippocampal behaviors. In the aged animals, there is not only a substantial decrease in the generation of newborn granule cells but also increasing failure in circuit integration of these new neurons. This raises the importance of understanding the strategy for circuit integration of new neurons in the adult brain, which remains largely unknown. In one of our recent studies in collaboration with Dr. Dan's group, we found that clonally-related sister neurons in the developing cortex are initially synchronized. This suggests that new neurons may share similar properties during integration, and are co- activation during hippocampal function. This motivates us to establish a method to label and manipulate clonally-related newborn granule cells and study their neural circuit integration and activation. As an exploratory study, we will first characterize the development of clonally-related adult-born granule cells. We will perform dual patch clamp whole cell recording of clonally-related granule cells to test their neuronal and synaptic properties during development. Secondly, we will test whether clonally-related adult-born granule cells are preferentially co-activated during 2+ hippocampal activities. To achieve this goal, we will perform Ca and c-fos imaging to study the activation of clonally-related granule cells after they are fully integrated. Importantly, we will test whether the initial synchronizatio of clonally-related adult-born granule cells is required for their development and function. Additionally, using optogenetic method, we will test whether clonally-related new neurons are differentially activated by different laminar activation. Our finding will delineate whether clonaly-related newborn granule cells share a similar developmental track and preferentially recruited during hippocampal activities. We will also test whether the initial gap junction coupling is necessary to normal development and function of clonally-related newborn neurons. These studies will provide some basis for studying the generation and development of new neurons in the aged brain.

Public Health Relevance

Adult or aged brain continuously generates new neurons. Mounting evidence revealed that neural stem cells, once activated, divide a few times and give rise to several neuronal progeny. These neuronal progeny integrate into the adult neural circuits and play important roles in circuit and behavioral functions. However, how newborn neurons manage themselves into the existing hostile neural circuits remains largely unknown. Recently, in collaboration with Dr. Dan's and Dr. Shi's group, we found that clonally-related neurons in the developing visual cortex respond to similar orientation stimulation. This finding inspired us to think whether newborn neurons in the adult or age brain are co-integrated into the existing neural circuits and co-activated during hippocampal functions. As a first-step study, we established a new method to label clonally- related neurons. As shown in one of the pilot study, we are for the first time able to label clonally-related neurons of similar age. We propose to test the ontogenetic development and function of clonally-related granule cells. We will test whether newborn neurons share similar properties during integration into the neural circuits. We will then test whether these neurons are preferentially co-activated during hippocampal functions. This study will provide insights into understanding the development and function of clonally-related granule cells in the adult and age brains. It will also provide a basis for mechanistically studyin the neurogensis in the adult or aged brain.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Wise, Bradley C
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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Kirschen, Gregory W; Kéry, Rachel; Liu, Hanxiao et al. (2018) Genetic dissection of the neuro-glio-vascular machinery in the adult brain. Mol Brain 11:2
Kirschen, Gregory W; Shen, Jia; Tian, Mu et al. (2017) Active Dentate Granule Cells Encode Experience to Promote the Addition of Adult-Born Hippocampal Neurons. J Neurosci 37:4661-4678
Rhee, Soyoung; Kirschen, Gregory W; Gu, Yan et al. (2016) Depletion of primary cilia from mature dentate granule cells impairs hippocampus-dependent contextual memory. Sci Rep 6:34370