Area:
Molecular Neuroscience
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High-probability grants
According to our matching algorithm, Karl D. Murray is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2020 |
Murray, Karl Daniel |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Proteomic Analysis of Maturing Adult-Born Hippocampal Mossy Fiber Boutons @ University of California At Davis
The birth of new neurons (called neurogenesis) in the adult hippocampus is critical for learning and memory and disruption of this process is associated with human neurological disorders such as Alzheimer?s disease. Rates of adult hippocampal neurogenesis (AHN) are tightly linked with changes in physiological activity. Activities such as enhanced exercise or learning as well as pathophysiological changes such as epilepsy, profoundly alter AHN. Knowing how ANH neurogenesis regulates neuronal circuitry is therefore important for understanding its overall impact on brain physiology. Central to this issue is understanding how newborn neurons in adult brain achieve long-term integration. Understand the molecular and cellular mechanisms regulating synaptic integration in AHN could lead to selective pharmacological targets for functional improvement during pathological conditions or in aging where levels of adult neurogenesis are dramatically decreased. Neuronal progenitors in the adult hippocampal dentate gyrus give rise to newborn granule (GCs) cells that, when fully differentiated, receive synaptic inputs from entorhinal cortex and send axons along the mossy fiber pathway to form synaptic outputs with CA3 pyramidal neurons. We and others have shown that it takes about eight weeks for the newborn GCs to fully differentiate and form mature synaptic inputs and outputs. The major focus of this proposal is to determine the molecular changes in the synaptic outputs when newborn mossy fiber boutons from GC are forming synapses with mature CA3 pyramidal cells. We propose to use superresolution immunofluorescent array tomography and conjugate array tomography coupled with electron microscopy to profile the proteomic changes of the pre- and post-synaptic elements during the establishment of mature synapses. We have found that to establish a mature synaptic contact the mossy fiber can either 1) form a de novo nascent synapse or 2) replace an existing mossy fiber bouton assuming control of the existing postsynaptic CA3 dendrite. The molecular mechanisms regulating these disparate cellular processes are unknown. Here we will use array tomography analysis to profile the proteomic changes in these synapses to test the hypothesis that the synaptic molecular composition of integrating newborn neurons in adult hippocampus is highly dynamic during the entire maturation process. We have two main focuses: (1) to establish a proteomic profile of the developing and mature presynaptic mossy fiber terminal during adult hippocampal neurogenesis and (2) to establish a proteomic profile of the developing and mature postsynaptic mossy fiber terminal during adult hippocampal neurogenesis. These experiments will be the first to address the intricate proteomic changes essential for establishing new synaptic outputs during adult neurogenesis and will potentially identify a pharmacological target for therapeutic strategies to improve the function of adult brain.
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1 |
2021 |
Murray, Karl Daniel |
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. |
Neuronal Integration of Newborn Granule Cells in Aged Brains @ University of California At Davis
The birth of new neurons (called neurogenesis) in the adult hippocampus is critical for learning and memory, and disruption of this process during aging is associated with neuropsychiatric illnesses that undermine cognition in the aged brain. Most of our knowledge about adult neurogenesis relates to the survival and differentiation of newborn neurons in the young adult brain. Much less is known about how these neurons integrate into existing neural circuits in the aged hippocampus. Neuronal progenitors in the hippocampus give rise to granule cells that, when fully differentiated, send axons along the mossy fiber pathway, where they form synaptic connections (called boutons) to CA3 pyramidal neurons. Previously we developed a serial immuno- electron microscopic approach to study the development of these newborn mossy fiber boutons in the adult brain. Here, using a reporter mouse that we can induce to label the new neurons that are born in a particular time period, we investigate the development and integration of newborn granule cells in the aged hippocampus. This mouse line allows us to birth-date and characterize neurogenesis at any age, including in aged mice 18 months or older. Our preliminary studies show that the progenitor pool changes in the aged hippocampus; more quiescent (inactive) progenitors are present compared to young-adult brain. We have also found the potential for newborn granule cells to form de novo synapses in aged brain is significantly reduced; instead existing boutons have to be replaced when these newborn neurons form synapses. These results reveal previously unknown changes in newborn neurons and their progenitors in the aged brain. In this proposal, we focus on three questions. (1) What are the molecular phenotype and developmental origin of the neuronal progenitors in aged hippocampus? These experiments will reveal how progenitors in the aged brain are different from those in young adults. (2) What is the age and developmental origin of the existing boutons that are replaced by the newborn mossy-fiber boutons in aged brain? Why do the newborn granular cells in the aged brain lose their ability to form de novo synapses? Is this loss due to changes in the neuronal progenitors or to changes to the environment in the aged hippocampus? The answers to these questions will help us understand the specific functional role of adult neurogenesis in the aged brain. (3) How do changes in neuronal activity affect neurogenesis in the aged brain? We have found that the aged hippocampus loses a voltage- gated potassium channel that regulates neuronal intrinsic excitability, and that this channel has a significant effect on adult neurogenesis. We will ask how the changes in neuronal activity resulting from the loss of this channel affect the development and integration of newborn granule cells in the aged hippocampus. These experiments will fill an important gap in our knowledge about neurogenesis in the aged brain, which we expect will contribute to the future development of rehabilitative or therapeutic strategies to improve the function of the aging brain.
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1 |