Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. ABSTRACT Recent studies indicate that astrocytes are spatially diversified, which may have consequence for psychiatric diseases with regional brain dysfunction. However, establishing diversified functions of astrocytes in brain development and disease has been limited by a lack of tools for lineage-specific astrocyte manipulation. Recently, we developed novel transgenic methods to label, purify and characterize regional astrocyte populations in mouse brain. The midbrain and brainstem contain dopaminergic nuclei of the ventral tegmental area (VTA) and substantia nigra (SN) that are implicated in schizophrenia, ADHD and Parkinson's disease. We will test the hypothesis that regionally-specified astrocytes from the ventral midbrain are uniquely suited to support survival and connectivity of dopaminergic projections from the VTA and SN. We will determine molecular diversity of region-restricted midbrain astrocytes as a first step towards uncovering the role of regionally diverse astrocytes in neurological disorders. Deliverables include validated transgenic mouse tools for conditional temporal- spatial labeling, purification of astrocytes throughout the CNS as well as markers of regionally heterogeneous astrocytes subtypes of mid/hindbrain compiled into a public database. The project is intended to reveal signatures of astrocyte subtypes and provide insight into the role of astrocytes in mental health.
The role of astrocytes in brain function and dysfunction remains one of the great unknowns in neurobiology. The major objective of this proposal is to develop these tools to more clearly define astrocyte diversity and function in midbrain dopaminergic neuron survival and axon path finding. Upon successful completion of these studies we will have a clearer understanding of astrocyte diversity and function and their potential roles in human psychiatric disease.
|Krencik, Robert; van Asperen, Jessy V; Ullian, Erik M (2017) Human astrocytes are distinct contributors to the complexity of synaptic function. Brain Res Bull 129:66-73|
|Krencik, Robert; Seo, Kyounghee; van Asperen, Jessy V et al. (2017) Systematic Three-Dimensional Coculture Rapidly Recapitulates Interactions between Human Neurons and Astrocytes. Stem Cell Reports 9:1745-1753|
|Krejciova, Zuzana; Alibhai, James; Zhao, Chen et al. (2017) Human stem cell-derived astrocytes replicate human prions in a PRNP genotype-dependent manner. J Exp Med 214:3481-3495|
|Ou, Yvonne; Jo, Rebecca E; Ullian, Erik M et al. (2016) Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses after Transient Ocular Hypertension. J Neurosci 36:9240-52|
|Retallack, Hanna; Di Lullo, Elizabeth; Arias, Carolina et al. (2016) Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci U S A 113:14408-14413|
|Rooney, Gemma E; Goodwin, Alice F; Depeille, Philippe et al. (2016) Human iPS Cell-Derived Neurons Uncover the Impact of Increased Ras Signaling in Costello Syndrome. J Neurosci 36:142-52|
|Krencik, Robert; Hokanson, Kenton C; Narayan, Aditi R et al. (2015) Dysregulation of astrocyte extracellular signaling in Costello syndrome. Sci Transl Med 7:286ra66|
|Molofsky, Anna V; Kelley, Kevin W; Tsai, Hui-Hsin et al. (2014) Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509:189-94|
|Molofsky, Anna V; Glasgow, Stacey M; Chaboub, Lesley S et al. (2013) Expression profiling of Aldh1l1-precursors in the developing spinal cord reveals glial lineage-specific genes and direct Sox9-Nfe2l1 interactions. Glia 61:1518-32|