Browsing by Subject "Corpus Striatum"
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Item Cell-Type-Specific Contributions of the Transcription Factor FOXP1 to Striatal Development and Function(2019-08-07) Anderson, Ashley Grace; Kourrich, Said; Konopka, Genevieve; Takahashi, Joseph; Huber, Kimberly M.Mutations in FOXP1, a member of the forkhead box protein (FOXP) family of transcription factors, have been identified as among the most significantly recurring de novo mutations associated with autism spectrum disorder (ASD). ASD is a genetically complex disorder, however, recent studies have identified distinct neuronal cell-types particularly vulnerable in this disorder. These cell-types include deep layer cortical neurons and dopamine receptor 1 (D1) and 2 (D2) expressing striatal spiny projection neurons (SPNs) where FOXP1 is highly expressed. However, the role of Foxp1 within these cell-types was largely unknown. Using a Foxp1 heterozygous mouse model and a human in vitro model system, I reported that FoxP1 regulates conserved pathways within the striatum based on a module preservation analysis between human and rodent gene co-expression networks. I also found a cell-type-specific functional consequence of reduced Foxp1 expression in Foxp1 heterozygous mice, whereby D2 SPNs had increased intrinsic excitability with no significant changes in dSPNs. Together, these data strongly support a conserved, cell-type-specific role for Foxp1 in striatal development and function. The striatum is a critical forebrain structure for integrating cognitive, sensory, and motor information from diverse brain regions into meaningful behavioral output. Therefore, the overarching goal of my project is to investigate the cell-type specific molecular pathways regulated by Foxp1 within distinct striatal SPNs and link these molecular pathways to functional and behavioral outcomes. To do this, I generated mice with deletion of Foxp1 from D1 SPNs, D2 SPNs, or both populations, and used a combination of single-cell RNA-sequencing (scRNA-seq), serial-two-photon tomography, and behavioral assays to delineate the contribution of Foxp1 to striatal development and function. I show that Foxp1 is crucial for maintaining the cellular composition of the striatum, especially D2 SPN specification, and proper formation of the striosome-matrix compartments at early postnatal and adult timepoints. I uncover downstream targets regulated by Foxp1 within D1 and D2 SPNs and connect these molecular findings to cell-type-specific deficits in motor and limbic system-associated behaviors, including motor-learning, ultrasonic vocalizations, and fear conditioning. Moreover, I identify non-cell autonomous molecular and functional effects produced by disruption of Foxp1 within one SPN subpopulation and the molecular compensation that occurs. Using the scRNA-seq data, I also examined gene expression changes within neuronal and non-neuronal cell-types of the developing striatum. Using my above findings, I attempted to pharmacologically rescue motor-learning deficits in Foxp1 cKO mice by targeting dopaminergic and mTOR-regulated pathways. Finally, I discuss the current challenges and future strategies for therapeutic intervention in cases of FOXP1 mutations. Overall, the findings presented in this thesis provide an important molecular window into striatal development and furthers our understanding of striatal circuits underlying ASD-relevant phenotypes.Item Compensation Between Foxp Transcription Factors Maintains Proper Striatal Function(August 2023) Ahmed, Newaz Ibrahim; Tsai, Peter; Chahrour, Maria; Roberts, Todd; Konopka, GenevieveSpiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Paralogous transcription factors are thought to have the ability to compensate for each other and previous work published by the lab supports the hypothesis that Foxp1 and Foxp2 have compensatory roles in D1 SPNs as well. For my dissertation work, I utilized mice with a D1-SPN specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell type specific genomic analysis to address if there was compensation occurring. It is only upon the loss of both genes that motor behavior was impaired whereas Foxp1 mediated social behavior impairments were exacerbated upon the further loss of Foxp2 (Chapter Two). I also found that while loss of Foxp1 resulted in KLeak mediated hyperexcitability of D1-SPNs, this too was further impaired with the additional loss of Foxp2 (Chapter Three). Viral mediated re-expression of Foxp1 in the double knockouts was sufficient to restore both behavioral and electrophysiological impairments to baseline. I further studied the contribution of Foxp1 and Foxp2 to regulation of downstream targets genes using single-nuclei RNA-seq and found that in both juvenile and adult D1-SPNs, loss of both transcription factors resulted in differential expression of hundreds of genes (Chapter Four). I was able to use these experiments to also investigate how loss of these transcription factors from the D1-SPNs impacted gene expression in other cell-types (Chapter Five). I also utilized single-nuclei ATAC-Seq and again found that loss of both genes resulted in large scale dysregulation of chromatin state not seen in the single knockouts, including in regions enriched for Fox motifs (Chapter Six). I also began to address the open question of what the direct binding targets of Foxp1 and Foxp2 are using the newly developed CUT&RUN technique (Chapter Seven). The findings from my experiments point towards a form of compensation between Foxp1 and Foxp2 where one transcription factor maintains striatal function upon the loss of the other, which I discuss more in depth (Chapter Eight). I also discuss my involvement in a project where we further study the role of Foxp1 in D1- and D2-SPNs, which I am working on in collaboration with Dr. Nitin Khandelwal (Chapter Nine). I conclude by discussing the implications of my findings and suggest recommendations for further study (Chapter Ten).Item Surprising Behavioral and Neurochemical Enhancements in Mice with Combined Mutations Linked to Parkinson's Disease(2013-11-29) Hennis, Meghan Reilly; Yu, Gang; Goldberg, Matthew S.; Eisch, Amelia J.; Hsieh, Jenny; Johnson, Jane E.Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease, afflicting over a million people in the United States alone. PD is an age-dependent disease that causes progressive death of dopamine-producing neurons in the substrantia nigra and depleted dopamine in the striatum. Loss of striatal dopamine results in locomotor symptoms such as bradykinesia, tremor, rigidity and postural instability. Although most forms of the disease are spontaneous, a subset of cases are genetic and humans lacking expression of either Parkin or DJ-1 develop PD. However, one limitation to studying PD is a lack of rodent models that recapitulate both the dopaminergic and motor symptoms as well as the age-dependent development of this disease. In fact, mice deficient for either one or both Parkin and DJ-1 genes have no dopaminergic neuron loss or deficiency in motor abilities. Therefore, I aimed to develop a rodent model of Parkinson’s disease that mimics the progressive symptoms observed in humans by crossing mice deficient for two genes causative for PD, Parkin and DJ-1. I also crossed mice deficient for Parkin and DJ-1 with mice deficient for glutathione peroxidase 1 (Gpx1), an antioxidant that is decreased in the brains of PD patients and increased in aged DJ-1 deficient mouse brains. Instead of the expected loss of dopamine, Parkin-/-DJ-1-/-Gpx1-/- mice exhibit increased striatal dopamine while Parkin-/-DJ-1-/- mice have increased serotonin in multiple brain regions. Additionally, motor phenotypes in these mice do not replicate symptoms observed in PD because Parkin-/-DJ-1-/- mice have an unexpected increase in latency to fall from the rotarod in the absence of other significant behavioral phenotypes. These results led me to examine the levels of proteins related to neurotransmitter synthesis and transport and to test non-motor behaviors in Parkin-/-DJ-1-/- mice. Behavior tests suggest that Parkin-/-DJ-1-/- mice have improved rotarod performance due to cognitive, rather than motor changes.