Browsing by Subject "Neural Pathways"
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Item Characterizing the Molecular Mechanisms of Axon Guidance: Activation and Regulation of the Axon Guidance Receptor Plexin A(2012-07-17) Yang, Taehong; Terman, Jonathan R.Neuronal connectivity is precisely determined by axonal pathfinding during development. The navigating axons detect attractive and repulsive environmental cues by axon guidance receptors. However, the biochemical means through which multiple signaling pathways are integrated in navigating axons is poorly understood. Semaphorins are the largest family of axon guidance cues and utilize Plexin receptors to exert repulsive effects on axon extension. The intracellular region of Plexins contains a Ras GTPase activating protein (GAP) domain, which is necessary for repulsive guidance effects. Previous studies suggest that activation of Plexin RasGAP requires interactions with both Semaphorin at the extracellular region and a Rho-family GTPase at the Rho family GTPase-binding domain (RBD). Interestingly, Semaphorin repulsion can be rapidly "turned-off" by other distinct cues and signaling cascades. However, the molecular mechanisms to activate or modulate Plexin RasGAP remain unclear. First, to further understand how the Plexin RasGAP is activated, I collaborated with the Zhang lab, and following determination of the crystal structure of the intracellular region of Plexin, I examined the roles of residues interfacing with the RasGAP domain using functional mutagenesis in the Drosophila model system. Our results demonstrate that Plexin exhibits an auto-inhibited conformation, and suggest that interaction among the previously uncharacterized juxtamembrane segment, the RBD, and the RasGAP domain is critical for Plexin RasGAP activation. Second, to better understand how Semaphorin/Plexin signaling is modulated, I characterized the results of a large-scale screen to look for proteins interacting with the cytoplasmic portion of Plexin and identified the phosphoserine binding protein 14-3-3epsilon as a specific Plexin-interacting protein. My results reveal that 14-3-3epsilon is specifically required for axon guidance during development. Moreover, Protein kinase A is found to phosphorylate Plexin in the RasGAP domain and mediates the 14-3-3epsilon interaction. Plexin-14-3-3epsilon interactions prevent Plexin from interacting with its Ras-family GTPase substrate, which effectively switches Plexin-mediated axonal repulsion to Integrin-mediated adhesion. These findings uncover both a new molecular integration point between important axon guidance signaling pathways and a biochemical logic by which this guidance information is coalesced to steer the growing axon. Therefore, these new observations on activating and silencing specific signals that are repulsive to axon growth also illuminate new approaches to neutralize axonal growth inhibition and encourage axon regeneration.Item Finding the Engram: A Pathway for Song Memory in Zebra Finches(2019-07-01) Zhao, Wenchan; Xu, Wei; Meeks, Julian P.; Cooper, Brenton; Elmquist, Joel; Roberts, ToddFinding memory traces, also called engrams, has been a major goal in the neuroscience field for decades. Although episodic memory -- the memory of autobiographical events -- is known to rely on the hippocampus for its formation, procedural memory -- the memory of motor skills -- does not require hippocampus and the exact nature and mechanism of it has remained largely unknown. Vocal learning is a form of procedural learning of a sequence of vocal movements from a social model, a rare trait detected in only few animal species including songbirds and humans. The learning of vocal production is guided by the retention of the memory of the social model's vocal behavior. In this dissertation, I used song learning in zebra finches as the animal model to study the neural basis of song memory. I used a newly developed spatiotemporally specific optogenetic method combined with neuron population-specific genetic lesion to target a neural pathway of zebra finches and examined its role in song memory. Through this series of experiments, I showed that 1) imposing artificial activity in this pathway results in birds singing songs with temporal structure conforming to the imposed activity, suggesting a mechanism for encoding the temporal structure of song; 2) imposing activity paired with live bird tutoring cause the birds to learn only from the imposed activity, but not from the live bird tutor, suggesting this pathway is either able to override other pathways for acquiring song memory, or a non-redundant pathway for encoding the temporal structure of song; 3) genetic lesioning of cells in this pathway precludes birds from learning from a tutor, but does not affect song learning if birds received tutoring before lesioning, suggesting this pathway is necessary for acquiring song memory and that memory transmitted via this pathway is not stored within but downstream of it. This study is the first case showing artificial activity imposed in a neural pathway implants memories that subsequently guide the learning of a motor skill. In Part I of this dissertation, I introduce memory and strategies that can be used to find engram, song learning of zebra finches and previous work in search of the engram of song memory and discuss the rationale of my design of experiments. In Part II, I present in three separate chapters experiments I conducted to examine of the role of a neural pathway of zebra finches in song memory.Item Resting State Functional Magnetic Resonance Imaging Alterations In Psychosis Spectrum Disorders(2015-03-20) Samudra, Niyatee; Tamminga, CarolBACKGROUND: Many psychiatric disorders, especially those on the psychosis spectrum, are as yet without good diagnostic and treatment options. Neuroimaging research, most recently research into brain functional connectivity via resting-state fMRI, may provide a window into this problem, creating possibilities for discovering disease state-specific biomarkers important for diagnosis or to follow treatment efficacy. Hippocampal hyperactivity is known to be a feature of schizophrenia. The anterior hippocampus in particular, because of its structural connectivity relationships to frontal and limbic areas, may have specific connectivity alterations in psychosis spectrum disorders. In addition, it is important to understand whether putative changes in hippocampal functional connectivity are unique to a particular conventional (Diagnostic and Statistical Manual) psychosis disorder or whether they are present in multiple psychosis spectrum disorders, as this helps establish a biological foundation for psychosis. This work examines hippocampal functional connectivity changes in psychosis spectrum disorders in light of a possible imaging signature for psychosis. It is best understood in light of the work done by the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, a multi-site study group to establish imaging and molecular biomarkers across the psychosis dimension. OBJECTIVES: 1) To understand abnormal hippocampal connectivity and its targets in the rest of the brain in psychosis spectrum disorders. 2) To assess whether hippocampal connectivity changes are specific to one DSM diagnostic group or common across the psychosis spectrum. 3) To correlate hippocampal connectivity alterations with specific cognitive and clinical outcomes. METHODS: We tested resting state connectivity in 88 participants with psychosis disorders (21 schizophrenia; 40 schizoaffective disorder; 27 psychotic bipolar I disorder) and 65 healthy controls. Image processing and seed-based, voxel-wise connectivity analyses were carried out in the Analysis of Functional Neuroimaging (AFNI) software package to understand differential connectivity in psychosis spectrum vs. healthy controls using whole, anterior, and posterior hippocampal seeds. Connectivity measures for psychosis participants, as assessed by z-scores, were correlated with multiple clinical and cognitive measures. RESULTS: We found no significant differences in hippocampal functional connectivity across the three DSM diagnoses tested, thus justifying combining the groups for an analysis versus healthy controls. For the whole psychosis group, there were strong reductions in anterior hippocampal connectivity to anterior neocortical regions, including medial frontal and anterior cingulate cortices, as well as to superior temporal gyrus, precuneus, thalamus and cerebellum. Posterior hippocampal seeds also demonstrated decreased connectivity in psychosis subjects, with fewer regions of altered connectivity and a predominantly posterior/cerebellar distribution. Whole hippocampal outcomes were consistent with anterior/posterior hippocampal connectivity changes. These changes did not correspond to measures of cognition, medication effect, or clinical symptoms. CONCLUSION: This research underlines the possibility of a neuroimaging signature for psychosis spectrum disorders consisting of decreased predominantly anterior hippocampal connectivity with frontal and temporal regions, among others. The changes observed do not seem to correspond to medication effect or demographic variables in our analysis, thereby suggesting a primary disease effect. Further research is necessary to establish a hippocampal network in psychosis which may serve as a biomarker, with implications for more definitive diagnosis and treatment response prediction.Item Transitioning Between Preparatory and Precisely Sequenced Neuronal Activity in Production of a Skilled Motor Behavior(2019-06-18) Daliparthi, Vamsi Krishna; Pfeiffer, Brad E.; Meeks, Julian P.; Li, Wen-Hong; Fiolka, Reto; Roberts, ToddPrecise neural sequences are associated with the production of well-learned skilled behaviors. Yet, how neural sequences arise in the brain remains unclear. In songbirds, premotor projection neurons in the cortical song nucleus HVC are necessary for producing learned song and exhibit precise sequential activity during singing. Using cell-type specific calcium imaging we identify populations of HVC premotor neurons associated with the beginning and ending of singing-related neural sequences. We characterize neurons that bookend singing-related sequences and neuronal populations that transition from sparse preparatory activity prior to song to precise neural sequences during singing. Recordings from downstream premotor neurons or the respiratory system suggest that pre-song activity may be involved in motor preparation to sing. These findings reveal population mechanisms associated with moving from non-vocal to vocal behavioral states and suggest that precise neural sequences begin and end as part of orchestrated activity across functionally diverse populations of cortical premotor neurons.