Matching Items (5)
Description
For two centuries, electrical stimulation has been the conventional method for interfacing with the nervous system. As interfaces with the peripheral nervous system become more refined and higher-resolution, several challenges appear, including immune responses to invasive electrode application, large-to-small axon recruitment order, and electrode size-dependent spatial selectivity. Optogenetics offers a solution that is less invasive, more tissue-selective, and has small-to-large axon recruitment order. By adding genes to express photosensitive proteins optogenetics provides neuroscientists the ability to genetically select cell populations to stimulate with simple illumination. However, optogenetic stimulation of peripheral nerves uses diffuse light to activate the photosensitive neural cell lines. To increase the specificity of stimulus response, research was conducted to test the hypothesis that multiple, focused light emissions placed around the circumference of optogenetic mouse sciatic nerve could be driven to produce differential responses in hindlimb motor movement depending on the pattern of light presented. A Monte Carlo computer simulation was created to model the number of emitters, the light emission size, and the focal power of accompanying micro-lenses to provide targeted stimulation to select regions within the sciatic nerve. The computer simulation results were used to parameterize the design of micro-lenses. By modeling multiple focused beams, only fascicles within a nerve diameter less than 1 mm are expected to be fully accessible to focused optical stimulation; a minimum of 4 light sources is required to generate a photon intensity at a point in a nerve over the initial contact along its surface. To elicit the same effect in larger nerves, focusing lenses would require a numerical aperture > 1. Microlenses which met the simulation requirements were fabricated and deployed on a flexible nerve cuff which was used to stimulate the sciatic nerve in optogenetic mice. Motor neuron responses from this stimulation were compared to global illumination; stimulation using the optical cuff resulted in fine motor movement of the extensor muscles of the digits in the hindlimb. Increasing optical power resulted in a shift to gross motor movement of hindlimb. Finally, varying illumination intensity across the cuff showed changes in the extension of individual digits.
ContributorsFritz, Nicholas (Author) / Blain Christen, Jennifer (Thesis advisor) / Abbas, James (Committee member) / Goryll, Michael (Committee member) / Sadleir, Rosalind (Committee member) / Helms-Tillery, Stephen (Committee member) / Arizona State University (Publisher)
Created2021
Description
Heart disease is the leading cause of death in the developed world and often occurs following myocardial infarction. Apelin is an endogenous prepropeptide that has been studied for its role in improving cardiac contractility and vasodilation but suffers from a short half-life in the body. By encasing apelin in a nanoparticle patch, we were able to slowly release apelin to cardiac tissue and observe its effects for one month following induced myocardial infarction surgery in mice. This study demonstrates that the apelin nanoparticles can protect the heart from myocardial-induced heart failure, observing overall improved cardiac function and reduction of fibrotic scarring associated with post-myocardial infarction compared to a nontreated group.
ContributorsHenderson, Adam (Author) / Chen, Qiang (Thesis director) / Zhu, Wuqiang (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor)
Created2022-05
Description
Autism spectrum disorder (ASD) is characterized by deficits in flexible cognition and social behavior. The most common atypical brain structure in ASD, the cerebellum, has multisynaptic connections through the cerebellar nuclei (CN) and thalamus to cognitive- and social-associated brain regions, yet formation and modulation of these pathways are not fully understood. Additionally, a CN output mechanism, perineuronal nets (PNNs), structure and function are undefined. PNNs are specialized extracellular matrix structures whose appearance is associated with the end of the critical period of plasticity and have been implicated in learning and neurodevelopmental disorders, but their role in the CN during development is unknown.To examine the role of CN on cognition, CN activity was increased or decreased in both male and female mice using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) from postnatal day 21-35. Learning and reversal was analyzed using a pairwise visual discrimination task. Social behavior was assessed using a classic three-chamber assay and analyzed using SLEAP (Social Leap Estimates Animal Poses). A marker of critical periods, perineuronal nets (PNNs), was examined to understand relationships between neural development and behavior.
Interestingly, adolescent CN disruption did not alter task acquisition, yet correct choice reversal performance was dependent on DREADD manipulation and sex. CN inhibition improved reversal learning in males (5 days faster to criteria) and CN excitation improved female reversal learning (10 days faster to criteria) compared to controls. Analysis of social behavior revealed male social preference was abolished in CN manipulated groups, whereas females failed to demonstrate a social preference. Interestingly, CN manipulation in females regardless of direction, reduced PNN intensity, whereas in males only CN inhibition reduced PNN intensity. PNN intensity negatively correlated with reversal performance. CN PNN intensity showed no relation to social behavior. These data suggest chronic adolescent CN manipulation may have compensatory changes in PNN structure and CN output to improve reversal learning and PNN function was unrelated to social behavior. This study provides new evidence for CN in non-motor functions and sex-dependent differences in behavior and CN plasticity.
ContributorsLyle, Tristan (Author) / Verpeut, Jessica (Thesis advisor) / Sanabria, Federico (Committee member) / Newbern, Jason (Committee member) / Arizona State University (Publisher)
Created2024
Description
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects 5.4 million Americans. AD leads to memory loss, changes in behavior, and death. The key hallmarks of the disease are amyloid plaques and tau tangles, consisting of amyloid-β oligomers and hyperphosphorylated tau, respectively.
Rho-associated, coiled-coil-containing protein kinase (ROCK) is an enzyme that plays important roles in neuronal cells including mediating actin organization and dendritic spine morphogenesis. The ROCK inhibitor Fasudil has been shown to increase learning and working memory in aged rats, but another ROCK inhibitor, Y27632, was shown to impair learning and memory. I am interested in exploring how these, and other ROCK inhibitors, may be acting mechanistically to result in very different outcomes in treated animals.
Preliminary research on thirteen different ROCK inhibitors provides evidence that while Fasudil and a novel ROCK inhibitor, T343, decrease tau phosphorylation in vitro, Y27632 increases tau phosphorylation at a low dose and decreases at a high dose. Meanwhile, novel ROCK inhibitor T299 increases tau phosphorylation at a high dosage.
Further, an in vivo study using triple transgenic AD mice provides evidence that Fasudil improves reference memory and fear memory in both transgenic and wild-type mice, while Y27632 impairs reference memory in transgenic mice. Fasudil also decreases tau phosphorylation and Aβ in vivo, while Y27632 significantly increases the p-tau to total tau ratio.
Rho-associated, coiled-coil-containing protein kinase (ROCK) is an enzyme that plays important roles in neuronal cells including mediating actin organization and dendritic spine morphogenesis. The ROCK inhibitor Fasudil has been shown to increase learning and working memory in aged rats, but another ROCK inhibitor, Y27632, was shown to impair learning and memory. I am interested in exploring how these, and other ROCK inhibitors, may be acting mechanistically to result in very different outcomes in treated animals.
Preliminary research on thirteen different ROCK inhibitors provides evidence that while Fasudil and a novel ROCK inhibitor, T343, decrease tau phosphorylation in vitro, Y27632 increases tau phosphorylation at a low dose and decreases at a high dose. Meanwhile, novel ROCK inhibitor T299 increases tau phosphorylation at a high dosage.
Further, an in vivo study using triple transgenic AD mice provides evidence that Fasudil improves reference memory and fear memory in both transgenic and wild-type mice, while Y27632 impairs reference memory in transgenic mice. Fasudil also decreases tau phosphorylation and Aβ in vivo, while Y27632 significantly increases the p-tau to total tau ratio.
ContributorsTurk, Mari (Author) / Huentelman, Matt (Thesis advisor) / Kusumi, Kenro (Thesis advisor) / Jensen, Kendall (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2017
Description
Development of the cerebral cortex requires the complex integration of extracellular stimuli to affect changes in gene expression. Trophic stimulation activates specialized intracellular signaling cascades to instruct processes necessary for the elaborate cellular diversity, architecture, and function of the cortex. The canonical RAS/RAF/MEK/ERK (ERK/MAPK) cascade is a ubiquitously expressed kinase pathway that regulates crucial aspects of neurodevelopment. Mutations in the ERK/MAPK pathway or its regulators give rise to neurodevelopmental syndromes termed the “RASopathies.” RASopathy individuals present with neurological symptoms that include intellectual disability, ADHD, and seizures. The precise cellular mechanisms that drive neurological impairments in RASopathy individuals remain unclear. In this thesis, I aimed to 1) address how RASopathy mutations affect neurodevelopment, 2) elucidate fundamental requirements of ERK/MAPK in GABAergic circuits, and 3) determine how aberrant ERK/MAPK signaling disrupts GABAergic development.
Here, I show that a Noonan Syndrome-linked gain-of-function mutation Raf1L613V, drives modest changes in astrocyte and oligodendrocyte progenitor cell (OPC) density in the mouse cortex and hippocampus. Raf1L613V mutant mice exhibited enhanced performance in hippocampal-dependent spatial reference and working memory and amygdala-dependent fear learning tasks. However, we observed normal perineuronal net (PNN) accumulation around mutant parvalbumin-expressing (PV) interneurons. Though PV-interneurons were minimally affected by the Raf1L613V mutation, other RASopathy mutations converge on aberrant GABAergic development as a mediator of neurological dysfunction.
I therefore hypothesized interneuron expression of the constitutively active Mek1S217/221E (caMek1) mutation would be sufficient to perturb GABAergic circuit development. Interestingly, the caMek1 mutation selectively disrupted crucial PV-interneuron developmental processes. During embryogenesis, I detected expression of cleaved-caspase 3 (CC3) in the medial ganglionic eminence (MGE). Interestingly, adult mutant cortices displayed a selective 50% reduction in PV-expressing interneurons, but not other interneuron subtypes. PV-interneuron loss was associated with seizure-like activity in mutants and coincided with reduced perisomatic synapses. Mature mutant PV-interneurons exhibited somal hypertrophy and a substantial increase in PNN accumulation. Aberrant GABAergic development culminated in reduced behavioral response inhibition, a process linked to ADHD-like behaviors. Collectively, these data provide insight into the mechanistic underpinnings of RASopathy neuropathology and suggest that modulation of GABAergic circuits may be an effective therapeutic option for RASopathy individuals.
Here, I show that a Noonan Syndrome-linked gain-of-function mutation Raf1L613V, drives modest changes in astrocyte and oligodendrocyte progenitor cell (OPC) density in the mouse cortex and hippocampus. Raf1L613V mutant mice exhibited enhanced performance in hippocampal-dependent spatial reference and working memory and amygdala-dependent fear learning tasks. However, we observed normal perineuronal net (PNN) accumulation around mutant parvalbumin-expressing (PV) interneurons. Though PV-interneurons were minimally affected by the Raf1L613V mutation, other RASopathy mutations converge on aberrant GABAergic development as a mediator of neurological dysfunction.
I therefore hypothesized interneuron expression of the constitutively active Mek1S217/221E (caMek1) mutation would be sufficient to perturb GABAergic circuit development. Interestingly, the caMek1 mutation selectively disrupted crucial PV-interneuron developmental processes. During embryogenesis, I detected expression of cleaved-caspase 3 (CC3) in the medial ganglionic eminence (MGE). Interestingly, adult mutant cortices displayed a selective 50% reduction in PV-expressing interneurons, but not other interneuron subtypes. PV-interneuron loss was associated with seizure-like activity in mutants and coincided with reduced perisomatic synapses. Mature mutant PV-interneurons exhibited somal hypertrophy and a substantial increase in PNN accumulation. Aberrant GABAergic development culminated in reduced behavioral response inhibition, a process linked to ADHD-like behaviors. Collectively, these data provide insight into the mechanistic underpinnings of RASopathy neuropathology and suggest that modulation of GABAergic circuits may be an effective therapeutic option for RASopathy individuals.
ContributorsHolter, Michael (Author) / Newbern, Jason (Thesis advisor) / Anderson, Trent (Committee member) / Mehta, Shwetal (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2019