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ItemThe Potential Role of Kv3.3 in Chemotherapy-Induced Neuropathy(Georgia Institute of Technology, 2021-05) Pfahl, Emily LynnOxaliplatin (OX) is a widely used chemotherapy compound used in the treatment of colorectal cancers (CRCs). Patients treated with OX often exhibit severe side effects, including motor dysfunction and imbalance, potentially influenced by the inability of sensory neurons, including muscle spindle afferents (MSAs), to repetitively fire, which is needed to properly encode information about limb movement. Even though OX is prescribed in a majority of CRCs, it is currently unknown how the compound causes the aforementioned side effects. The aim of the present study was to determine if OX acts through modification of the voltage-gated potassium channel Kv3.3, which is hypothesized to promote repetitive firing. To test this hypothesis, the soleus nerve and muscle were isolated from control mice. A series of ramp and triangular stretches were applied to the muscles, and afferent firing responses were recorded. A synthetic Kv3.3-knockdown line of mice was created using Kv3.3 siRNA (ThermoFischer Scientific). The soleus nerve and muscle were isolated from these mice, the same stretches were applied to the muscle, and MSA recordings were taken and compared to the control MSA responses. Preliminary data suggest that afferent responses to stretch are altered in the Kv3.3-knockdown mice, but as of this time, not enough data has been collected to make statistically significant claims. Future work will focus on collecting enough Kv3.3-knockdown data to perform statistical analyses on the data, as well as on performing immunohistochemical (IHC) staining of tissue from knockdown animals to ensure silencing of Kv3.3.
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ItemAnalysis of Neural Stem Cells and Neurospheres(Georgia Institute of Technology, 2020-05) Palanivel, ShivaniNeural stem cells (NSCs) are important multipotent adult stem cells capable of self-renewal and differentiation into various cell types present in the central nervous system. Studying the characteristics of NSCs and their differentiation offers insights into developmental mechanisms and allows us to assess their utility in vitro disease modeling and neurotoxicological research. This study investigates the properties of NSC during propagation and differentiation in culture. Neurospheres, formed from NSC aggregates, were cultured and examined for morphology and growth rate by cell counting and size analysis. Neurospheres were induced to differentiate toward neural network formation. The expression of markers of NSC and astrocytes in neurospheres during differentiation was detected by immunostaining methods. NSC multiplied with an exponential proliferation rate accompanied by a steady increase in neurosphere diameter. The neurosphere cells expressed Nestin, an NSC/ progenitor cell marker, when cultured in self-renewal media, and displayed pronounced GFAP expression after induction of differentiation indicating a prevalence of astrocytes. Further studies will provide better understanding of NSC characteristics that may be applied for the advancement of stem cell therapy to help combat neurodegenerative diseases.
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ItemChemotherapy Induced Sensory Neuropathy Depends on Non-Linear Interactions with Cancer(Georgia Institute of Technology, 2020-03-30) Housley, Stephen N.For the constellation of neurological disorders known as chemotherapy induced neuropathy, mechanistic understanding, and treatment remain deficient. In project one, I leveraged a multi-scale experimental approach to provide the first evidence that chronic sensory neuropathy depends on non-linear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed amplified differential expression, notably in regulators of neuronal excitability, metabolism and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding in vivo and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as candidate mechanisms explaining sensory neuron dysfunction. The sufficiency of this novel molecular mechanism was tested in an in silico biophysical model of mechanosensory function. Finally, validated measures of sensorimotor behavior in awake behaving animals confirmed that dysfunction after chronic chemotherapy treatment is exacerbated by cancer. Notably, errors in precise fore-limb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy, and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer across multiple levels of biological control. In project two, I extend study to multiple classes of mechanosensory neurons that are necessary for generating the information content (population code) needed for proprioception. I first tested the hypothesis that exacerbated neuronal dysfunction is conserved across multiple classes of mechanosensory neurons. Results revealed co-suppression of specific signaling parameters across all neuronal classes. To understand the consequences of corrupt population code, I employed a long-short-term memory neural network (LSTM), a deep-learning algorithm, to test how decoding of spatiotemporal features of movement are altered after chemotherapy treatment of cancer. Results indicate that spiking activity from the population of neurons in animals with cancer, treated by chemotherapy contain significantly less information about key features of movement including, e.g. timing, magnitudes, and velocity. I then modeled the central nervous systems (CNS) capacity to compensate for this information loss. Even under optimal learning conditions, the inability to fully restore predictive power suggests that the CNS would not be able to compensate and restore full function. Our results support our proposal that lasting deficits in mobility and perception experienced by cancer survivors can originate from sensory information that is corrupted and un-interpretable by CNS neurons or networks. Collectively, I present the first evidence that chronic cancer neuropathy cannot be explained by the effects of chemotherapy alone but instead depend on non-linear interactions with cancer. This understanding is a prerequisite for designing future studies and for developing effective treatments or preventative measures.