<p> The human brain functions within a narrow range of temperatures and variations outside of this range incur cellular damage and death and, ultimately, death of the organism. Other organisms, like the poikilotherm <i>Drosophila melanogaster</i>, have adapted mechanisms to maintain brain function over wide ranges in temperature and, if exposed to high temperatures where brain function is no longer supported, these animals enter a protective coma to promote survival of the organism once the acute temperature stress is alleviated. </p><p> This research characterized the role of different neuronal cell types, including glia, in the protection of brain function during acute hyperthermia, specifically looking at two protective pathways: the heat shock protein (HSP) pathway and the cGMP-dependent protein kinase G (PKG) pathway. Whole animal behavioral assays were used in combination with tissue-specific genetic manipulation of protective pathways to determine the specific cell types sufficient to confer protection of neuronal function during acute hyperthermia. Using the neuromuscular junction (NMJ) preparation, calcium imaging techniques were combined with pharmacological and genetic manipulations to test the hypothesis that alterations in ion channel conductance via endogenous mechanisms regulating the cellular response to high temperature stress alter neuronal function. </p><p> Expression of <i>foraging</i> RNAi to inhibit PKG expression in neurons or glia demonstrated protection of function during acute hyperthermia measured behaviorally through the extension of locomotor function. This extension of function with the tissue-specific inhibition of PKG was also confirmed at the cellular level using the genetically encoded calcium indicator (GECI), GCaMP3, to image calcium dynamics at the NMJ, where preparations expressing <i> foraging</i> RNAi could continue to elicit changes in calcium dynamics in response to stimulation. Over the course of this study, the mechanism underlying a novel glial calcium wave in the peripheral nervous system was characterized in order to elucidate glia&rsquo;s role in the protection of neuronal function during acute hyperthermia.</p><p>

<p> Taste is one of the fundamental senses that organisms have evolved, which is critical for survival. Taste receptor cells have the function to detect chemicals in the oral cavity and transmit the chemical information to the brain. Those taste receptor cells are housed in taste buds. Within each taste bud, there are type I, type II, type III and basal cells, which have different morphological structures and different cellular functions. In mammals, taste buds are located in 3 distinct sets of specialized taste papillae within the oral cavity, including circumvallate papillae, foliate papillae and fungiform papillae. As those cells are in contact with the external environment and easy to damage, they keep turning over throughout an organism&rsquo;s life. However, either aging or disease can cause loss of taste. Despite the importance of taste to our life, currently very little is known about the development and maintenance of the taste system. </p><p> Some factors have been identified to be important in regulating taste development, including sonic hedgehog, bone morphogenetic protein 4 and multiple members of the Wnt/&beta;-catenin signaling pathway. However, the understanding about the regulation of these factors is lacking. Here I focused on studying the role for the Wilms&rsquo; tumor 1 protein (WT1), which is important for the development of other sensory tissues, and in the development of circumvallate papillae. I found WT1 is expressed in developing circumvallate papillae (CV) since the placode formation, and its expression is gradually confined to the taste epithelium by birth. The CV of mice lacking WT1 fails to develop normally and early taste development markers are dysregulated. ChIP assay results show that WT1 directly binds to the promoter region of <i>Lef1, Ptch1</i> and <i>Bmp4</i>. The expression levels of WT1 target genes are significantly reduced in WT1 KO tongue. WT1&rsquo;s transcription function on Lef1 and Ptch1 is confirmed by primary cultured taste cells. Our results demonstrate that WT1 is a critical transcription factor in the development of the CV by regulating multiple factors that have known roles in taste placode formation (Chapter 2). </p><p> Since multiple studies have shown that WT1&rsquo;s transcriptional function is regulated by its corepressor BASP1, I hypothesized that in the taste system, WT1 is also regulated by BASP1. I found BASP1 is exclusively expressed in the gustatory nerve during embryonic development. However, BASP1 is highly expressed in taste cells starting around birth and this expression pattern is maintained until adulthood. This suggests a potential role of BASP1 in the renewal/maintenance of taste buds. BASP1 is co-localized with WT1 in lots of taste cells and occupies the promoter of WT1 targets <i>Lef1</i> and <i>Ptch1</i>. Conditional deletion of BASP1 in Krt8-positive taste cells causes elevated levels of <i>Lef1</i> and <i>Ptch </i>. Immunohistochemistry experiments with different taste cell markers reveal that BASP1 KO taste buds gain more type I taste cell features and lose type II and III taste cell features. This is consistent with previous findings that different expression levels of Wnt signaling and Shh signaling bias cell fate. Physiological studies using calcium imaging show that significantly less taste cells from BASP1 KO mice show detectible responses to taste solutions compared to wild type. The amplitudes of the remaining responses of taste cells from BASP1 KO mice were significantly smaller than wild type. Behavior study show that BASP1 KO mice have less sensitivity to different taste solutions. These data demonstrate that BASP1 regulates WT1 targets in the adult taste system and plays an important role in the maintenance of the adult CV. </p><p> My data have identified a new role for WT1 and WT1-BASP1 complex in the development and maintenance of the taste system. These findings provide new insights into the current understanding of the molecular mechanisms of the taste development and maintenance.</p><p>

abstract: An accurate sense of upper limb position is crucial to reaching movements where sensory information about upper limb position and target location is combined to specify critical features of the movement plan. This dissertation was dedicated to studying the mechanisms of how the brain estimates the limb position in space and the consequences of misestimation of limb position on movements. Two independent but related studies were performed. The first involved characterizing the neural mechanisms of limb position estimation in the non-human primate brain. Single unit recordings were obtained in area 5 of the posterior parietal cortex in order to examine the role of this area in estimating limb position based on visual and somatic signals (proprioceptive, efference copy). When examined individually, many area 5 neurons were tuned to the position of the limb in the workspace but very few neurons were modulated by visual feedback. At the population level however decoding of limb position was somewhat more accurate when visual feedback was provided. These findings support a role for area 5 in limb position estimation but also suggest that visual signals regarding limb position are only weakly represented in this area, and only at the population level. The second part of this dissertation focused on the consequences of misestimation of limb position for movement production. It is well known that limb movements are inherently variable. This variability could be the result of noise arising at one or more stages of movement production. Here we used biomechanical modeling and simulation techniques to characterize movement variability resulting from noise in estimating limb position ('sensing noise') and in planning required movement vectors ('planning noise'), and compared that to the variability expected due to noise in movement execution. We found that the effects of sensing and planning related noise on movement variability were dependent upon both the planned movement direction and the initial configuration of the arm and were different in many respects from the effects of execution noise. / Dissertation/Thesis / Ph.D. Bioengineering 2011

<p> Vectors, defined by distance and direction information, can represent the spatial relationships between reference objects and target objects. Reference boundaries help to define the space and are mathematically definable by lines, while reference landmarks define specific locations and are definable by points. How do vectors, containing two sources of information relate references and targets? Congruent with neuroscientific evidence we argued that humans rely differentially on distance and direction information when recalling the spatial location of objects. We showed that direction information was better encoded or remembered than distance information relative to landmarks, and that distance information was better encoded or remembered than direction information relative to boundaries. We proposed that the type of reference influences the fidelity of distance and direction information in the spatial representation. </p><p>

<p> Using tools, writing, and eating are all important behaviors that involve manipulating objects. Successful manipulation requires the control of both the force exerted on the object and its resultant motion. Both have been associated with neural activity in the motor cortex and we are interested in the extent to which neural firing rates in this brain region are related to their combined control. The mechanical relation between force and motion is impedance and we hypothesized that motor cortical activity encodes an impedance signal that reflects the force and motion demands of behavior. We examined this possibility with a paradigm in which subjects manipulated a handle that moved along a track. The handle was locked in place until the subject exerted enough force to cross a specific threshold; it was then released and moved along the track. We hypothesized that this ballistic-release task would encourage subjects to modify their arm impedance in anticipation of the upcoming movement. </p><p> We modeled the behavior as a physical dynamical system and found that one component of model impedance, stiffness, varied in a way that matched the behavioral demands of the task and that stiffness could be dissociated from changes in force and displacement. We recorded activity from a population of motor cortical neurons and found that the temporal and time-averaged neural responses encoded information about motion and force. We also could decode model impedance parameters that we then used to approximate the time-varying force exerted on the handle. The force exerted on the handle and the model stiffness depended on muscle activity and we found components of muscle activity related to both force and model stiffness. Additional components of motor cortical activity were also related iv to both force and stiffness, suggesting a possible parceling of muscle-related representations in motor cortical activity. In addition to extending current models of neural activity to include manipulations, this study may be helpful in understanding how information encoded in motor cortical activity might be transformed into muscle activity during object interaction.</p><p>

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder caused by repeated concussive or subconcussive blows to the head. Clinically, this disease is characterized by cognitive dysfunction, short-term memory loss, and motor deficits. Pathologically, deposition of the abnormal protein tau, cerebral atrophy, and white matter degeneration is common. CTE has been categorized into Stages I-IV based on increased severity of protein deposition and cerebral atrophy. Acutely, mild traumatic brain injury (TBI) damages the long white matter tracks in the corpus callosum. In addition, it initiates a neuroinflammatory cascade aimed at protecting healthy tissue by clearing any toxic or damaging debris. This cascade results predominantly from the activation of the resident immune cells of the brain, microglia. Inflammation begins immediately and then subsides weeks or months after injury. However, pathological chronic activation of microglia can occur that can cause cell death and degeneration. Several studies have linked traumatic brain injury as well as chronic neuroinflammation to a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy (CTE). The present study quantifies the level of inflammation found in the brains of those diagnosed with varying stages of CTE compared to normal, healthy controls. The thickness of the corpus callosum was measured to investigate the correlation between microglial density and white matter degeneration. Cases were selected from the donated brains of former athletes and military veterans who had a history of repetitive mild TBI. Eleven healthy control cases, ten early stage (Stage I/II), and nine late stage (Stage III/IV) CTE cases were selected for analysis. Tissue sections of the anterior and posterior cingulate of each case were stained for microglia, reactive astrocytes, and macrophages using IBA-1, GFAP, and CD68 markers. The percent area stained of each section was calculated to compare inflammatory cell density across progressive stages of the disease. Analysis showed a significant thinning of the corpus callosum of Stage III/IV CTE cases compared to normal controls. There was a significant decrease in microglia and reactive astrocytes of both the anterior and posterior portions of the corpus callosum in both early and advanced stage CTE cases compared to healthy controls. Corpus callosum thickness was significantly decreased in advanced stage (III-IV), but not early stage (I-II) disease. Overall, this suggests that neuroinflammation is decreased in the corpus callosum in CTE despite marked degeneration. Repetitive mild TBI might impair mechanisms of brain inflammation and repair.

Reduction from a more to a less noxious stimulus intensity produces a disproportionate but transient decrease in perceived pain. Although the relationship between the central nervous system and this offset analgesia has come under investigation using brain imaging, whether offset analgesia is primarily mediated by central rather than peripheral mechanisms has not been established. Here we investigate this question in healthy volunteers using thermal stimuli while recording continuous pain ratings. We constructed a composite stimulus using one Peltier thermode to deliver a constant painful test stimulus while a separate thermode coincidentally delivered a shorter but more intense conditioning stimulus at a distinct location. Three spatial configurations were investigated all delivering stimulation to the ventral forearm either proximally or distally from one another on the same forearm or with thermodes on opposing forearms. We demonstrate a decrease in test stimulus pain levels following offset of an ipsilateral but not contralateral conditioning stimulus. This decrease is comparable in magnitude to that observed during a single thermode classic offset analgesia stimulation. The manifestation of analgesia in one sensory field following cessation of stimulation in a distinct sensory field shows antinociceptive adaptation of primary afferent neurons is unnecessary to produce offset analgesia, and demonstrates central mechanisms are sufficient to achieve temporal filtering of nociceptive information during stimulus offset. / 2017-08-01

PURPOSE: To compare white matter neuron density across 3 regions, prefrontal, temporal, and posterior parietal (PFC, TE, PP) in macaque monkey, with further analysis of subdivisions within the gyral white matter. METHODS: Histological tissue from three adult macaque monkeys, previously prepared with the neuron-specific pan-neuronal marker Neuronal-N, was used for analysis. Tissue was digitized and processed electronically to investigate cross- and intra-regional differences in the distribution of white matter neurons. RESULTS: Statistical analysis showed significant differences across all regions sampled and across most intra-regional subdivisions, although the more conservative post-hoc tests failed to find significant differences between specific regions. CONCLUSIONS: The results of the current study support regional differences. Further studies using a larger sample size may help elucidate the relatively unknown properties of white matter neurons.

Short-term and long-term neurological damage as a result of sports-related brain trauma is a major concern for athletes today. In the last decade, studies of subconcussive repetitive head impacts (RHI) in contact sports have found associations with functional and structural brain changes, even in the absence of diagnosed concussion. Risk and thresholds for brain dysfunction in the setting of sports-related RHI remain poorly understood. This prospective study enrolled 119 athletes (72 contact, 47 noncontact) of both sexes (79 male, 40 female), to explore the effect of one season of subconcussive RHI on brain function in high school football, boys lacrosse, and boys and girls soccer versus a comparison group of noncontact athletes. This study is the first to assess the effects of one season of RHI exposure on traditional and novel cognitive measures as well as self-reported emotion, sleep and headache in high school athletes. Contact sport athletes wore a commercial accelerometer to investigate if there is a dose-response relationship between RHI exposure and brain function. Paired t-test comparisons of all measures revealed contact sport athletes were not different than noncontact athletes in experiencing negative changes over the course of one season on the assessment battery. Given the number of subjects evaluated and the resultant power to detect change, this study had an 82.5% power to detect a Cohenʼs d of 0.66. Regression analysis of multiple measures of RHI among contact sport athletes did not identify a significant relationship between exposure and changes in cognition, emotion, sleep or headache over one season. Secondary analyses found significant relationships between a greater number of total head impacts at postseason assessment and higher scores on NIH Emotion Battery elements Perceived Stress (p=0.0002) and Perceived Hostility (p=0.0004), but it was unrelated to total years of football exposure. Overall, this study showed that there does not appear to be an association between one season of RHI exposure and short-term changes in cognition or self-reported aspects of emotion, sleep, or headache. Results from this study may help in the design of future investigations that will increase our understanding of the short-term consequences of RHI. Future studies should concentrate on the question of a clinically significant threshold at which RHI above a certain magnitude is more likely to cause brain dysfunction.

<p> This dissertation is about impacts to the capacities for autonomy and collaboration for the cyborg self integrated with brain-machine (BMI) and brain-to-brain interfaces (BTBI). These capacities are dependent on the reorganization of the cyborg self boundaries which are contingent on the development cycle of the underlying BTBI multidimensional systems as evidenced in recent neuroscience research and development (Carmena et al., 2003; Fitzsimmons, Lebedev, Peikon &amp; Nicolelis, 2009; Hochberg et al., 2012; Pais-Vieira, Lebedev, Kunicki, Wang, &amp; Nicolelis, 2013; Pais-Vieira, Chiuffa, Lebedev, Yadav, &amp; Nicolelis, 2015; Ramakrishnan et al., 2015; Wessberg et al., 2000) and speculated by the science fiction of the Nexus trilogy (Naam, 2015a, 2015b, 2015c). </p><p> The central accomplishments of this study include furthering the concept of the cyborg by positing a cyborg self with representational, cognitive, and functional dimensions, and identifying the cyborg self as a special case of the &ldquo;cognitive assemblage&rdquo; (Hayles, 2017, p 11). My analysis entails understanding an interdisciplinary model of the self that addresses the dynamic nature of the biological self, the self as a process, as a complex system emerging from material, physiological, cognitive, psychological, and social processes that is autobiographical and unified, having ownership and agency of mind and body (Damasio, 2010; Hayles, 2017; Marks-Tarlow, 1999; Ramachandran, 2004) dovetailing (Clark, 2003, 2008) with nonconscious cognitive assemblages (Hayles, 2017). I demonstrate that the dimensions of the cyborg self are reorganized by the development process of BMI and BTBI further affecting the locus or loci of self. The recursive reorganization of the cyborg self boundaries and dimensions leads to greatly fluctuating capacities for autonomy and collaboration. </p><p> I discuss the competing cultural forces such as transhumanism, and government and corporate interests promoting and hindering the advancement of NBIC and BTBI research and development, as well as the role of science fiction as a futuring tool, and the possibility, probability, and preferability of a cyborg self in 2040. </p><p> The research design is essentially a case study of contemporary and speculative BTBI in which I analyzed the multidimensional systems that comprise BTBI, their functionalities, and their development evolution. I analyzed how the cyborg self, autonomy, and collaboration showed up for the subjects integrated with BTBI. As NBIC and BTBI progresses, autonomy and collaboration face many challenges as they become pendulums swinging between ever increasing and decreasing capacities that are contingent upon the latest development cycle.</p><p>