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- All Subjects: Electrophysiology
- All Subjects: Learning
- All Subjects: Traumatic Brain Injury
- Creators: Kleim, Jeffrey
- Resource Type: Text
- Status: Published
Description
Traumatic brain injury (TBI) is a leading cause of disability worldwide with 1.7 million TBIs reported annually in the United States. Broadly, TBI can be classified into focal injury, associated with cerebral contusion, and diffuse injury, a widespread injury pathology. TBI results in a host of pathological alterations and may lead to a transient blood-brain-barrier (BBB) breakdown. Although the BBB dysfunction after TBI may provide a window for therapeutic delivery, the current drug delivery approaches remains largely inefficient due to rapid clearance, inactivation and degradation. One potential strategy to address the current therapeutic limitations is to employ nanoparticle (NP)-based technology to archive greater efficacy and reduced clearance compared to standard drug administration. However, NP application for TBI is challenging not only due to the transient temporal resolution of the BBB breakdown, but also due to the heterogeneous (focal/diffuse) aspect of the disease itself. Furthermore, recent literature suggests sex of the animal influences neuroinflammation/outcome after TBI; yet, the influence of sex on BBB integrity following TBI and subsequent NP delivery has not been previously investigated. The overarching hypothesis for this thesis is that TBI-induced compromised BBB and leaky vasculature will enable delivery of systemically injected NPs to the injury penumbra. This study specifically explored the feasibility and the temporal accumulation of NPs in preclinical mouse models of focal and diffuse TBI. Key findings from these studies include the following. (1) After focal TBI, NPs ranging from 20-500nm exhibited peak accumulation within the injury penumbra acutely (1h) post-injury. (2) A smaller delayed peak of NP accumulation (40nm) was observed sub-acutely (3d) after focal brain injury. (3) Mild diffuse TBI simulated with a mild closed head injury model did not display any measurable NP accumulation after 1h post-injury. (4) In contrast, a moderate diffuse model (fluid percussion injury) demonstrated peak accumulation at 3h post-injury with up to 500 nm size NPs accumulating in cortical tissue. (5) Robust NP accumulation (40nm) was found in female mice compared to the males at 24h and 3d following focal brain injury. Taken together, these results demonstrate the potential for NP delivery at acute and sub-acute time points after TBI by exploiting the compromised BBB. Results also reveal a potential sex dependent component of BBB disruption leading to altered NP accumulation. The applications of this research are far-reaching ranging from theranostic delivery to personalized NP delivery for effective therapeutic outcome.
ContributorsBharadwaj, Vimala Nagabhushana (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Kodibagkar, Vikram D (Thesis advisor) / Kleim, Jeffrey (Committee member) / Tian, Yanqing (Committee member) / Lifshitz, Jonathan (Committee member) / Anderson, Trent R (Committee member) / Arizona State University (Publisher)
Created2018
Description
Communication amongst eusocial insect is key to their success. Ants rely on signaling to mediate many different functions within a colony such as policing and nest mate recognition. Camponotus floridanus uses chemosensory signaling in the form of cuticular hydrocarbons to regulate these functions. Each cuticular hydrocarbon profile contains numerous hydrocarbons, however it is yet to be seen if Camponotus floridanus can discriminate between linear hydrocarbons of similar length. Individual specimens were conditioned in three different ways: 5 conditioning with high concentration of sugar water (1;1 ratio), 1 conditioning with high concentration of sugar water, and 5 conditioning with low concentration of sugar water (1;4). Two linear hydrocarbons were use, C23 and C24, with C23 always being the conditioned stimulus. Specimens who were conditioned 5 times with high concentration of sugar water were the only group to show a significant response to the conditioned stimulus with a p-value of .008 and exhibited discrimination behavior 46% of the time. When compared 5 conditioning with high concentration to the other two testing conditioning groups, 1 conditioning with high concentration produced an insignificant p-value of .13 was obtained whereas when comparing it with 5 conditioning low concentration of sugar a significant p-value of .0132 was obtained. This indiciates that Camponotus floridanus are capable of discrimination however must be conditioned with high concentration of sugar water, while number of conditioning is insignificant.
ContributorsDamari, Ben Aviv (Author) / Liebig, Juergen (Thesis director) / Ghaninia, Majid (Committee member) / Pratt, Stephen (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2014-05
Description
A previous study demonstrated that learning to lift an object is context-based and that in the presence of both the memory and visual cues, the acquired sensorimotor memory to manipulate an object in one context interferes with the performance of the same task in presence of visual information about a different context (Fu et al, 2012).
The purpose of this study is to know whether the primary motor cortex (M1) plays a role in the sensorimotor memory. It was hypothesized that temporary disruption of the M1 following the learning to minimize a tilt using a ‘L’ shaped object would negatively affect the retention of sensorimotor memory and thus reduce interference between the memory acquired in one context and the visual cues to perform the same task in a different context.
Significant findings were shown in blocks 1, 2, and 4. In block 3, subjects displayed insignificant amount of learning. However, it cannot be concluded that there is full interference in block 3. Therefore, looked into 3 effects in statistical analysis: the main effects of the blocks, the main effects of the trials, and the effects of the blocks and trials combined. From the block effects, there is a p-value of 0.001, and from the trial effects, the p-value is less than 0.001. Both of these effects indicate that there is learning occurring. However, when looking at the blocks * trials effects, we see a p-value of 0.002 < 0.05 indicating significant interaction between sensorimotor memories. Based on the results that were found, there is a presence of interference in all the blocks but not enough to justify the use of TMS in order to reduce interference because there is a partial reduction of interference from the control experiment. It is evident that the time delay might be the issue between context switches. By reducing the time delay between block 2 and 3 from 10 minutes to 5 minutes, I will hope to see significant learning to occur from the first trial to the second trial.
The purpose of this study is to know whether the primary motor cortex (M1) plays a role in the sensorimotor memory. It was hypothesized that temporary disruption of the M1 following the learning to minimize a tilt using a ‘L’ shaped object would negatively affect the retention of sensorimotor memory and thus reduce interference between the memory acquired in one context and the visual cues to perform the same task in a different context.
Significant findings were shown in blocks 1, 2, and 4. In block 3, subjects displayed insignificant amount of learning. However, it cannot be concluded that there is full interference in block 3. Therefore, looked into 3 effects in statistical analysis: the main effects of the blocks, the main effects of the trials, and the effects of the blocks and trials combined. From the block effects, there is a p-value of 0.001, and from the trial effects, the p-value is less than 0.001. Both of these effects indicate that there is learning occurring. However, when looking at the blocks * trials effects, we see a p-value of 0.002 < 0.05 indicating significant interaction between sensorimotor memories. Based on the results that were found, there is a presence of interference in all the blocks but not enough to justify the use of TMS in order to reduce interference because there is a partial reduction of interference from the control experiment. It is evident that the time delay might be the issue between context switches. By reducing the time delay between block 2 and 3 from 10 minutes to 5 minutes, I will hope to see significant learning to occur from the first trial to the second trial.
ContributorsHasan, Salman Bashir (Author) / Santello, Marco (Thesis director) / Kleim, Jeffrey (Committee member) / Helms Tillery, Stephen (Committee member) / Barrett, The Honors College (Contributor) / W. P. Carey School of Business (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
Description
ABSTRACT Communication is vital in the context of everyday life for all organisms, but particularly so in social insects, such as Z. nevadensis. The overall lifestyle and need for altruistic acts of individuals within a colony depends primarily on intracolony chemical communication, with a focus on odorants. The perception of these odorants is made possible by the chemoreceptive functions of sensilla basiconica and sensilla trichoid which exist on the antennal structure. The present study consists of both a morphological analysis and electrophysiological experiment concerning sensilla basiconica. It attempts to characterize the function of neurons present in sensilla basiconica through single sensillum recordings and contributes to existing literature by determining if a social insect, such as the dampwood termite, is able to perceive a wide spectrum of odorants despite having significantly fewer olfactory receptors than most other social insect species. Results indicated that sensilla basiconica presence significantly out-paced that of sensilla trichoid and sensilla chaetica combined, on all flagellomeres. Analysis demonstrated significant responses to all general odorants and several cuticular hydrocarbons. Combined with the knowledge of fewer olfactory receptors present in this species and their lifestyle, results may indicate a positive association between the the social complexity of an insect's lifestyle and the number of ORs the individuals within that colony possess.
ContributorsMcGlone, Taylor (Author) / Liebig, Juergen (Thesis director) / Ghaninia, Majid (Committee member) / Barrett, The Honors College (Contributor)
Created2015-05
Description
Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States each year and is a leading cause of death and disability for children and young adults in industrialized countries. Unfortunately, the molecular and cellular mechanisms of injury progression have yet to be fully elucidated. Consequently, this complexity impacts the development of accurate diagnosis and treatment options. Biomarkers, objective signatures of injury, can inform and facilitate development of sensitive and specific theranostic devices. Discovery techniques that take advantage of mining the temporal complexity of TBI are critical for the identification of high specificity biomarkers.
Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential.
My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate.
The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity.
Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential.
My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate.
The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity.
ContributorsMartinez, Briana Isabella (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Lifshitz, Jonathan (Committee member) / Sierks, Michael (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2020
Description
Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for 70-90% of all TBI cases, yet its neuropathophysiology is still poorly understood. While a single mTBI injury can lead to persistent deficits, repeat injuries increase the severity and duration of both acute symptoms and long term deficits. In this study, to model pediatric repetitive mTBI (rmTBI) we subjected unrestrained juvenile animals (post-natal day 20) to repeat weight drop impact. Animals were anesthetized and subjected to sham or rmTBI once per day for 5 days. At 14 days post injury (PID), magnetic resonance imaging (MRI) revealed that rmTBI animals displayed marked cortical atrophy and ventriculomegaly. Specifically, the thickness of the cortex was reduced up to 46% beneath and the ventricles increased up to 970% beneath the impact zone. Immunostaining with the neuron specific marker NeuN revealed an overall loss of neurons within the motor cortex but no change in neuronal density. Examination of intrinsic and synaptic properties of layer II/III pyramidal neurons revealed no significant difference between sham and rmTBI animals at rest or under convulsant challenge with the potassium channel blocker, 4-Aminophyridine. Overall, our findings indicate that the neuropathological changes reported after pediatric rmTBI can be effectively modeled by repeat weight drop in juvenile animals. Developing a better understanding of how rmTBI alters the pediatric brain may help improve patient care and direct "return to game" decision making in adolescents.
ContributorsGoddeyne, Corey (Author) / Anderson, Trent (Thesis advisor) / Smith, Brian (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2014