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Falling, an epidemic most prevalently seen in the elderly population, accounts for the majority of injury-related cases seen by emergency departments across the United States. Unfortunately, with no large-scale institutionalization of a solution, the problem is only expected to exacerbate as our planet’s population approaches the 7 billion mark. In the wake of the recent surge of falls among the elderly, Japan has implemented a program to include unicycling in the physical education curriculum for elementary schools across the country. The goal for this program is to encourage children to establish strong fundamental balancing skills, which could potentially alleviate the pain—physical, emotional, and financial—incurred from falls in the elderly. This senior thesis study builds off Japan’s unicycling program by investigating ways to improve wobble board balancing, a more practical alternative to unicycling. In previous research, the skill of stick balancing, a motor task that has been shown to behave with the same power laws as wobble board balancing, has been improved with the use of vibrations. Here, we show that learning to wobble board balance is not expedited and wobble board balancing skill is not improved with the employment of vibrations, unlike stick balancing. Nonetheless, those who learned to wobble board balance with background vibrations went on to later outperform those who learned to wobble board balance without vibrations. These results suggest that vibrations (50 Hz, 0.18 mm amplitude) have a beneficial effect on the development of skill for wobble board balancing that is not related to the direct physical effects of the vibration. The observations also suggest that in the presence of vibrations, the nervous system develops more robust strategies for controlling balance.

M.A. (Philosophy) / Philosophy of mind has begun to rely on input from neurobiology and neuroscience to answer questions concerning consciousness, representation and the subjective character of experience. Some philosophers believe that through studies done on the brain, neuroscience will help us answer the hard-problems of consciousness. The first chapter of this paper is concerned with the kind of contributions neurobiology can make to certain debates in philosophy of mind and proceeds to explain that even though neurobiology is mostly a positive contributor to philosophy of mind, it still fails to answer some of the more pressing issues in philosophy of mind. In the second chapter of this paper, I focus on Frank Jackson’s Knowledge Argument. Jackson’s Knowledge Argument is perhaps one of the most challenged arguments concerning experience in philosophy of mind and responses to this argument will possibly tell us more about the mind. Jackson argues that we gain a new kind of knowledge when we experience something, for example when seeing the colour red. He argues that these new learnt facts are non-physical. David Lewis argues that a person learns no new facts upon experiencing red, but rather abilities such as the ability to recognize, imagine and remember. In this chapter I also examine some of the counterarguments to Jackson’s Knowledge Argument and conclude that these philosophers have approached the Knowledge Argument incorrectly. I suggest a different physicalist response to the Knowledge Argument. In the third chapter of this paper, I propose a new physicalist account of experience I call ‘bifactualism’. The Knowledge Argument is an argument for dualism that claims that there are both physical and non-physical facts which can be learnt through experience. I reject the Knowledge Argument and suggest bifactualism. Bifactualism is a new physicalist account essentially comprising two elements. First, it distinguishes between two kinds of physical facts: general and particular. The second element is the claim that this distinction explains facts about consciousness, without resorting to dualism. I disagree with the dualist claims made in the Knowledge Argument and show that the Knowledge Argument neither supports dualist claims nor does it refute bifactualist claims. Most contributions made with regards to the Knowledge Argument focus on what Mary is able to learn once outside the black and white room. Bifactualism is interested in what she is able to learn in the black and white room which makes this a novel approach to the Knowledge Argument. In the fourth chapter of this paper I propose bifactualist responses to several issues that have been highlighted throughout this paper. In this chapter, I primarily focus on Nagel’s What it is Like to be a Bat? Nagel claims that we cannot know what it is like to be a bat subjective character of experience. This chapter argues that it is as difficult to know the feeling of what it is like, or WIL (Prinz, 2012), to be a bat which has a feeling of WIL, as it is to know the feeling of what it is like to be a book (which has no feeling of what it is like: non- WIL). I argue that this is not because of two different ways of knowing two different properties, but rather that there are two different physical facts about both WIL and non-WIL properties. I show that with a bifactualist account, there are particular physical facts that can be known about WIL and non-WIL properties alike that are not expressible in the language of physics.

Millions of individuals suffer disability or death from immune-based inflammatory diseases. If psychiatric disorders could be empirically linked to the prediction of immune-based inflammatory diseases, there would be a basis for promoting disease prevention measures for individuals diagnosed with one of four psychiatric disorders. Psychoneuroimmunology provided the theoretical base for understanding emotionally induced medical disease development. In this quantitative study, a parallel archival research design was used to investigate the degree to which generalized anxiety disorder, posttraumatic stress disorder, major depression recurrent, and dysthymic disorder predicted the presence of atherosclerosis, cardiovascular heart disease, rheumatoid arthritis, cancer, and type II diabetes. There were 1,209 electronic medical records of adult patients obtained through purposive stratified sampling. A secondary data analysis was employed using descriptive cross tabulation, chi-square test of independence, and multinomial logistic regression. The findings revealed major depression recurrent was a statistically significant predictor for atherosclerosis, rheumatoid arthritis, type II diabetes and cancer. Generalized anxiety disorder was a statistically significant predictor for cancer. The results can promote positive social change by providing information that could be used to develop assessment plans that identity individuals who are at risk of developing the comorbid diseases. The prevention programs could effectively be used to minimize the subsequent development of inflammatory diseases, which in turn could decrease the onset of the medical diseases among individuals with psychiatric disorders.

In this two-part study, I investigated whether the cyclic-adenosine monophosphate response element-binding (CREB) protein has the potential to be clinically modulated as a therapeutic target for the treatment of neurodegenerative diseases. Part one consisted of a systematic review that was conducted on select articles gathered through a stepwise method to explore (1) the relationship between diseased, neurodegenerative brains and levels of active, phosphorylated CREB (pCREB), (2) increased activation of CREB as a treatment for neurodegenerative symptoms, and (3) a potential therapeutic drug for neurodegenerative diseases that can target CREB signaling. The results of the systematic review showed evidence that suggested excitotoxic concentrations of N-methyl-D-aspartate (NMDA) results in decreased pCREB levels, while decreased pCREB levels were associated with impaired cognition and behavior, increased cell death, as well as decreased CRE-gene transcription and long-term potentiation (LTP). Part two consisted of a systematic review and meta-analysis on clinical trials that used the phosphodiesterase type IV inhibitor, roflumilast, on healthy and schizophrenic patients. It was found that 100 µM roflumilast was able to improve verbal learning in healthy and schizophrenic subjects (ES = 64). Initial evidence indicates that future research on neurodegenerative diseases should further investigate CREB’s potential to be clinically modulated and research investigating PDE4 inhibitor drug therapy for the treatment of neurodegeneration should be expanded upon further in subsequent studies.

<p>The striatum is part of a neural feedback network that modifies the functioning of the cerebral cortex. The importance of the striatum is underlined by the clinical consequences of striatal dysfunction: disordered signaling in the striatum gives rise to the clinical syndrome of Parkinson's disease, while degeneration of striatal output neurons produces the clinical manifestations of Huntington's disease. The striatum is a complex structure comprised of two major populations of neurons: the spiny projection neurons that carry the striatal output to other nuclei in the basal ganglia; and several subtypes of aspiny cells that project locally within the striatum to modify striatal output. The two major inputs to the striatum are the glutamatergic pathway from the cerebral cortex and the dopaminergic pathway from the substantia nigra. The goal of my research is to explore the nature and functional significance of dopamine-glutamate signaling and its role in the striatum and basal ganglia. My first series of studies in vivo demonstrated that altering dopaminergic tone in the striatum by D2-dopamine receptor blockade or by 6-hydroxy-dopamine lesion of the nigrostriatal dopamine projection in the rat could modify the pathological, neurochemical and behavioural consequences of glutamate-receptor-mediated-stimulation. In order to investigate the details of this interaction, I developed an in vitro tissue culture system. I showed initially that the growth of striatal neurons in serum free culture parallels their in vivo development. I then went on to use this in vitro system to demonstrate the differential effects of selective glutamate receptor agonists on transmitter release from subpopulations of the two major classes of striatal neurons: (i) those in which somatostatin and neuropeptide Y are colocalised with nitric oxide and (ii) the substance P-containing spiny projection neurons. This series of studies demonstrated that substance P release was selectively stimulated through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor while somatostatin and neuropeptide Y release were selectively provoked by stimulation of the kainate receptor. Stimulation of the metabotropic glutamate receptor had little effect on the release of any of the three peptides. My final series of experiments examined the differential effects of selective dopamine receptor stimulation on glutamate-receptor-induced release of substance P, somatostatin and neuropeptide Y. The D1 agonist SKF 38393, and to a significantly lesser extent the D2 agonist quinpirole, attenuated glutamatergic release of substance P from the spiny neurons. In contrast, the D2 agonist quinpirole potentiated the release of neuropeptide Y and somatostatin from aspiny neurons. The D1 agonist SKF 38393 attenuated glutamate receptor stimulated release of neuropeptide Y, without significantly affecting the release of somatostatin from the same cultures. This latter result indicates that dopamine can differentially regulate transmitter release not only from separate populations of striatal neurons but also differentially control release of transmitter that are colocalised within a single population of neurons. To my knowledge these studies are the first to demonstrate this differential regulation in the striatum, and implies that the delicate balance required for both normal cognition and movement may be intimately related to the balance of signaling between the intrinsic (somatostatin-neuropeptide Y-containing) and extrinsic (substance P-containing) neuronal populations in the striatum.</p> / Doctor of Philosophy (PhD)

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterizeby devastating symptoms, such as muscle weakness, paralysis, and death within 5 years of disease onset. Mutations in human (VAMP)-associated protein B (hVAPB) gene cause ALS8. Interestingly, the Drosophila VAPB (DVAP) is required at the Drosophila larval neuromuscular junction (NMJ), to control bouton morphology. In Pennetta’s lab Drosophila Sac1, a phosphoinositide-4- phosphate (PI4P) phosphatase, was identified during a genome-wide yeast twohybrid screen, as a DVAP binding partner. VAP plays a role in regulating PI4P turnover in yeast and phosphoinositides are implicated in some neurodegenerative processes. In this PhD thesis, Sac1-DVAP interaction is used as the starting point to identify the mechanism that is altered when DVAP function is impaired. Thus, the possibility that the cellular pathways regulated by PI4P are affected in VAPB-mediated neurodegeneration was explored. First, the Sac1-DVAP association was confirmed in vitro by coimmunoprecipitation. Subsequently, we found that these two proteins colocalize in vivo at the ER membranes. Then, immunohistochemical analysis of Drosophila larval NMJ revealed that Sac1 and DVAP are involved in similar pathways. They both have a function in microtubule stabilization in the presynaptic boutons and axonal vesicle transport at the presynaptic compartment. They also seem to contribute to the spectrin-actin cytoskeleton stabilization at the postsynaptic compartment of the NMJ. Lastly, we reported that reduced levels of Sac1 phosphatase cause progressive neurodegeneration. Moreover, Sac1 is trapped into cytosolic aggregates induced by the expression of the ALS8-mutant allele of DVAP, and it does not localize to its original place in the cell. All together these results suggest that in ALS8 hVAPB seems to have a dominant negative effect on Sac1. Sac1 mislocalization could inhibit the dephosphorylation of PI4P. This PhD work further confirms Sac1-DVAP interaction and it suggests a mechanism underlying ALS8 pathogenesis, supporting the idea that altered metabolism of phosphoinositides can cause neurodegeneration.

No description available.

In this thesis, I describe the development of a novel method to selectively modulate neural activity cell-type selectively. Binding of Zolpidem, an allosteric modulator that enhances GABAa receptor function and the inverse agonist β-carboline, require a phenylalanine residue (F77) in the γ subunit.

Abstract Background: Cusk-eels from the subfamily Neobythiitinae are one of the major groups of sound-producing fishes on the continental slope. Sounds have never been recorded from a member of this subfamily, and sonic anatomy is considered a proxy for sound production. As the first part of a study on the effects of depth on sonic anatomy, we examined three relatively shallow species from the upper continental slope. Methods: Three species (Hoplobrotula armata, Neobythites longipes and Neobythites unimaculatus) were examined for sonic anatomy (skeleton, swimbladder and sonic muscles), and sonic and epaxial muscle fibers were measured for diameter. Regressions of dimensions and weights of sonic muscles and swimbladders against fish total length and weight were compared to determine sexual dimorphism and relative development between species. Results: Four pairs of sonic muscles (two medial and two lateral) originate on the skull and insert on the medial swimbladder or on modified epineural ribs that attach to the lateral swimbladder. The medial and medial intermediate muscles are generally larger in males than females and are made of relatively small fibers (ca 10 um in diameter), and lateral muscles are generally larger in females and consist of larger fibers as in epaxial muscles. Medial muscles are considerably larger in Hoplobrotula armata than in the Neobythites species. Conclusion: Neobythitines from the upper slope have relatively well-developed sexually-dimorphic sonic systems, suggesting that males produce advertisement calls for courtship. There are major quantitative differences between species. We suggest that sound production involves tonic contraction of the large-fibered lateral muscle pair and oscillatory contractions of the smaller medial fibers setting the swimbladder into vibration. Hoplobrotula armata is probably capable of making more intense sounds than the Neobythies spp.