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Reduced activity of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine site on the NR1 subunit that may be a promising therapeutic target for psychiatric illness. Recently, D-serine has been discovered to be a high-affinity endogenous activator of the NMDAR glycine site. Levels of D-serine in the brain are controlled by its synthesis enzyme serine racemase (Srr) and its catabolic enzyme D-amino acid oxidase (DAO). This work investigates the NMDAR glycine site, D-serine, and D-serine-regulatory enzymes Srr and DAO in the pathophysiology and treatment of symptomatology relevant to schizophrenia and other psychiatric disorders. Pharmacological and genetic mouse models were used to alter glycine site function and D-serine availability. Behavioral responses in these models were assessed. Administration of exogenous D-serine and the glycine transporter 1 (GlyT-1) inhibitor ALX-5407 improved performance of C57BL/6J mice in behavioral tests examining prepulse inhibition (PPI) or latent inhibition (LI). These compounds also reversed impairments induced by the NMDAR antagonist MK-801, and produced similar beneficial effects to the classical atypical antipsychotic clozapine. Mice carrying a point mutation that leads to diminished NMDAR glycine site function demonstrated abnormally persistent LI and deficits in social approach and spatial recognition that were reversible by D-serine or clozapine administration. Similarly, mutant mice that lacked Srr function and had a severe reduction in D-serine displayed impairments in sociability, PPI, spatial recognition and memory. Behavioral deficits in mice without Srr were exacerbated by MK-801 and rescued by treatment with D-serine or clozapine. A genetically-induced loss of DAO function in mice resulted in the elevation of brain D-serine levels, and produced improvements in spatial reversal memory and extinction of a learned response in the Morris water maze, consistent with the effects of exogenous D-serine application in wild-type mice. Thus, deficiencies in NMDAR glycine site function and D-serine availability produce behavioral disturbances that are relevant to the negative and cognitive symptoms of schizophrenia. Activation of the NMDAR glycine site by D-serine, GlyT-1 inhibition, or diminished DAO activity may be beneficial for the treatment of schizophrenia and other psychopathologies involving cognitive dysfunction and persistent repetitive behaviors.

This thesis investigates the behavioural and anatomical correlates of recovery from motor cortex damage in rats. The effectiveness of behavioural, pharmacological, and regenerative treatments was investigated using models of focal stroke. Chronic bilateral motor deficits were found after motor cortex damage induced by various methods. These behavioural deficits were similar in severity and duration although they were correlated with different patterns of reorganization seen in Golgi-stained tissue. Animals with motor cortex injury benefited from postinjury olfactory stimulation, chronic administration of nicotine, and infusions of epidermal growth factor followed by erythroprotein. Different mechanisms of plasticity in remaining cortical circuits are discussed as possible candidates responsible for the behavioural improvement. The current thesis expands the current knowledge of the effects of adult cortical damage to ares critical to motor control. It may also stimulate research on therapies and possible mechanisms that might enhance recovery after stroke. / xviii, 299 leaves : ill. (some col.) ; 29 cm.

Stroke is the third leading cause of death and survivors suffer motor impairments. The rodent sensorimotor system is similar to the human's, making rodents a good model to study the effects of stroke. Transgenic technology makes the mouse a desirable stroke model, however, there are few behavioural tests to assess behavioural outcome. This thesis evaluates mice subjected to permanent or temporary occlusion focal motor cortex strokes in a skilled reaching task. The first experiment documents changes in skilled movements in mice with a permanent occlusion focal motor cortex stroke. The second experiment is identical but uses a temporary occlusion focal motor cortex stroke. The third experiment compares the two strokes. The results indicate permanent occlusion mice suffer great impairments, and a larger injury, than temporarily occluded animals. The mice with the largest insults were most impaired. Mice make an excellent behavioural and genetic model for studying motor system stroke. / viii, 115 leaves : ill. ; 29 cm.

Antinuclear antibodies (ANA) are used in screening and diagnosis of autoimmune connective tissue disorders including systemic lupus erythematosus (SLE). CNS related disorders are prevalent in SLE patients (–80%) and ANA binds specific sites within the brain. To investigate ANA infiltration across the blood-brain barrier (BBB), an ANA injectable Lewis rat model was created using 3 rat groups (saline, ANA, and ANA with histamine; since histamine promotes BBB permeability). ANA serum levels were tested for all three rat groups and rats injected with histamine demonstrated signs of histadelia. Brain slices were obtained and examined for the presence of ANA using immunofluorescence. ANA infiltration across the BBB was observed in ANA injected groups. Though the ANA and ANA histamine groups were significantly different from controls (p<0.034, p<0.030, respectively), no significance between ANA and ANA histamine groups was observed. This model could further be used to examine BBB permeability and potential drug therapy. / Department of Physiology and Health Science

Multiple sclerosis is a progressive autoimmune disease where myelin is gradually stripped from axons. Axon degeneration inevitably follows protracted myelin loss ultimately leading to irreversible neurological decline. To better understand the cellular mechanisms associated with the axon loss phase of the disease, spinal cord axons from the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis were examined using correlated in vivo time-lapse microscopy and serial section transmission electron microscopic (ssTEM) reconstruction. A novel technique, termed near infrared burning (NIRB), was developed that took advantage of a femtosecond-pulsed mode locked laser’s ability to create photoconvertable fiducial markers for routine identification of previously imaged axons for ssTEM reconstruction. This combination of imaging techniques revealed the subcellular milieu that underlies axon degeneration at both the light and electron microscopic level. In particular, paranodal regions of axons in EAE animals contained a significantly higher population of mitochondria with large rounded, electron lucid, vesiculated mitochondria with unorganized cristae compared to controls. This effect was largely restricted to the paranodal region and was not always associated with direct immune cell interaction or myelin loss. Together, these results suggest a novel mechanism for axon degeneration that is not only focal in nature, but decoupled with myelin loss in the EAE animal model of multiple sclerosis. / Department of Biology

The following research paper was concerned with five basic objectives:(1) outlining the major theoretical and methodological approaches used in the reconstruction of early hominid social behavior/social structure as a context in which to view Richard Wrangham's and Michael Ghiglieri's phylogenetic models of stem-hominid social structure.(2) examining Wrangham's and Ghiglieri's models of stem-hominid and chimpanzee social structure.(3) indicating how theoretical and methodological aspects of structure essentially represent an extension of the theoretical and methodological approaches the same researchers applied to their models of chimpanzee social structure.(4) addressing the theoretical and methodological deficiences of Wrangham's and Ghiglieri's models of chimpanzee social structure.(5) providing suggestions for improved phylogenetic models of early hominid social structure.The first objective was achieved by: (a) reviewing Tooby and Devore's (1986) and Wrangham's (1986) evaluations of the major theoretical approaches and methodologies used in the reconstruction of hominid social behavior/structure (b) defining, classifying and evaluating Wrangham's and Ghiglieri's phylogenetic approaches within this context.The second objective was accomplished by outlining, analyzing, and comparing/contrasting Wrangham's and Ghiglieri's phylogenetic models of stem-hominid social structure (i.e.Wrangham 1986; Ghiglieri 1987, 1989) and Wrangham's and Ghiglieri's models of chimpanzee social structure (i.e. Wrangham 1975, 1979; Ghiglieri 1984, 1985, 1987, 1989).The third objective was achieved by recognizing how Wrangham and Ghiglieri used/stressed principles and concepts derived from evolutionary biology and/or behavioral ecology to develop their models of stem-hominid and chimpanzee social structure. This analysis showed that Wrangham's models of social structure were more favorably inclined toward the method of behavioral ecology than Ghiglieri's models, which favored a sociobiological paradigm. Furthermore, although neither researcher relied exclusively on the above theoretical approaches, the main thrust of their argument often centered around it. For instance, Wrangham's analysis of chimpanzee social structure (Wrangham 1975, 1979) indicated that the ultimate cause of that structure was ecological i.e., patchy food distribution leads to wide female dispersal for optimal foraging efficiency, which in turn favors a male kin breeding group that can maintain a territority that includes several individual female ranges. In contrast, Wrangham's phylogenetic model of the social structure of the stem-hominid (Wrangham, 1986) suggested that phylogenetic inertia may be partially responsible for the shared social features found among African Hominoidea. However, in the same work, Wrangham also suggested that further socioecological analysis of African apes may indicate whether food distribution and its effects on female dispersion/association may partially explain conservative African ape social features.Ghiglieri's phylogenetic model of the stem-hominid (1987, 1989), on the other hand, explained the conservative social features of bonobos, common chimpanzees, and hominids to be primarily a product of phylogenetic inertia and sexual selection. Furthermore, for Ghiglieri the most important sexual selection variable was a male communal reproductive strategy. This, according to Ghiglieri, is the ultimate cause of social structure. Notably, Ghiglieri (1984, 1985) had earlier stressed the overiding importance of a male communal reproductive strategy but was less dogmatic in his insistence that chimpanzees had essentially solved their ecological problems (e.g. that they had solved the food distribution problem by fusion-fission sociality; predators were never a real problem). Nevertheless, Ghiglieri's earlier position similarily expressed the idea that a communal reproductive strategy constituted the ultimate cause of social structure.The fourth objective was accomplished by presentation of an alternative model of chimpanzee social behavior which suggested that structure; the effect of phylogenetic inertia on social structure; chimpanzee social structure is the combined product of ecological and sexual selection forces: female optimal foraging, male mating strategies, and predator pressure. The model was considered by the author to be unique in that it integrated essential aspects of both Wrangham's and Ghiglieri's models and, in addition, provided support for Alexander's (1974) contention that predation pressure is an ultimate cause of ape social structure. The model also outlined scenarios for the evolution of chimpanzee group._ extensibility (fusion-fission sociality) and the capacity for warfare among chimpanzees.The last objective was achieved by a discussion of the implications that the author's model had for phylogenetic models of stem-hominid social structure. In this discussion the author reviewed the following issues as they related to the phylogenetic reconstruction of hominid social structure: the role of phylogeny and/or ecology in the causation of social encountered when using a phylogenetic referential model for the personal biases that enter into phylogenetic econstructions; pitfalls reconstruction of early hominid social evolution; the significance of chimpanzee models of social structure.The importance of the preceding study lay in its ability to stimulate improved conceptual models of African hominoid social structure. / Department of Anthropology

Bifidobacterium infantis (BI) and other probiotics are non-pathogenic living organisms that have recently gained attention for their possible therapeutic implications on the health of the digestive tract. The mechanisms by which probiotics exert their effects are largely unknown. This study explored the protective and regulatory effect of oral BI on the enteric nervous system (ENS) in the TNBS-induced colitis rats. Electrical field stimulation and chemical stimulation by serotonin (5-HT) were used to elicit changes in the short-circuit current (Isc) response of the colonic rat tissue. BI-fed colitis rats expressed trends of higher secretomotor activity and revealed signs of decreased macroscopic inflammatory damage when compared to sham-fed colitis rats, suggesting a protective and preventative role of oral BI. These findings may provide additional insights for understanding the prophylactic and therapeutic value of specific probiotics in intestinal inflammatory disorders, offering the possibility of a noninvasive alternative to toxic and immune-compromising drugs. / Access to thesis permanently restricted to Ball State community only / Department of Physiology and Health Science

<p>Understanding the structure of the brain has been a major goal of neuroscience research over the past century, driven in part by the understanding that brain structure closely follows function. Normative brain maps, or atlases, can be used to understand normal brain structure, and to identify structural differences resulting from disease. Recently, diffusion tensor magnetic resonance imaging has emerged as a powerful tool for brain atlasing; however, its utility is hindered by image resolution and signal limitations. These limitations can be overcome by imaging fixed ex-vivo specimens stained with MRI contrast agents, a technique known as diffusion tensor magnetic resonance histology (DT-MRH). DT-MRH represents a unique, quantitative tool for mapping the brain with unprecedented structural detail. This technique has engendered a new generation of 3D, digital brain atlases, capable of representing complex dynamic processes such as neurodevelopment. This dissertation explores the use of DT-MRH for quantitative brain atlasing in an animal model and initial work in the human brain. </p><p>Chapter 1 describes the advantages of the DT-MRH technique, and the motivations for generating a quantitative atlas of rat postnatal neurodevelopment. The second chapter covers optimization of the DT-MRH hardware and pulse sequence design for imaging the developing rat brain. Chapter 3 details the acquisition and curation of rat neurodevelopmental atlas data. Chapter 4 describes the creation and implementation of an ontology-based segmentation scheme for tracking changes in the developing brain. Chapters 5 and 6 pertain to analyses of volumetric changes and diffusion tensor parameter changes throughout rat postnatal neurodevelopment, respectively. Together, the first six chapters demonstrate many of the unique and scientifically valuable features of DT-MRH brain atlases in a popular animal model.</p><p>The final two chapters are concerned with translating the DT-MRH technique for use in human and non-human primate brain atlasing. Chapter 7 explores the validity of assumptions imposed by DT-MRH in the primate brain. Specifically, it analyzes computer models and experimental data to determine the extent to which intravoxel diffusion complexity exists in the rhesus macaque brain, a close model for the human brain. Finally, Chapter 8 presents conclusions and future directions for DT-MRH brain atlasing, and includes initial work in creating DT-MRH atlases of the human brain. In conclusion, this work demonstrates the utility of a DT-MRH brain atlasing with an atlas of rat postnatal neurodevelopment, and lays the foundation for creating a DT-MRH atlas of the human brain.</p> / Dissertation