Thesis--Polyteknisk læreanstalt, Copenhagen. / Summary in Danish. Thesis statement inserted. Bibliography: p. 455-460.

Thesis (M.S.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains vii, 79 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 70-78).

The extracellular environment of the central nervous system (CNS) through which neuritic processes must traverse during development or after injury is complex, and may vary from stabile conditions to a milieu favorable for neural plasticity and growth. The extracellular space in the CNS accounts for about 20% of brain volume and is composed of aggregating complexes of several different extracellular matrix (ECM) molecules. The ECM supports neural networks and acts as a barrier for neurite extention, depending on the type of molecules involved and the various signals they induce. One mechansim that may produce an environment favoring plasticity is the proteolytic cleavage of ECM. Brevican belongs to the lectican family of aggregating, chondroitin sulfate-containing proteoglycans (CSPGs) and is abundant in brain ECM complexes. It is localized peri-synaptically, inhibits neurite outgrowth, and is thought to stabilize synaptic networks in the adult. Interestingly, a significant proportion of brevican in the CNS is observed as a fragment of the protein core formed by proteolytic cleavage. Endogenous matrix-degrading proteinases, such as the MMPs (matrix metalloproteinases) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), cleave brevican and other lecticans potentially promoting neural plasticity. Cleavage of brevican and similar lectican family members may "loosen" the aggregated complexes and change the extracellular environment to one that is more permissive toward neural plasticity. After injury, during inflammation or with disease, alterations in the ECM may influence development and/or progression of neurological disease. The purpose of these studies was to investigate the catabolism of brevican in the ECM and its potential role in neural plasticity under each of these influences, taking an in depth look at how brevican is processed after (1) undergoing a classical model of neural plasticity, the entorhinal cortex lesion (ECL); (2) a disease state that is thought to have dysregulated neural and synaptic plasticity; and (3) how brevican catabolism and neural plasticity is effected by deleting the protease responsible for the cleavage of lecticans in a mouse model. Overall, these experiments provide evidence that the proteolytic cleavage of brevican, and lecticans in general, may play an important role in the regulation of neural plasticity.

Alteration of one sensory system can have striking effects on the processing and organization of the remaining senses, a phenomenon known as cross-modal plasticity. The goal of this thesis was to understand the circuit basis of this form of plasticity. I established the mouse as a model system for studying cross-modal plasticity by comparing population activity in visual cortex between animals reared in complete darkness from birth (DR) to those housed in a normal light/dark environment (LR). I found that secondary visual cortex (V2L) responds much more strongly to auditory stimuli in DR than LR. I provide evidence that there is a sensitive period for cross-modal responses that ends in early adulthood. I also show that exposure to light later in life reduces V2L auditory activity to LR levels. I recorded single units to show that there is a higher percentage of auditory responsive neurons in DR V2L. In collaboration with Lia Min in Michela Fagiolini’s laboratory, we discovered that this was associated with an increase in the number of projections from auditory thalamus and auditory cortex. We also provide evidence that V2L is multimodal from birth and becomes less so with visual experience. I examined several molecular pathways that are affected by dark-rearing to see if they are involved in cross-modal plasticity. I found that Nogo receptor (NgR), Lynx1, and Icam5 signaling all play a fundamental role in controlling the duration of plasticity. I also show that the hyperconnectivity in NgR -/- and DR mice leads to an increase in multisensory enhancement. In primary visual cortex, cross-modal influences were much weaker. Similar to V2L, the distribution of cell types was affected by NgR signaling. I also found that both the range of cross-modal influence and its sign (excitatory or inhibitory) is dependent on visual experience. Finally, I show that NgR signaling and the maturation of inhibitory circuits affect these two properties. Together, these results provide evidence of the molecular mechanisms underlying cross-modal plasticity. We believe that this will further our knowledge of how to improve rehabilitation strategies after loss of a sensory system.

This thesis investigates the mechanical behavior of electrodes in Li-ion batteries. Each electrode in a Li-ion battery consists of host atoms and guest atoms (Li atoms). The host atoms form a framework, into which Li atoms are inserted via chemical reactions. During charge and discharge, the amount of Li in the electrode varies substantially, and the host framework deforms. The deformation induces in an electrode a field of stress, which may lead to fracture or morphological change. Such mechanical degradation over lithiation cycles can cause the capacity to fade substantially in a commercial battery. We study fracture of elastic electrodes caused by fast charging using a combination of diffusion kinetics and fracture mechanics. A theory is outlined to investigate how material properties, electrode particle size, and charging rate affect fracture of electrodes in Li-ion batteries. We model an inelastic host of Li by considering diffusion, elastic-plastic deformation, and fracture. The model shows that fracture is averted for a small and soft host—an inelastic host of a small feature size and low yield strength. We present a model of concurrent reaction and plasticity during lithiation of crystalline silicon electrodes. It accounts for observed lithiated silicon of anisotropic morphologies. We further explore the microscopic deformation mechanism of lithiated silicon based on first-principles calculations. We attribute to the microscopic mechanism of large plastic deformation to continuous Li-assisted breaking and reforming of Si-Si bonds. In addition, we model the evolution of the biaxial stress in an amorphous Si thin film electrode during lithiation cycle. We find that both the atomic insertion driven by the chemomechanical load and plasticity driven by the mechanical load contribute to reactive flow of lithiated silicon. In such concurrent process, the lithiation reaction promotes plastic deformation by lowering the stress needed to flow. Li-ion battery is an emerging field that couples electrochemistry and mechanics. This thesis aims to understand the deformation mechanism, stresses and fracture associated with the lithiation reaction in Li-ion batteries, and hopes to provide insight on the generic phenomenon that involves interactive chemical reactions and mechanics. / Engineering and Applied Sciences

Unlike principal excitatory neurons, cortical interneurons comprise a diverse group of distinct subtypes. They can be classified by their morphology, molecular content, developmental origins, electrophysiological properties and specific connectivity patterns. The parvalbumin-positive \((PV^+)\), large basket interneuron has been implicated in two cortical functions: 1) the control and shaping of the excitatory response, and 2) the initiation of critical periods for plasticity. Disruptions in both phenomena have been implicated in the etiology of cognitive developmental disorders. Careful characterization of \(PV^+\) cell function and plasticity in response to their primary afferent, the thalamocortical synapse, is needed to directly relate their vital contribution at a synapse-specific or network level to whole animal behavior. Here, I used electrophysiological, anatomical and molecular genetic techniques in a novel slice preparation to elucidate \(PV^+\) circuit development and plasticity in mouse visual cortex. I found that GFP-positive \(PV^+\) cells in layer 4 undergo a rapid maturation after eye opening just prior to onset of the critical period. This development occurs across a number of intrinsic physiological properties that shape their precise, fast spiking. I further optimized and characterized a visual thalamocortical slice to examine the primary afferent input onto both pyramidal and \(PV^+\) cells. Thalamic input onto \(PV^+\) cells is larger, faster and again matures ahead of the critical period. Both the intrinsic and synaptic properties of \(PV^+\) cells are then maintained by a secreted homeoprotein, Otx2 (Sugiyama et al, 2008), which is mediated by an extracellular glycosaminoglycan recognition. Since the plasticity of fast-spiking, inhibitory neurons is dramatically distinct from their neighboring pyramidal neurons in vivo (Yazaki-Sugiyama et al. 2009), I directly examined the plasticity of thalamocortical synapses in vitro. After brief monocular deprivation, thalamic input specifically onto \(PV^+\) cells is reduced while remaining unaltered in pyramidal cells. Deprivations prior to critical period onset or in GAD65 knockout mice neither produce a shift of visual responsiveness in vivo (Hensch et al, 1998) nor reduce thalamocortical input onto \(PV^+\) cells. These results directly confirm that \(PV^+\) cells are uniquely sensitive to visual experience, which may drive further rewiring of the surrounding excitatory cortical network.

Extensive experience-dependent refinement of cortical circuits is restricted to critical periods of plasticity early in life. The timing of these critical periods is tightly regulated by the relative levels of excitatory and inhibitory (E/I) neurotransmission during development. Genetic disruption of synaptic proteins that normally maintain E/I balance can result in severe behavioral dysfunction in neurodevelopmental disorders like autism, but the mechanisms are unclear. We propose that abnormal critical periods of sensory circuit refinement could represent a key link between E/I imbalance and the cognitive and behavioral problems in autism.

The goal of the "Quantitative Trait Gene" (QTG) program is to identify genes and mutations that underlie natural phenotypic variation. My goal with this work was to contribute an additional model to the program: ovariole number evolution in Drosophila. In this thesis I describe the progress I have made towards identifying a specific genetic change that contributed to the divergence of ovariole number between two Drosophila lineages. I identify specific developmental mechanisms relevant to establishing ovariole number in different Drosophila lineages by detailing ovarian cell-type specific specification, proliferation, and differentiation. I test specific candidates of genetic regulators of these developmental mechanisms with mutational analysis in D. melanogaster. I show that independent evolution of ovariole number has resulted from changes in distinct developmental mechanisms, each of which may have a different underlying genetic basis in Drosophila. I use the interspecies comparison of D. melanogaster versus D. sechellia to test for functional differences in insulin/insulin-like growth factor (IIS) signaling between the two species. I show that IIS activity levels and sensitivity have diverged between species, leading to both species-specific ovariole number and species-specific nutritional plasticity in ovariole number. Moreover, plastic range of ovariole number correlates with ecological niche, suggesting that the degree of nutritional plasticity may be an adaptive trait. My work and quantitative genetic analyses strongly support the hypothesis that evolution of the Drosophila insulin-like receptor (InR) gene, specifically, is at least partially responsible for the divergence in ovariole number and nutritional plasticity of ovariole number between D. melanogaster and D. sechellia. I detail ongoing experiments to test this hypothesis explicitly via cross-species transgenesis.

Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug-related experiences are formed, resulting in persistent and uncontrollable drug-seeking behavior. However, it is well known that both acute and chronic alcohol (ethanol) exposures impair various types of learning and memory in both humans and animals. Consistent with these observations, both acute and chronic exposures to ethanol suppress synaptic plasticity, the major neural substrate for learning and memory, in multiple brain areas. Therefore, it remains unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. The mesolimbic dopaminergic system is critically involved in the learning of information related to rewards, including drugs of abuse. Both natural and drug rewards, such as ethanol, cause release of dopamine in the nucleus accumbens and other limbic structures, which is thought to drive learning by enhancing synaptic plasticity. Accumulating evidence indicates that plasticity of glutamatergic transmission onto dopamine neurons may play an important role in the development of addiction. Plasticity of NMDA receptor (NMDAR)-mediated transmission may be of particular interest, as NMDAR activation is necessary for dopamine neuron burst firing and phasic dopamine release in projection areas that occurs in response to rewards or reward-predicting stimuli. NMDAR plasticity may, therefore, drive the learning of stimuli associated with rewards, including drugs of abuse. This dissertation finds that repeated in vivo ethanol exposure induces a metaplasticity of NMDAR-mediated transmission in mesolimbic dopamine neurons, expressed as an increased susceptibility to the induction of NMDAR LTP. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5- trisphosphate (IP3) in producing the facilitation of action potential-evoked Ca2+ signals critical for LTP induction. Interestingly, amphetamine exposure produces a similar enhancement of IP3R function, suggesting this neuroadaptation may be a common response to exposure to multiple drugs of abuse. Additionally, ethanol-treated mice display enhanced learning of cues associated with cocaine exposure. These findings suggest that metaplasticity of NMDAR LTP may contribute to the formation of powerful memories related to drug experiences and provide an important insight into the learning component of addiction. / text

The ability of an animal to respond and adapt to stimuli is necessary for its survival and involves plasticity and coordination of multiple levels of biological organization, including behavior, tissue organization, hormones, and gene expression. Each of these levels of response is complex, and none of them responds to stimuli in isolation. Thus, to understand how each system responds, it is necessary to consider its role in the context of the entire organism. Here, I have used the African cichlid fish Astatotilapia burtoni and its extraordinary phenotypic plasticity to investigate how animals respond to a change in social status from subordinate to dominant and attempted to integrate these multiple levels of biological response, as well as the roles of several candidate neuromodulators,. First, I have described how male A. burtoni become more aggressive and reproductive during their transition to dominance as well as increasing circulating levels of testosterone and estradiol and the histological organization of their testes. I then mapped the distribution of expression of two behaviorally relevant neuropeptides, arginine vasotocin and isotocin, and their respective receptors, throughout the A. burtoni brain, and found that they were highly expressed in several brain areas important for social behavior and decision-making. I then investigated the role of arginine vasotocin in social status and behavior via pharmacological manipulation and qPCR, showing the importance of arginine vasotocin in controlling the transition to dominance. Lastly, I investigated the role of aromatase, testosterone, and estradiol in male A. burtoni, both in stable dominant males and in males as they transition to dominance, using pharmacological manipulation and quantitative radioactive in situ hybridization, illustrating that estradiol synthesis during dominance is dependent on aromatase activity and necessary for aggressive behavior. / text