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<p> The possible contribution of neural plasticity to ON, OFF and steady state responses elicited by brief, repetitive trains of stimulation was investigated in the intact human subject with the use of the electroencephalogram (EEG). Experiment One implemented trains of stimulation at three different repetition rates, 1.5Hz, 4Hz and 13Hz. The goal was to investigate the nature of the ON, OFF and steady state responses evoked at these repetition rates. The experiment was carried out in three modalities: visual (n=13), auditory (n=lO) and somatosensory (n=12). The main result was that the ON and OFF responses were enhanced at 13Hz compared to the lower repetition rates. Experiment Two sought to answer the question of whether enhancement depended on the repetition rate or the increased experience provided by the higher frequencies. The number of stimuli in the 13Hz trains was reduced to equal the 1.5Hz condition from Experiment One. Graded exposure was then provided to the 13Hz stimulation. This procedure was implemented in two groups of subjects: Replication One (n=12) used 13Hz stimulation and Replication Two (n=24) used 14Hz stimulation. A subset (n=IO) of the Replication Two subjects returned for a second session (Day 2) 24 hours after the first. An assessment of effects was made after minutes and hours. There were four main results. The OFF response was observed after nine 13Hz pulses and did not change over the course of the experiment. The ON response increased with exposure to the 13Hz trains. Steady state responses diminished and showed a phase shift over the experimental session. Results for Day 1 and Day 2 were not different. Within session changes, as a result of exposure to the stimulus, were seen. These effects were not long lasting. </p> / Thesis / Master of Science (MSc)

Following unilateral stroke there is significant loss of function in the body side contralateral to the damage and a robust degenerative-regenerative cascade of events in both hemispheres. It is natural to compensate for loss of function by relying more on the less-affected body side to accomplish everyday living tasks (e.g. brushing teeth, drinking coffee). This is accompanied by a “learned disuse” of the impaired side thought to occur due to repeated experience with its ineptness. However, as investigated in these studies, it may also be due to brain changes instigated by experience with the intact body side. The central hypothesis of these dissertation studies is that experience with the intact forelimb, after unilateral sensorimotor cortex (SMC) damage, disrupts functional recovery with the impaired forelimb and interferes with peri-lesion neural plasticity. Following unilateral ischemic lesions, rats were trained on a skilled reaching task with their intact (less-affected) forelimb or received control procedures. The impaired forelimb was then trained and tested on the same skilled reaching task. Intact forelimb experience worsened performance with the impaired forelimb even when initiated at a more delayed time point following lesions. Intact forelimb training also reduced peri-lesion expression of FosB/ΔFosB, a marker of neuronal activation, and caudal forelimb motor map areas compared to animals without intact forelimb training. It was further established that it is focused training of the intact forelimb and not experience with this limb per se, as animals trained with both forelimbs in an alternating fashion did not exhibit this effect. Transections of the corpus callosum blocked the maladaptive effect of intact forelimb experience on impaired forelimb recovery, suggesting a disruptive influence of the intact hemisphere onto the lesion hemisphere that is mediated by experience. Together these dissertation studies provide insight into how experience with the less-affected, intact body side, can influence peri-lesion neural plasticity and recovery of function with the impaired forelimb. The findings from these studies suggest that compensatory use of the less-affected (intact) body side following unilateral brain damage is not advantageous if the ultimate goal is to improve function in the impaired body side. / text

Learning and memory offer animals the ability to modify their behavior in response to changes in the environment. A main target of neuroscience is to understand mechanisms underlying learning, memory formation and memory maintenance. Honeybees and bumblebees exhibit remarkable learning and memory abilities with a small brain, which makes them popular models for studying the neurobiological basis of learning and memory. However, almost all of previous molecular level research on bees' learning and memory has focused on the olfactory domain. Our understanding of the neurobiological basis underlying bee visual learning and memory is limited. In this thesis, I explore how synaptic organization and gene expression change in the context of visual learning. In Chapter 2, I investigate the effects of color learning and experience on synaptic connectivity and find that color learning result in an increase of the density of synaptic complexes (microglomeruli; MG), while exposure to color information may play a large role in experience-dependent changes in microglomerular density increase. In addition, microglomerular surface area increases as a result of long-term memory formation. In Chapter 3, I investigate the correlations between synaptic organizations and individual performance and the results show that bees with a higher density of microglomeruli in visual association areas of the brain are predisposed to faster learning and better long-term memory during a visual discrimination task. In Chapter 4, I explore the genes involved in visual learning and memory by transcriptome sequencing and I show the unique gene expression patterns at different times after visual learning. In summary, my findings shed light on the relationship between synaptic connections and visual learning and memory in bees at the group and individual level and show new candidate genes involved in visual learning, which provide new avenue for future study.

When most omnivores and herbivores become sodium depleted they engage in the motivated behavior of sodium appetite (AKA salt appetite), or the seeking out and ingestion of salty substances. Sodium appetite is associated with psychological processes that serve to enhance the incentive and rewarding value of salty substances in order to attract animals to salty substances and reinforce the ingestion of them. The experience of sodium depletion also produces long-lasting changes in behavior; one of the most apparent changes being a seemingly life-long increase in hypertonic salt intake which indicates sodium appetite is sensitized. Two neural circuits have been implicated in the sensitization of sodium appetite: 1) a forebrain neural circuit that regulates body fluid homeostasis, and 2) the mesolimbic dopamine system which mediates motivated behaviors. This dissertation has three aims that serve the overall purpose of providing a better understanding of the neurobiological mechanisms that mediate the sensitization of sodium appetite. The first aim is to develop a model of sodium depletion that is amenable to pharmacological manipulation in order to determine whether the -blockade of N-methyl-d-aspartate receptors, which are critical for neural plasticity, will prevent the sensitization of sodium appetite. The second aim is to determine whether sensitization is associated with relatively long-term molecular changes in forebrain areas that regulate body fluid homeostasis. The third aim is to identify how forebrain areas involved in body fluid homeostasis may connect to and influence activity in the mesolimbic dopamine system.

Brain development and function depend on intrinsic and extrinsic factors. In particular, the proper functioning of sensory systems can be altered according to the quality of extrinsic sensory information received during life. In this context, questions concerning neuroplasticity take on special relevance when considering that sensory experience has a big impact on the degree of plasticity of the brain. In this thesis, we have sought to understand how visual deprivation affects the development and maintenance of visual centers in the brain and the role of visual deprivation on plasticity throughout life. We have addressed this question by studying the retinocollicular projection, which is the neuronal pathway that connects the retina with a visual input processing center, the superior colliculus (SC). Unexpectedly, we found that in Syrian hamsters (Mesocricetus auratus) the size of receptive fields (RFs) of neurons in the SC is plastic in adult animals if they have been deprived of a minimum of visual experience when juveniles. Specifically, dark-reared (DR) hamsters refine SC RFs as do their normally-reared counterparts, but they lose RF refinement if they remain in the dark after their RFs get refined. We found that a well defined period and duration of visual experience can stabilize RF size in adulthood. Furthermore, we sought to investigate the mechanisms by which RF size is increased in adult DR hamsters. By testing the strength of intracollicular inhibition using electrophysiological and molecular techniques, we have found that visually-deprived animals have weaker inhibitory circuitry in their SC than normal animals. The quantity of GABA receptors and GABA containing neurons is decreased in the SC of adult DR animals. We propose that these results explain at least in part the RF enlargement we find in visually-deprived animals. Knowledge from this study provides general insight into sensory system plasticity in adulthood and new information about visual system development that is relevant for treatments of diseases.

Background. A visual prosthesis is a conceptual device designed to activate residual functional neurons in the visual pathway of blind individuals to produce artificial vision. Such device, when applied to stimulate the vitreous surface of the retina, has proven feasible in producing patterned light perception in blind individuals suffering from dystrophic diseases of the retina, such as aged-related macular degeneration (AMD). However the practicality of such approach has been challenged by the difficulty of surgical access and the risks of damaging the neuroretina. Positioning a visual implant over the scleral surface of the eye could present a safer alternative but this stimulation modality has not been tested in diseased retinas. Additionally, recent research has shown that the adult neocortex retains substantial plasticity following a disruption to its visual input and the potential deterioration in visual capabilities as a result of such experience modification may undermine the overall bionic rescue strategy. Methods. Two animal models mimicking the principal pathologies found in AMD, namely photoreceptor degeneration and reduced retinal ganglion cell mass, were used to evaluate the efficacy of trans-scleral stimulation of the retina by recording electrical evoked potentials in the visual cortex. The visual performance following the loss of pattern vision induced by bilateral eyelid suturing in adult mice was examined by analysing visual evoked potentials. Findings. Spatially differentiated cortical activations were obtained notwithstanding the underlying retinopathy in the experiment animals. The charge density thresholds were found to be similar to controls and below the bioelectric safety limit. After prolonged visual deprivation (weeks) in the mouse, the visual cortical responses evoked by either electrical or photic stimuli were both significantly reduced. An assessment of different visual capabilities using patterned stimuli demonstrated that whilst visual acuity and motion sensitivity were preserved, significant depression in luminance and contrast sensitivities was detected. Conclusion. Trans-scleral stimulation of the retina is a feasible approach for the development of a visual prosthesis. Following visual loss the adult brain exhibits significant experience-dependent modifications. These new insights may force a revision on the current bionic rescue strategy.

Background. A visual prosthesis is a conceptual device designed to activate residual functional neurons in the visual pathway of blind individuals to produce artificial vision. Such device, when applied to stimulate the vitreous surface of the retina, has proven feasible in producing patterned light perception in blind individuals suffering from dystrophic diseases of the retina, such as aged-related macular degeneration (AMD). However the practicality of such approach has been challenged by the difficulty of surgical access and the risks of damaging the neuroretina. Positioning a visual implant over the scleral surface of the eye could present a safer alternative but this stimulation modality has not been tested in diseased retinas. Additionally, recent research has shown that the adult neocortex retains substantial plasticity following a disruption to its visual input and the potential deterioration in visual capabilities as a result of such experience modification may undermine the overall bionic rescue strategy. Methods. Two animal models mimicking the principal pathologies found in AMD, namely photoreceptor degeneration and reduced retinal ganglion cell mass, were used to evaluate the efficacy of trans-scleral stimulation of the retina by recording electrical evoked potentials in the visual cortex. The visual performance following the loss of pattern vision induced by bilateral eyelid suturing in adult mice was examined by analysing visual evoked potentials. Findings. Spatially differentiated cortical activations were obtained notwithstanding the underlying retinopathy in the experiment animals. The charge density thresholds were found to be similar to controls and below the bioelectric safety limit. After prolonged visual deprivation (weeks) in the mouse, the visual cortical responses evoked by either electrical or photic stimuli were both significantly reduced. An assessment of different visual capabilities using patterned stimuli demonstrated that whilst visual acuity and motion sensitivity were preserved, significant depression in luminance and contrast sensitivities was detected. Conclusion. Trans-scleral stimulation of the retina is a feasible approach for the development of a visual prosthesis. Following visual loss the adult brain exhibits significant experience-dependent modifications. These new insights may force a revision on the current bionic rescue strategy.

Neuropsychiatric disorders severely impact quality of life in millions of patients, contributing more Disease Affected Life Years (DALYs) than cancer or cardiovascular disease. The human brain is a complex system of 100 billion neurons connected by 100 trillion synapses, and human studies of neural disease focus on network-level circuit activity changes, rather than on cellular mechanisms. To probe for neural dynamics on the cellular level, animal models such as the nematode C. elegans have been used to investigate the biochemical and genetic factors contributing to neurological disease. C. elegans are ideal for neurophysiological studies due to their small nervous system, neurochemical homology to humans, and compatibility with non-invasive neural imaging. To better study the cellular mechanisms contributing to neurological disease, we developed automated analysis methods for characterizing the behaviors and associated neural activity during sleep and learning in C. elegans: two neural functions that involve a high degree of behavioral and neural plasticity. We developed two methods to study previously uncharacterized spontaneous adult sleep in C. elegans. A large microfluidic device facilitates population-wide assessment of long-term sleep behavior over 12 hours including effects of fluid flow, oxygen, feeding, odors, and genetic perturbations. Smaller devices allow simultaneous recording of sleep behavior and neuronal activity. Since the onset of adult sleep is stochastically timed, we developed a closed-loop sleep detection system that delivers chemical stimuli to individual animals during sleep and awake states to assess state-dependent changes to neural responses. Sleep increased the arousal threshold to aversive chemical stimulation, yet sensory neuron (ASH) and first-layer interneuron (AIB) responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the AVA premotor interneurons, rather than afferent sensory circuits. Traditionally, the study of learning in C. elegans observes taxis on agar plates which present variable environmental conditions that can lead to a reduction in test-to-test reproducibility. We also translated the butanone enhancement learning assay such that animals can be trained and tested all within the controlled environment of a microfluidic device. Using this system, we demonstrated that C. elegans are capable of associative learning by observing stimulus evoked behavioral responses, rather than taxis. This system allows for more reproducible results and can be used to seamlessly study stimulus-evoked neural plasticity associated with learning. Together, these systems provide platforms for studying the connections between behavioral plasticity and neural circuit modulation in sleep and learning. We can use these systems to further our understanding of the mechanisms underlying neural regulation, function, and disorder using human disease models in C. elegans.

Memory is one of the highest cognitive functions that differentiates higher organisms from others because of its fundamental function to all learning and studying process. Recently, it was suggested that lactate works as a signaling molecule in neuronal plasticity system in long-term memory (LTM). These functions are reported only at mice so far, but it would be a universal phenomenon among various higher organisms. Because lactate is organic acid that is involved with energy production, it is of particular interest to know how memory associated genes including lactate-mediated neural plasticity (LMNP) genes get involved during evolution. I here set the purpose of my studies to understand the evolutionary origin and process of these memory-associated genes. Conducting an extensive literature survey, I collected a total of 302 genes of mice as memory associated genes. I, then, compared the number of genes orthologous to the 302 mice memory-associated genes among 11 representative organisms that I have chosen for the present study. As a result, I found that these memory-associated genes emerged at different time points during evolution, even before the emergence time of the organisms where memory function was reported. It suggests that memory function could be evolutionarily established gradually but not at once. Moreover, I examined 386 of LMNP-related genes of mice and other organisms to understand the evolutionary origin and processes of those genes that were identified by RNA-seq analyses (Margineanu et al., 2018). I found that the emergence times of LMNP genes were varied with genes, suggesting that the LMNP system may have been also formed gradually until its completion of the system around at the time of the common ancestor of vertebrates. Interestingly, I found that there are 13 genes overlap between the memory system and the LMNP system, indicating the critical role of those genes in connecting between both systems. From those studies, I conclude that the memory system and LMNP system has been formed by gradual participation of newly emerging genes during evolution, suggesting that the function of LMNP as a signaling molecule may be evolutionarily related to memory system by an unknown system that may exist to link both systems.