Le domaine des neurosciences computationnelles s'intéresse à la modélisation des fonctions cognitives à travers des modèles numériques bio-inspirés. Dans cette thèse, nous nous intéressons en particulier à l'apprentissage dans un contexte multimodal, c'est à dire à la formation de représentations cohérentes à partir de plusieurs modalités sensorielles et/ou motrices. Notre modèle s'inspire du cortex cérébral, lieu supposé de la fusion multimodale dans le cerveau, et le représente à une échelle mésoscopique par des colonnes corticales regroupées en cartes et des projections axoniques entre ces cartes. Pour effectuer nos simulations, nous proposons une bibliothèque simplifiant la construction et l'évaluation de modèles mésoscopiques. Notre modèle d'apprentissage se base sur le modèle BCM (Bienenstock-Cooper-Munro), qui propose un algorithme d'apprentissage non-supervisé local (une unité apprend à partir de ses entrées de manière autonome) et biologiquement plausible. Nous adaptons BCM en introduisant la notion d'apprentissage guidé, un moyen de biaiser la convergence de l'apprentissage BCM en faveur d'un stimulus choisi. Puis, nous mettons ce mécanisme à profit pour effectuer un co-apprentissage entre plusieurs modalités. Grâce au co-apprentissage, les sélectivités développées sur chaque modalité tendent à représenter le même phénomène, perçu à travers différentes modalités, élaborant ainsi une représentation multimodale cohérente dudit phénomène / The field of computational neurosciences is interested in modeling the cognitive functions through biologically-inspired, numerical models. In this thesis, we focus on learning in a multimodal context, ie the combination of several sensitive/motor modalities. Our model draws from the cerebral cortex, supposedly linked to multimodal integration in the brain, and modelize it on a mesoscopic scale with 2d maps of cortical columns and axonic projections between maps. To build our simulations, we propose a library to simplify the construction and evaluation of mesoscopic models. Our learning model is based on the BCM model (Bienenstock-Cooper-Munro), which offers a local, unsupervized, biologically plausible learning algorithm (one unit learns autonomously from its entries). We adapt this algorithm by introducing the notion of guided learning, a mean to bias the convergence to the benefit of a chosen stimuli. Then, we use this mecanism to establish correlated learning between several modalities. Thanks to correlated leanring, the selectivities acquired tend to account for the same phenomenon, perceived through different modalities. This is the basis for a coherent, multimodal representation of this phenomenon

Acute and chronic methylphenidate (MPD) administration was recorded simultaneously in freely moving adolescent rats previously implanted with permanent semi-microelectrodes using telemetric wireless technology for the rat's locomotor activity and for the locus coeruleus (LC) neuronal activity. The evaluation of neuronal events was separated based on the rat's behavioral response to chronic MPD exposure, with rats eliciting behavioral sensitization or behavioral tolerance. On experimental day (ED) 1, the locomotor and neuronal activity was recorded after saline (baseline) and MPD (0.6, 2.5, or 10.0 mg/kg) injection (i.p.). The rats were administered daily with a single dose of MPD for five consecutive days (ED2-ED6) to elicit behavioral sensitization or behavioral tolerance. Following three washout days with no drugs, the locomotor and neuronal activity recordings resumed on ED10 post saline and rechallenge MPD administration. The main findings were as follows. The same dose of chronic MPD administration elicited behavioral sensitization in some rats and behavioral tolerance in other rats. A total of 51.5%, 56.6%, and 86.3% of LC units responded significantly to acute 0.6, 2.5, and 10.0 mg/kg MPD respectively. A total of 51.5%, 72.4%, and 82.3% of LC units responded significantly by changing their baseline activity on ED10 compared to that on ED1 in 0.6, 2.5, and 10.0 mg/kg MPD dose groups respectively. A total of 53%, 67.1%, and 90.2% of LC units responded significantly to chronic 0.6, 2.5, and 10.0 mg/kg MPD respectively. The LC neuronal population recording following acute MPD on ED1 and rechallenge MPD on ED10 from the rats eliciting behavioral sensitization was significantly different from the neuronal population recorded from the rats eliciting behavioral tolerance. Overall, these findings show that the same dose of chronic MPD can elicit behavioral sensitization or behavioral tolerance. We were able to verify our hypothesis that the LC units recorded from the rats eliciting behavioral sensitization responded significantly different to MPD from the rats eliciting behavioral tolerance. This correlation suggests that LC neuronal activity plays an important role in the expression of behavioral sensitization and behavioral tolerance by chronic MPD exposure.

The gut and the brain are in constant communication through pathways that include the immune system, the nervous system, neurotransmitters, and hormones. Modifications in the gut, especially the gut microbiome, have the potential to cause changes in the brain resulting in behavioral and cognitive changes. A healthy and diverse microbiome, which may be achieved by a high fiber diet or probiotic or prebiotic treatments, is associated with improvements in cognition. Gut dysbiosis and a decrease in diversity of the microbiota, which may be caused by a western diet or antibiotic treatments, is associated with cognitive decline and decreased memory. There are many possible pathways through which these changes in the gut act to change cognition, including the immune system, the expression of brain derived neurotropic factor, metabolites such as short chain fatty acids, gut hormones, and neurotransmitters. If researchers can decipher which pathways are involved in modifying cognition, they may be able to identify treatments that can help improve memory and specifically decrease age-related cognitive decline.

This study aims to discover whether there is a correlation between atypical clinical presentations of Alzheimer’s disease (AD) and atypical distribution patterns of AD pathology. To provide a measure of the atypical clinical presentations, we obtained standardized neuropsychological test scores for a group of 345 subjects of the Boston University Alzheimer’s Disease Center cohort that had received a clinical or pathological diagnosis of AD. Each of the neuropsychological test scores included in our analyses was classified into one of five cognitive domains, according to the primary domain each test assesses: memory, executive function, attention, visuospatial function, and language. From these test scores, global cognitive performance scores and individual domain performance scores were calculated for a subset of 53 subjects that had brain tissue slides available for pathological analysis. Difference scores were computed for each domain, providing a within-subject comparison of performance between each individual cognitive domain and overall cognitive performance. For these same 53 subjects, tissue slides from six brain regions were obtained and digitally scanned. Neurofibrillary tangle (NFT) quantification was performed for all tissue slides using a computer algorithm modified to recognize AT8 staining patterns. NFT densities were then calculated for five general brain regions (frontal, parietal, temporal, limbic and occipital). In addition, a global NFT density score was computed for each subject, averaging NFT densities across all regions. From these densities, difference scores were calculated for each brain region individually, providing a measure of how each region’s NFT density compares to the overall brain NFT density. Multiple linear regressions analyses were performed with five pairs of cognitive domain difference scores and region NFT density difference scores: memory difference scores and limbic difference scores, executive function difference scores and frontal difference scores, attention difference scores and parietal difference scores, visuospatial difference scores and occipital difference scores, and language difference scores and occipital difference scores. Though we expected to observe significant negative correlations between each of the five difference score pairs, the only statistically significant correlation observed was between memory difference scores and limbic difference scores (β= -0.361, p<0.05). These results suggest that poorer performance in memory-related neuropsychological tests, when compared to global cognitive performance, can predict higher NFT densities in limbic regions when compared to the overall brain pathology. Although no other difference score pairs showed any statistically significant correlations, many study limitations, including small sample size and simplifications in analysis, should be addressed in the future to provide better understanding of these atypical presentations of AD and their underlying pathologies.

Alcoholism has been linked to cognitive, behavioral, and emotional defects, and damage to the cerebellum has been associated with aspects of these impairments. However, little is known about the role of damage to specific cerebellar subregions in the deficits, nor about possible gender differences in alcoholism-related cerebellar abnormalities. In this study, volumetric analyses of specific cerebellar regions were performed in relation to the interactions of alcoholism, gender, and measures of drinking history. Structural brain scans of 44 alcoholics (23 men) and 39 nonalcoholic controls (18 men) were obtained using T1 magnetic resonance imaging at 3T. Scans were manually labeled according to cerebellar features, using methodology developed at the Center for Morphometric Analyses, Massachusetts General Hospital, Boston. Each lobule was parcellated and mediolateral divisions were delineated. In addition to measuring total cerebellar gray and white matter, along with the anterior and posterior lobes, we also measured volumes for a priori regions of interest that have been shown to correspond to functions impaired in alcoholism: emotion, executive functions, working memory, motor abilities, and spatial abilities. Total cerebellar white matter volume was observed to be smaller in alcoholic than in nonalcoholic participants, but this difference was not observed for total gray matter volume. Moreover, the volumes of the cortical parcellation units we selected varied with drinking history, including negative associations between (a) years of heavy drinking, and (b) volumes of the anterior and flocculonodular lobes, and of the spinocerebellar region. The negative association between anterior volume and years of heavy drinking was driven primarily by alcoholic men. Additionally, we observed that white and gray cerebellar volumes for alcoholic women were significantly larger than for alcoholic men, but this pattern of gender differences was not significant for the control group. The identification of drinking-related abnormalities in cerebellar subregions builds upon prior findings in other regions of the brain, and lays a foundation that can be utilized to inform how cerebro-cerebellar networks are perturbed in this pathological condition. The results also provide estimates of how individual differences in drinking history can predict cerebellar volumes, and how the impact of drinking differs for men and women.

Despite years of research, an effective therapy for treatment of ischemic stroke has yet to be found. Survivors of stroke may suffer debilitating and permanent motor dysfunction for the remainder of their lives. Current treatments are limited to physical therapy and tissue plasminogen factor (tPA), a thrombolytic medication with a time- window of efficacy up to only three hours after symptom onset. Clinical studies and animal models have shown that partial recovery of motor function occurs with or without pharmacological interventions due to adaptive plasticity and reorganization in the brain. The precise mechanisms, though unclear, have become a major focus of stroke research. In the following study, we investigated inosine, a naturally occurring purine nucleoside that stimulates axonal growth, as a potential long-term stroke treatment. Following controlled cortical ischemia in the motor cortex of rhesus monkeys, recovery of dominant hand function was monitored through NHP Upper Extremity Motor Dysfunction Scale ratings for two weeks post-operation and through performance on two motor tasks, the Hand Dexterity Task (HDT) and the Digit Coordination Task (DCT). Results of cage- side assessment ratings demonstrated a trend towards greater recovery in the group treated with inosine for functional strength in the dominant hand on 12-14 days after surgery. The suggested trend is enough evidence to pursue research on the use of inosine as a therapeutic agent in post-stroke functional recovery.

<p> Alzheimer&rsquo;s disease (AD) is the most common irreversible form of dementia and accounts for 60&ndash;80% of all dementia cases. It is not a normal part of aging and causes memory problems and other cognitive dysfunctions that may result in unpredictable changes in behavior. AD can be caused by many factors. Recently, Vitamin D deficiency has been recognized as a risk factor for AD. Vitamin D insufficiency and deficiency are major health problems affecting 1 billion people worldwide, across all ethnicities and age groups. Unfortunately, public knowledge about Vitamin D deficiency and risk of AD is limited. The creation of two leaflets as informational tools for experts/professionals and families/caregivers/participants of Alzheimer&rsquo;s Orange County was the goal of this project. The leaflets were reviewed by experts in the field and revisions were made. Future research should evaluate the effectiveness of the leaflets on increasing knowledge about Vitamin D and AD.</p><p>

This thesis describes efforts at the interface of chemistry and neuroscience to design and characterize fluorescent probes capable of tracing neurotransmitters from individual release sites in brain tissue. As part of the Fluorescent False Neurotransmitters (FFNs) program, small organic fluorophores have been developed that undergo uptake into specific presynaptic release sites and synaptic vesicles by utilizing the native protein machinery, which can then be released during neuronal firing. The most advanced generation of FFNs are pH-sensitive, and display an increase in fluorescence when released from the acidic vesicular lumen into the extracellular space, called a “FFN Flash.” In Chapter 2, the utility of the dopamine-selective and pH-sensitive functionality of FFN102 to study the mechanisms that regulate changes in pre-synaptic plasticity, a critical component of neurotransmission was explored. This included using the FFN flash to quantitatively trace dopamine release, changes in the release probability of individual release sites, and changes in vesicular loading that can affect quantal size. The second goal of this thesis research, as detailed in Chapters 3 and 4, sought to expand the substrate scope of the FFN program to neurotransmitter systems other than dopamine. Described in Chapter 3, is the identification of a fluorescent phenylpyridinium, APP+, with excellent labeling for dopamine, norepinephrine, and serotonin neurons, however, the properties of the probe were found to be ill-suited for measuring neurotransmitter release. As a result, it was concluded that this class of compounds was not suitable for generating viable FFN leads. In contrast, Chapter 4 highlights the design, synthesis, and screening towards generating the novel noradrenergic-specific FFN, FFN270. This probe was further tested for application in acute murine brain slices where it labeled noradrenergic neurons, and was demonstrated to release upon stimulation. This chapter also describes the application of this compound in a series of in vivo experiments, where the ability to measure norepinephrine release from individual release sites was demonstrated in a living animal for the first time. This work opens the possibility for many exciting future FFN experiments studying the presynaptic regulation of neurotransmission in vivo.

Lexical tones have presented great difficulties for second language learners whose native language is non-tonal. A number of recent studies suggest categorical-like perception of lexical tones by native Mandarin speakers. Can native speakers of non-tonal languages acquire categorical representations of lexical tones? Are there any differences between L1 and L2 tone perceptions? This study investigates brain responses to lexical tone categorization for three groups of adult listeners: 1) native English speakers who had no exposure to Mandarin before age 17, but took advanced Mandarin courses as adults; 2) naïve English speakers; and 3) native Mandarin speakers. Two tonal continua were derived from natural speech through interpolation within two tonal contrasts (Tone 1/Tone 4; Tone 2/Tone 3). Firstly, category boundaries were examined through classic identification and discrimination tasks. Secondly, high-density electroencephalography (EEG) was used to record brain responses while participants listened to tones in two oddball paradigms: across-category and within-category. If perception of lexical tones is categorical, cross-category deviants are expected to elicit larger ERP responses (specifically, mismatch negativity (MMN) and P300) than within-category deviants. Both behavioral and ERP results indicate that lexical tones are perceived categorically by native Chinese speakers but not by inexperienced English speakers. Although English learners of Chinese demonstrated categorical perception in behavioral tasks, their ERP response did not differ between within- and across-category conditions, however, significantly greater P300 responses were observed. Acoustic cues and characteristics of L2 phonological learning in adulthood are discussed.

The monkey lateral intraparietal area (LIP) is involved in visual attention and eye movements. It has traditionally been studied using extracellular recording, where often a single neuron is recorded at a time. Thus we have a wealth of correlational knowledge of what LIP neurons do, but not how or why, i.e. we do not know the circuit mechanisms and functions of the observed LIP activity. In this thesis, we have aimed to uncover the circuit mechanisms underlying LIP activity by building tightly constrained computational models. In Part 1, we found that during two versions of a delayed-saccade task, beneath similar population average firing patterns across time lie radically different network dynamics. When neurons are not influenced by stimuli outside their receptive fields (RFs), dynamics of the high-dimensional LIP network lie predominantly in one multi-neuronal dimension, as predicted by an earlier model. However, when activity is suppressed by stimuli outside the RF, LIP dynamics markedly deviate from a single dimension. The conflicting results can be reconciled if two LIP local networks, each dominated by a single multi-neuronal activity pattern, are suppressively coupled to each other. These results demonstrate the low dimensionality of LIP local dynamics and suggest active involvement of LIP recurrent circuitry in surround suppression and, more generally, in processing attentional and movement priority and in related cognitive functions. In Part 2, we examine the mechanisms of learning in LIP. When monkeys learn to group visual stimuli into arbitrary categories, LIP neurons become category-selective. Surprisingly, the representations of learned categories are overwhelmingly biased: while different categories are behaviorally equivalent, nearly all LIP neurons in a given animal prefer the same category. We propose that Hebbian plasticity, at the synapses to LIP from prefrontal cortex and from lower sensory areas, could lead to the development of biased representations. In our model, LIP category selectivity arises due to competition between inputs encoding different categories, and bias develops due to excitatory lateral interactions among LIP neurons. This model reproduces the different levels of category selectivity and bias observed in multiple experiments. Our results suggest that the connectivity of LIP allows it to learn the behavioral importance of stimuli in order to guide attention.