It is well known that language processing depends on specialized areas in the left side of the brain in the majority of the population. A popular view is that developmental language disorders result from a poorly lateralized brain, but evidence in support of this has been weak and inconsistent. In this thesis, I investigated language-related asymmetries in brain structure and function, and their behavioural relevance in both individuals with specific language impairment (SLI) and typically developing adults. Combining different brain imaging techniques, I looked at group-level as well as individual estimates of language laterality and its relationship to language abilities. The aim of my first two studies was to investigate the neural underpinnings of SLI in terms of white matter microstructure and functional organization associated with auditory processing. For this, diffusion and functional MRI data was obtained in a small number of families with a history of SLI and in control families. Compared with neurotypical controls, children with SLI had lower white matter integrity in the corpus callosum, and in white matter areas corresponding to the dorsal and ventral language pathways. The expected functional lateralization for auditory processing was not observed in either group. In the second half of my thesis, I assessed language laterality in 215 neurotypical adults. I demonstrated that functional transcranial Doppler (FTCD) ultrasonography could reliably assess functional lateralization across different language processes. From this large group, I identified 16 individuals with atypical language lateralization and compared them to a group of 16 typically lateralized individuals using a combination of FTCD, MRI and behavioural measures of language laterality and language abilities. The two groups differed significantly in terms of lateralization assessed by functional MRI and diffusion imaging. The atypical group had lower left and greater right hemisphere activation compared with the typical group, and lacked the leftwards asymmetry in the ventral language tract seen in the typical group. The groups did not differ in terms of cognitive measures. Different functional laterality assessments were concordant in the typically lateralized individuals but were inconsistent in the individuals assessed as atypical by FTCD. In brief, my findings suggest that for some individuals language lateralization may be unstable and varies depending on task or other factors. Even so, such differences do not appear to have consequences for language or other cognitive development.

Brain development is an exquisitely coordinated process of progenitor cell proliferation followed by the migration of progeny to their final location in the developing brain. There are a myriad of points at which this process can be disturbed, and the examination of these perturbations help us further understand basic science, as well as epidemics sweeping through the world around us. Microcephaly, which is defined as a head circumference greater than 2 standard deviations below the mean, can occur through genetic, infectious, vascular, or metabolic etiologies, and the studies herein examine two forms by which microcephaly occurs. First, we investigate the role of the dynein regulatory protein Nde1 in the development of the neocortex, which is the outer region of the forebrain. NDE1 mutations are associated with severe microcephaly, and we find that unlike most microcephaly genes whose products have one role in the cell cycle, Nde1 is required at three discrete points in neuronal progenitors, termed radial glia progenitors (RGPs). We initially find that Nde1 is required to recruit dynein to the nuclear envelope to allow for interkinetic nuclear migration (INM) during G2. Additionally, Nde1 helps to initiate primary cilia resorption at the G1-to-S transition. Finally, there is a necessity for Nde1 at the G2-to-M transition after the completion of INM and prior to nuclear envelope breakdown. These three distinct roles for Nde1 illustrate the breadth of functions that the protein has during RGP proliferation, and help to explain why patients with NDE1 mutations have such severe microcephaly. As this work was ongoing there was a global outbreak of a new pathogen that had previously been dormant throughout Africa and Asia, only to emerge at epidemic proportions in the Western Hemisphere. This pathogen, the Zika Virus (ZIKV), is particularly alarming because of its subclinical course in adults but devastating consequences for fetal development, with the hallmark symptom being microcephaly. Using our organotypic brain slice model system, we demonstrate the ability of a variety of ZIKV isolates to infect and replicate in embryonic brain tissue. All ZIKV isolates that infect the organotypic slices lead to increases in apoptosis, though these increases are particularly pronounced in isolates from the Asian/American lineages. Notably, one isolate from a patient in Nigeria (termed 30656) does not replicate in mouse neuronal tissue, but electroporation of the 30656 ZIKV genome allows for a single cycle replication, suggesting that this isolate is unable to enter RGPs. All infectious isolates are pathogenic in early- and mid- gestation embryonic tissue, but only one isolate infects and replicates in late- gestation embryonic tissue. This was the most recently isolated sample tested, and it demonstrates a predilection for neurons, suggesting that ZIKV may be mutating as it spreads. These results provide foundational insight into the pathogenesis of ZIKV- associated microcephaly, and illustrate how studies of genetic forms of microcephaly can enhance and facilitate our understanding of infectious causes of the disease.

No description available.

Macrophages and other cells of the innate immune system recognize foreign particles that could be potentially dangerous and respond by initiating an inflammatory response. The biologically active chemical mediators of this response called pro-inflammatory cytokines are produced in various myeloid derived immune cells and can affect other cells of the body. Interleukin-1β, a pro-inflammatory cytokine, has been shown to have direct effects on dorsal root ganglion (DRG) cell bodies including the upregulation and direct release of a nociceptive neurotransmitter called substance P (SP). Using a zymosan-induced model of systemic inflammation, we hypothesized that murine DRG neurons and the nerve processes associated with them in the dorsal horn of the spinal cord (SC) at the L1 level will show an upregulation of SP expression in response to inflammation in the peritoneum. Experimental mice were treated with a zymosan suspension (500mg/kg, intraperitoneal injection), and control mice received sterile filtered solution (intraperitoneal injection). Both DRG and SC specimens were collected after in situ fixation and subjected to immunofluorescence staining to label SP. Using confocal microscopy, fluorescence microscopy, and image analysis software this expression of SP was quantified and compared. In both tissue specimen groups, an increase in SP expression was discovered in zymosan treated mice. The exact cause of this increase was not specifically determined in this experiment. This experiment provided valuable insight about how a systemic inflammatory response can affect sensory nerve function. Successful methods for further experimentation were identified and information about the zymosan model of inflammation was obtained

Using matched pairs of schools having a diagnosis of Sick Building Syndrome (SBS) and those not identified, and not having the potential of being identified as having the diagnosis, this study examined the relationship between factors assumed or determined to have an impact on a school's ability to carry out its mission as they related to the SBS diagnosis. The factors studied were student average daily attendance (ADA); students' mean standardized test scores in math and reading on the Iowa Test of Basic Skills and the Tests of Achievement and Proficiency; the need for students to take prophylactic medications; the rate of staff turnover; the percentages of short term suspensions (less than 10 days), long term suspensions (more than 10 days), and the percentage of recommendations for expulsion; as well as the impact of the public identification of a school as having a diagnosis of SBS on student ADA, mean standardized test scores in math and reading and staff turnover. A factorial ANOVA model (2 by 4) for repeated measures revealed no statistical significance for main or interaction effects on any of the six hypotheses addressed.

Incontinentia pigmenti (IP, OMIM # 308300) est une maladie génétique liée au chromosome X qui est létale chez les garçons. Chez les filles, une dermatose débute peu après la naissance et évolue selon une séquence complexe d’événements associant de l’inflammation, de l’hyperprolifération cellulaire et de l’apoptose. En dehors de ce problème cutané, les patientes IP peuvent aussi souffrir d’anomalies oculaires, dentaires et cérébrales. Les défauts cérébraux affectent environ 30% des patientes et se caractérisent par de l’épilepsie et des troubles cognitifs et/ou moteurs. Le gène causant IP code pour la protéine NEMO, un composant essentiel de la voie de signalisation NF-kB, qui régule les processus immunitaires, inflammatoires, ainsi que la prolifération et la mort cellulaire. Chez approximativement 70% des patientes IP, le même réarrangement chromosomique élimine presque intégralement le gène NEMO, générant une perte d’activation de la voie NF-kB. L’invalidation du gène Nemo chez la souris (femelles Nemo +/-) fournit un modèle pour l’étude de la dermatose associée à IP en récapitulant les événements cutanés observés chez les patientes.Dans le but de mieux définir les anomalies cérébrales des patientes IP ainsi que leur origine qui reste obscure, nous avons analysé le cerveau des souris Nemo +/-. Nous montrons ici, en utilisant un protocole d’IRM adapté à des cerveaux de sept jours (P7), que des anomalies sont détectées dans une fraction des échantillons. Ces anomalies sont hétérogènes et localisées de manière aspécifique, comme chez l’Homme. Elles incluent des zones hémorragiques diffuses, des cavités et de l’atrophie du corps calleux. Cela démontre l’utilité du système murin Nemo +/- pour étudier également les défauts cérébraux des patientes IP. De manière intéressante, ces lésions cérébrales peuvent être détectées avant la naissance, au jour 18 du développement, et ne sont pas causées par un dysfonctionnement neuronal, astrocytaire ou des oligodendrocytes. Utilisant une approche immunitaire couplée à une analyse in toto de cerveaux P7 après mise en transparence (Technique 3DISCO), nous avons détecté des anomalies vasculaires qui suggèrent que ce compartiment serait à l’origine des défauts cérébraux des patientes IP. / Incontinentia pigmenti (IP, OMIM # 308300) is an X-linked genetic disease which is lethal in boys. In girls, it causes a skin disease that begins soon after birth and evolves along a complex sequence of events involving inflammation, cell hyperproliferation and apoptosis. IP patients can also suffer from ocular, dental and brain anomalies. Brain defects affect about 30% of patients and are characterized by epilepsy and/or cognitive/motor disorders. The IP-causing gene encodes the protein NEMO, an essential component of the signaling pathway NF-kB that regulates immunity, inflammation, proliferation and cell death process. In approximately 70% of IP patients, the same chromosomal rearrangement eliminates almost completely the NEMO gene, generating a loss of activation of the NF-kB pathway. Invalidation of the gene in Nemo mice (Nemo +/- females) provides a model for the study of the cutaneous events observed in IP patients.In order to better define the IP brain anomalies of patients and their origin, which remains obscure, we analyzed the brains of Nemo +/- mice. We show here, using a MRI protocol adapted for brain of seven days (P7), that anomalies are detected in a fraction of the samples. These anomalies are heterogeneous and localized in a non-specific manner, as in humans. They include diffuse hemorrhagic areas, cavities and atrophy of the corpus callosum. This demonstrates the usefulness of the murine system Nemo +/- to also study the IP patient's brain defects. Interestingly, these brain lesions can be detected before birth, at day 18 of development, and are not caused by a neuron, astrocyte or oligodendrocyte dysfunction. Using an immune approach coupled to an in toto analysis of P7 brain, after treating them by chemicals to induce their transparency (iDISCO technique), we detected vascular anomalies, suggesting that this compartment causes the brain defects in IP patients.

Orofacial clefts are among the most common congenital defects in the United States, affecting roughly 1 in 600 births annually. A majority of these cases are considered to be “isolated” clefts of the lip and/or palate (ICLP). However the term “isolated” is somewhat of a misnomer, as functional deficits frequently accompany ICLP. One of the most problematic yet understudied of these deficits involves the high prevalence of reading disabilities in this population. It has been estimated that as high as 46% of children with ICLP will be diagnosed with a reading disability, particularly dyslexia. Despite this high prevalence and the well-established neurological basis of dyslexia, relatively little attention has been paid to the role that brain development plays in the reading problems in ICLP. Previous studies from our lab have demonstrated significant changes in brain structure in children with ICLP (that have importantly correlated with functional measures). However we have yet to combine both a structural and functional neuroimaging study with an in-depth analysis of reading dysfunction in this population. The current study examined boys with ICLP, age 8-12 (boys have a higher prevalence of ICLP and show more significant reading problems that girls with ICLP) compared to healthy control boys. Measures of cognitive functioning were obtained with an emphasis on reading and language skills. In addition MRI scans were obtained which included volumetric measures, diffusion-weighted measures (DWI; white matter), and connectivity measures (resting-state fMRI). Even after controlling for the effect of socioeconomic status, boys with ICLP showed significant decreases in reading and language skills (particularly reading fluency). Boys with ICLP did not show significant differences on phonlogical measures (the primary cause of dyslexia). In addition, phonological measures were not predictive of reading fluency, while object naming tasks were predictive of reading fluency in boys with ICLP. For white matter integrity, measures of fractional anisotropy (FA) were found to be increased in the right occipital lobe for boys with ICLP indicating more organized white matter in this region. This increase in right occipital FA was also predictive of better reading outcomes, particularly reading fluency. For more specific white matter tracts, only the fornix and the tapetum (both associated with the temporal lobes) showed a significant difference with a decrease in FA for boys with ICLP. The decrease in FA in the tapetum was also predictive of better reading outcomes in ICLP. When looking at resting-state networks, boys with ICLP showed an increase in connectivity within posterior and subcortical regions when compared to healthy control boys, indicating stronger network connections within the posterior language regions of the brain. Taken together, these results point to differences in both structural and functional connectivity in the brains boys with ICLP. Furthermore, this pattern is different than that found in children with developmental dyslexia as there appears to be no disruption of the posterior reading systems. Cognitive measures also indicate normal phonological awareness in this group, further distinguishing them from dyslexic children. Boys with ICLP instead may be over-relying on these posterior, more visually oriented reading systems as a compensatory mechanism to overcome problems with the development of the typical “lexical route” of reading.

Mitochondria are critical for energy production and Ca2+ homeostasis and undergo fission and fusion reactions, perturbation of which can contribute to neuronal injury and disease. Mitochondrial fission is catalyzed by Drp1 (dynamin-related protein 1), a large GTPase tightly controlled by various posttranslational modifications, including phosphorylation. Bβ2 is a neuron-specific postnatally induced protein phosphatase 2A (PP2A) regulatory subunit that mediates PP2A translocation to the outer mitochondrial membrane (OMM) to promote mitochondrial fragmentation and sensitize neurons to various injuries. Opposing PP2A/Bβ2's effect on mitochondrial morphology and cell death is protein kinase A (PKA) anchored to the OMM via A kinase anchoring protein 1 (AKAP1). This dissertation describes how reversible phosphorylation of Drp1 at a conserved Serine residue by an outer mitochondrial kinase (PKA/AKAP1) and phosphatase complex (PP2A/Bβ2) affects dendrite and synapse development in hippocampal neurons and synaptic plasticity and learning and memory in vivo. Inducing mitochondria fragmentation decreases dendritic arbor complexity, but increases spine and synapse number. Mitochondrial elongation induces opposite effects. L-carnitine increases mitochondria membrane potential and recapitulates the dendritic and synaptic effects of mitochondrial elongation. Epistasis experiments substantiate our hypothesis that PP2A/Bβ2 dephosphorylates and PKA/AKAP1 phosphorylates Drp1 to change mitochondrial shape and regulate mitochondria localization, dendrite outgrowth, and synapse development. Bβ2 null mice are viable and fertile, without obvious abnormalities. Bβ2 null mice demonstrate significantly larger cortical and hippocampal neuronal mitochondria than in wildtype. Bβ2 deletion decreases spine number on apical and basal cortical dendrites and hippocampal dendrites. Bβ2 null mice display significantly decreased input/output relationship in the hippocampus, consistent with a decrease in synapse number. In a combined context and cued fear-conditioning protocol, the hippocampal-dependent context recall trial revealed significant deficits in Bβ2 null and heterozygous mice. This deficit is also seen in hippocampal-dependent Barnes maze performance. These results are consistent with the reduced hippocampal long-term potentiation (LTP) found in Bβ2 null mice and demonstrate the importance of Bβ2 in hippocampal synaptic plasticity and memory. In conclusion, PP2A/Bβ2 and PKA/AKAP1 have important roles in mitochondria regulation and dendritic and synaptic development as seen in our results in vitro with rat hippocampal cultures and in vivo with Bβ2 null mice.

Psychosocial problems are exceedingly common following moderate-to-severe traumatic brain injury (TBI), and are thought to be the major predictor of long-term functional outcome. However, current rehabilitation protocols have shown little success in improving interpersonal and social abilities of individuals with TBI, revealing a critical need for new and more effective treatments. Recent research has shown that neuro-modulatory treatments (e.g., non-invasive brain stimulation, lifestyle interventions) targeting the functionality of specific brain systems—as opposed to focusing on re-teaching individuals with TBI the impaired behaviors— hold the potential to succeed where past behavioral protocols have failed. However, in order to implement such treatments it is crucial to gain a better knowledge of the neural systems underlying social functioning secondary to TBI. It is well established that in TBI populations the inability to identify and interpret social cues, and in particular to engage in successful recognition of facial affects, is one of the factors driving impaired social functioning following TBI. The aims of the work here described were threefold: (1) to determine the degree of impairment in individuals with moderate-to-severe TBI on tasks measuring different sub-types of facial affect recognition skills, (2) to determine the relationship between white matter integrity and different facial affect recognition ability in individuals with TBI by using diffusion tensor imaging, and (3) to determine the patterns of brain activation associated with facial affect recognition ability in individuals with TBI by using task-related functional magnetic resonance imaging (MRI). Our results revealed that individuals with TBI are impaired at both perceptual and verbal categorization facial affect recognition tasks, although they are significantly more impaired in the latter. Moreover, performance on tasks tapping into different types of emotion recognition abilities showed different white-matter neural correlates, with more individuals with TBI showing more extensive damage in the left inferior fronto-occipital fasciculus, uncinate fasciculus and inferior longitudinal fasciculus more likely to perform poorly on verbal categorization tasks. Lastly, our functional MRI study suggests an involvement of left dorsolateral prefrontal regions in the disruption of more perceptual emotion recognition skills, and involvement on the fusiform gyrus and of the ventromedial prefrontal cortex in more interpretative facial affect recognition deficits. The findings here presented further out understanding of the neurobiological mechanisms underlying facial affect impairment following TBI, and have the potential to inform the development of new and more effective treatments.

Decision makers flexibly deploy decision-making strategies based on the specific features of the problems they face (Ford, Schmitt, Schechtman, Hults, & Doherty, 1989; Payne, Bettman, & Johnson, 1993). However, research on the neuroscience of decision making has focused on a "policy capture" approach that utilizes static decision problems to study the relationships between input (the problem presented), output (the choices made), and the brain. Since the decision problems are prepackaged, this approach does not provide information about the neural bases of predecisional processes critical for flexible decision making, such as selecting an appropriate decision-making strategy and dynamically acquiring and integrating the information needed to progress toward choice. The aim of the current project is to use the lesion method to explore the neural bases of predecisional processes. The fronto-limbic information acquisition network (FLIAN) is proposed as a neural framework critical for predecisional processes in flexible decision making. According to the FLIAN model, the ventromedial prefrontal cortex (vmPFC) represents the decision problem as currently perceived (i.e., the decision space), which is the basis for selecting a decision strategy via interactions with limbic structures. The vmPFC implements the strategy through the coordination of attribute-based information acquisition induced by the amygdala and relational, option-based acquisition induced by the hippocampus. In Chapter 1, the literature pertinent to FLIAN structures is reviewed, including the neuroanatomical and functional backgrounds of those structures, their roles in decision making, and their potential roles in predecisional processes. Chapter 2 provides a review of the behavioral literature on predecisional processes and outlines the FLIAN model in detail. Chapters 3 and 4 present studies that test, and provide partial support for, the FLIAN model using the lesion method and information board tasks. As predicted, the hippocampus is shown to be critical for relational, option-based information acquisition. The vmPFC is shown to be critical for determining how attributes are weighted in the decision space representation and for organizing predecisional behavior. The amygdala was not found to play its role in attribute-based acquisition, but previous studies do support this function and further research is warranted on the role of the amygdala, as well as the hippocampus and vmPFC, in predecisional processes. Future research should also explore the consequences of abnormal predecisional functioning for social behavior, memory, and emotion processing.