<p>Appropriate social behaviour depends on the wiring together of relevant sensory and cognitive neural circuits during development and is impaired in Autism Spectrum Disorder (ASD). A functional variant of the <em>MET</em> gene at rs1858830 confers risk for ASD and a basic mechanistic hypothesis relating <em>MET</em> gene function to ASD has been proposed: Decreased MET protein expression during development increases the risk of ASD-relevant circuit miswiring. In the human, robust MET is localized to the posterior cingulate, inferior temporal, posterior parietal, and visual cortices, including face-processing regions. This pattern is consistent with the importance of vision in the social milieu of primates, suggesting a conserved developmental function of the MET receptor in facilitating the neural connectivity that allows for appropriate social behaviour. This study investigates the down-stream influence of the <em>MET</em> C allele at rs1858830 on morphological characteristics of brain regions involved in social processing of audiovisual information. We used an imaging-genetics approach to characterize neuroimaging intermediate phenotypes associated of the <em>MET</em> C allele in individuals with ASD (n= 14) and neurotypical controls. Audiovisual stimuli were presented in an emotion-matching task intended to engage diffuse networks of brain regions involved in cross-modal perceptual integration. We present modest evidence of an enhanced penetrance of the <em>MET </em>C risk allele in individuals with ASD, reflecting a mechanism whereby a common variant that is not disorder-causing in and of itself has a larger effect on network function in individuals with ASD compared to neurotypical individuals. Subtle differences between ASD and TD individuals were revealed when the cohort was stratified by <em>MET</em> risk genotype, demonstrating the potential power for an imaging-genetic approach to resolve phenotypic heterogeneity in ASD. Definition of neuroimaging intermediate phenotypes may prove to be a sensitive means of parsing out ASD subgroups, and could ultimately lead to the development of tailored therapeutic interventions.</p> / Master of Science (MSc)

<p>Pitch perception depends on two types of cues provided by acoustic stimuli: spectral cues arise from the tonotopic organization of the basilar membrane, while temporal cues are contained within the pattern of action potentials generated in auditory nerve fibers. Filtered iterated rippled noise (IRN) can be used to examine how adults and infants perceive stimuli without resolvable spectral cues. Chapter 2 uses event-related potentials (ERPs) to compare adult perception of IRN and complex harmonic stimuli. Functional imaging studies have revealed a common pitch centre along lateral Heschl’s gyrus, but lack the temporal resolution to index different stages of processing. Chapter 2 reveals differences between feature extraction-related ERP components elicited in response to different pitch-evoking stimuli. However, no differences were observed in the mismatch negativities (MMN), suggesting pitch percepts formed at this stage of processing are independent of stimulus type. Moreover, source estimates for the MMN were consistent with fMRI studies. Chapter 3 demonstrates that infants can perceive the pitch of stimuli that lack resolvable spectral cues. Eight-month-old infants discriminated between 167 Hz and 200 Hz IRN stimuli. However, performance was poor relative to when resolvable spectral cues were present, and required a period of pitch-priming (Experiment 2). Chapter 4 uses ERPs to further examine infants’ perception of IRN. Using an oddball paradigm, 4- and 8-month-old infants were shown to discriminate between 167 Hz and 200 Hz stimuli. However, successful discriminations again required pitch-priming (Experiment 2). Together, these findings suggest that infant pitch percepts are dominated by resolved spectral cues. Infants discriminate between stimuli without resolvable spectral cues, but appear to require a period of priming to do so, at least until 8 months of age. Thus, infant pitch perception may be impaired in challenging listening situations, such as extracting vocal pitch cues in the presence of background noise.</p> / Doctor of Philosophy (PhD)

An essential process to the development of the neural network of the nervous system is axon guidance. The noncanonical Wnt/Planar Cell Polarity pathway has been identified as an integral component in controlling the projection of axons during axon guidance. Prickle, ROR1 and ROR2 are PCP related proteins that do not have clearly defined roles in the process. This study aims to use zebrafish CoPA neurons as a model to study the roles of Prickle, ROR1, and ROR2 in axon guidance. Using in situ hybridization, morpholino knockdown, and CRISPR/Cas9 loss of function experiments were able to identify ror1, ror2 and prickle as potential required components in CoPA neuron axon guidance. Elucidating the role of these protein in axon guidance not only will increase our knowledge of the PCP pathway but it will also increase our understanding of the development of the nervous system.

No description available.

<p>The superior olivary complex (SOC) is comprised of nuclei involved in sound localization. To compute interaural sound level differences, lateral superior olive (LSO) neurons integrate converging glutamatergic inputs from the cochlear nucleus with glycinergic inputs from the medial nucleus of the trapezoid body (MNTB). To compute interaural timing differences, the medial superior olive (MSO) integrates converging glutamatergic inputs from the ipsilateral and contralateral cochlear nucleus. The MSO also receives a major inhibitory input from the MNTB. N-methyl-D-aspartate receptors (NMDARs) are thought to play a role in the developmental refinement of these auditory brainstem pathways. The GluN2A and GluN2B NMDAR subunits confer widely different properties on NMDARs, substantially affecting plasticity. We assessed postnatal developmental messenger RNA (mRNA) expression of GluN1, GluN2A and GluN2B subunits in the LSO, MSO and MNTB using quantitative <em>in-situ</em> hybridization in tissue from 10 litters, ages postnatal day 1 to 36 (P1-36).</p> <p>GluN1 mRNA expression in the LSO, MSO and MNTB decreased with age. In all three nuclei, GluN2B mRNA expression was highest during the first postnatal week, dropping to low levels thereafter. In the LSO, GluN2A levels increased, then decreased to moderate levels. In the MNTB, GluN2A levels decreased from initially high levels. In the MSO, GluN2A levels increased to intermediate levels. The GluN2A/2B ratio increased 2-fold between P1 and P8 in the MNTB, whereas the ratio increased 3-fold between P8 and P15 in the LSO and MSO. The changes in GluN2A:GluN2B ratio are consistent with a developmental switch from GluN2B-containing NMDARs to GluN2A-containing NMDARs. These results are consistent with prior electrophysiological experiments that show NMDAR-mediated currents declining with age in the aVCN-MNTB, aVCN-LSO and MNTB-LSO pathways. The GluN2A subunit exhibited different developmental expression patterns in MNTB, LSO and MNTB, which suggests that GluN2A mRNA expression is locally regulated between nuclei, whereas GluN2B may be globally regulated.</p> / Master of Science (MSc)

<p>The lateral superior olive (LSO) is an auditory brainstem nucleus crucial in the determination of sound source. To accomplish sound localization, principal neurons of the LSO compare the intensity of sounds reaching the two ears by integrating an excitatory input from the ipsilateral anteroventral cochlear nucleus (AVCN), which is activated by sound reaching one ear, with an inhibitory input from the ipsilateral medial nucleus of the trapezoid body (MNTB), which is activated by sound reaching the opposite ear. In order for LSO principal neurons to properly integrate these excitatory and inhibitory inputs, the inputs must be matched in a frequency-dependent matter to LSO neurons. The mechanisms that direct the organization, selection, and maturation of both the excitatory and inhibitory pathway during development are not well understood. The experiments presented in this thesis were aimed at understanding the mechanisms that may underlie these processes in the developing LSO.</p> <p>The excitatory neurotransmitter glutamate is released in both the excitatory AVCN-LSO pathway and the inhibitory MNTB-LSO pathway during their period of functional circuit refinement, and may be important in the development of both of these pathways. Using the patch-clamp technique in acute brainstem slices of rats, we evaluated glutamatergic transmission in both the excitatory AVCN-LSO pathway and the inhibitory MNTB-LSO pathway during their period of functional refinement. Additionally, using the patch-clamp technique in acute brainstem slices of mice, we examined what functions vesicular glutamate transporter 3 (VGlut3), the protein that supports glutamate release from MNTB terminals, may have in the developing MNTB-LSO pathway. When taken together, the results from the three studies presented support a model in which circuit maturation in the LSO relies on mechanisms driven through a specific glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor.</p> / Doctor of Philosophy (PhD)

The goal of this study was to identify critical regions of a novel gene, Nance-Horan syndrome-like 1b (nhsl1b). It was previously discovered that C-terminal truncation of the Nhsl1b protein in nhsl1b mutants resulted in a loss of migration in the facial motor neurons of the hindbrain (Walsh et al. 2011). As nhsl1b expresses many isoforms, multiple targets were investigated in order to determine which transcript bears the largest impact on the motor neurons. Using confocal microscopy to observe immunostained embryos, we examined a mutation in an nhsl1b transcript that encodes a WHD, a domain that is known to function within the actin nucleation and polymerization pathways. In situ hybridization and injection of antisense morpholino oligonucleotides indicate that it is not the WHD but another transcript (ex1bnhsl1b) that is necessary for migration. The control experiments for rescuing the mutant phenotype have successfully been performed, but inducing expression of full length nhsl1b in the nhsl1b mutants is proving difficult.

Neuronal migration is an essential process in the development of the nervous system. Neurons are born in one location and migrate sizable distances to their final location. In many other developmental processes, cells migrate as collectives, where the migration of one cell influences the migration of another cell; this process has yet to be shown in the developing central nervous system. Using the conserved tangential migration of facial branchiomotor neurons (FBMNs), I aim to determine the nature of the collective migration in the developing nervous system. Here, two models of FBMN collective migration are tested: the “Pioneer” model, where following FBMNs migrate intimately on the axon of the first neuron to migrate and the “Contact inhibition of locomotion (CIL)” model, where transient cell-cell contacts are the driving influence of the proper caudal migration of FBMNs. Using fixed tissue imaging, it was found that early born FBMNs do not contact the axon. In contrast, they are more likely to make soma-soma contact and display morphology typical of CIL. FBMNs that do contact the axon do not display an elongated morphology that is predicted of a cell using the leader axon as a substrate for migration. Further, wild-type FBMNs are able to rescue PCP-deficient FBMNs. Therefore, blastula-stage transplantation of PCP-deficient neurons into wild-type hosts allows us to live image the method of collective migration. CIL events were observed between PCP-deficient neurons and wild-type neurons, indicating that PCP is not required for CIL. In addition, PCP-deficient neurons making sustained contact with wildtype axons were not rescued, arguing against the Pioneer model. Taken together, these observations are more consistent with the “CIL” model of FBMN collective migration in which transient soma-soma interactions are required for the coordinated movement of neurons as they migrate in the developing nervous system.

The development of fluent reading requires coordinated development of key fiber pathways. While several fiber pathways have been implicated in reading, including the recently re-identified vertical occipital fasciculus (VOF), inferior longitudinal fasciculus (ILF), arcuate fasciculus and its 3 components, and inferior fronto-occipital fasciculus (IFOF), whether these fiber pathways support reading in young children with little to no exposure to print remains poorly understood. Consequently, over the course of three studies, the current dissertation aimed to narrow this research gap by addressing the following research questions: 1) Which fiber pathways support early literacy skill in young children 5-10 years old? 2) Are microstructural properties of these tracts predictive of age-related changes in reading across an interval of two years? 3) Do different components of the recently identified VOF differentially support reading? To answer these questions, we used diffusion-weighted imaging to measure white-matter development and to relate the microstructural properties of each fiber pathway to early literacy and literacy development. We report several novel findings that contribute to our growing understanding of the white matter connections supporting early literacy and literacy. For the first time, these studies revealed that the re-identified VOF can be reliably tracked in young children, bilaterally and is composed of three main components, which project from occipital temporal sulcus to angular, and middle and superior occipital gyri. We also found that the left AF, bilateral ILF, and particular components of the VOF play a role in early literacy and literacy development. Implications for contemporary models of reading development are discussed.

Prenatal stress has been correlated with adverse developmental outcomes affecting infant cognition and behavior. Previous studies have shown that prenatal stress can lead to increased susceptibility to adult disease but few studies have looked at the physiological stress response system by measuring the activity of the hypothalamicpituitary-adrenal (HPA) axis. Cortisol, the output of the HPA axis can be secreted in many different matrices (saliva, blood, urine, feces and hair). Most studies that do, only look at one measure of hormone production instead of examining multiple matrices. Additionally these studies do not look at the relationship between matrices. Hair provides a long-term assessment of cortisol hormone production as related to infant behavior. Four measures of cortisol representative of prenatal and postpartum periods were collected in a sample population of rhesus macaques at the NIH facility. No stress was applied to these animals and cortisol concentrations were assessed in maternal hair, infant hair, amniotic fluid, and mothers’ milk. These cortisol measures were then analyzed first to determine vii the relationships between the four measures and second to relate these cortisol values to infant behavior in the primate neonatal neurobehavioral assessment. Subjects of this study were 30 mothers and infants from the 2015 and 2016 breeding cohort. 25 of which, were unique dyads. Using four statistical analyses and 3 groupings of behavior, we found that maternal hair cortisol concentrations were correlated with different temperaments of infants, while milk cortisol concentrations were correlated with infant’s visual exploration of the environment. Additionally, an inverse relationship was found between hair cortisol concentrations and both hair cortisol concentrations with amniotic fluid cortisol. Together, the four statistical analyses show that Maternal HPA axis activation during and after pregnancy affects infant behavioral development 1 month postpartum.