The vestibular system provides us with sensory information that is essential for maintaining balance and stability. When sensory input is lost due to unilateral vestibular damage (UVD), our ability to maintain stable gaze and posture becomes compromised. Over time, vestibular function is partially restored through a process known as vestibular compensation, which is associated with the rebalancing of activity in the vestibular nuclear complex (VNC) of the brainstem. However, the physiological mechanisms associated with vestibular compensation remain elusive. We addressed several different experimental objectives pertaining to plasticity and sensory adaptation associated with vestibular compensation. First, we demonstrated that systemic manipulation of γ-amino-butyric acid type B (GABAB) receptors altered the course of vestibular behavioural recovery within the first several hours after UVD. Second, we showed that immunohistochemical labeling of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR4 was elevated in the VNC on the intact compared to lesioned side acutely following UVD. Third, we produced preliminary data suggesting that excitatory responses to vestibular nerve stimulation may be acutely potentiated by UVD on the intact side. Finally, we established that rapid sensory adaptation may increase the dynamic ranges of vestibular neurons and perhaps improve limited vestibular reflex function in the long term. Acutely following UVD, potentiation of vestibular nerve synapses appear to be associated with an increase in GluR4 subunit expression in the contralesional VNC. Also, such potentiation could be enhanced by acute modifications in pre-synaptic GABAB receptor activation. In the long term, and independent of these plastic changes, sensory adaptation may enable the vestibular system to overcome the persistent limitations imposed by UVD.

A persistent unanswered question in cognitive neuroscience has been what are the neural origins of human brain lateralization? Language is strongly lateralized to the left-hemisphere, however, lateralization varies with language experience. Bilinguals demonstrate a greater extent and variability of right-hemisphere involvement for language relative to monolinguals. Here, bilingualism is used as a lens into the conditions that drive brain lateralization. Why does bilingual language processing yields more robust bilateral neural activation relative to monolingual language processing? Neural activation and functional connectivity were measured to test hypotheses about the temporal dynamics of hemispheric recruitment during language processing in monolingual and bilingual children with varying ages of first bilingual language exposure. Hypothesis (1), The human brain is strongly left-hemisphere lateralized for language, but, when faced with the demands of two languages, additional right-hemisphere resources are recruited. Hypothesis (2), The human brain has the potential for enhanced dual hemispheric language processing that can be either potentiated or not based on early life bilingual versus monolingual language experience. If dual language experience places increased cognitive demands on the bilingual brain requiring additional right-hemisphere resources, asynchronous neural activation in left and right hemispheres was predicted. If dual language experience potentiates dual hemispheric language processing, synchronous neural activation in left and right hemispheres was predicted. Furthermore, only early-exposed bilinguals but not later-exposed bilinguals or monolinguals, would show synchronous neural activation across the hemispheres. Early experience with one language (monolinguals) or two languages at different times during a child's development (early-exposed bilinguals, later-exposed bilinguals) revealed differences in the time-course of activation across the two hemispheres' language areas, supporting Hypothesis (2). Monolinguals and later-exposed bilinguals showed asynchronous activation between the hemispheres. Early-exposed bilinguals showed synchronous activation between the hemispheres. The results provide a new view on how different experiences can drive lateralization in development and reveal the neural basis of bilateral activation in the bilingual brain. Synchronous temporal accessing of the hemispheres in bilinguals suggests early life bilingual language experience may support more equal and efficient hemispheric involvement, and, in turn, constitute the brain-based mechanism that makes possible the widely observed linguistic and cognitive advantages in young bilinguals.

Causality analysis is an approach to time series analysis that is being used increasingly to investigate neuroimaging data. The reason for its popularity is the useful perspective it provides in describing the ordered operations of various brain regions using indirectly and passively measured neurophysiological signals. Although there are numerous frameworks with which causality analysis can be performed, one concept in particular – termed Granger causality (GC) – is receiving much of the attention because of its ease of implementation and interpretability. GC makes use of the fact that a predictive relationship between the history of one signal and the future of another signal provides evidence for there being a causal relationship between the two signals, and as a result, the physical events underlying those signals. If such a relationship can be established across neural time series, causal dependencies between neural pathways can be inferred and their contribution to brain function can be studied. Several analysis frameworks exist for applying GC to neurophysiological questions but many of these frameworks have deficiencies that impede their application to large and highly multivariate neuroimaging datasets. To address some of these concerns, this study develops the theory and methods for a novel neural time series classification procedure – referred to as GC classification – based on concepts in GC analysis. Validation of this method in neuroimaging research is provided by showing that it can be applied to heterogeneous datasets, that it makes use of many parallel sources of information about causal relationships, and that it can be adapted to different types of preprocessing steps to uncover causal relationships in multivariate neural time series data. Application of this analysis method to human behavioural MEG data revealed that, during a cued button-pressing task, distinct causal relationships exist between sensory cortices and their downstream targets preceding the initiation of actions that differ by whether or not they were the result of a decision being made. These results provide evidence that the GC classification procedure is a useful and robust technique for studying causal relationships in neurophysiological time series.

Adult neurogenesis is a conserved feature of the central nervous system across the animal kingdom. This process takes place in restricted neurogenic niches of the brain, where active populations of adult stem/progenitor cells are capable of producing newborn neurons. The niche is tightly controlled by intrinsic signals within the microenvironment and from stimuli arising from the external world, which together determine the cellular behaviour of the niche and neuronal output. Currently, our understanding of the biological properties of adult neurogenesis rests mainly on two niches of the vertebrate forebrain. To broaden our view of the diversity of this trait comparative models and new niches must be explored. Here, I have taken advantage of the robust neurogenic capacity of the adult zebrafish brain to examine differences in forebrain and sensory neurogenic niches in regards to cytoarchitectural organization, neurogenic plasticity, and regulation. Five principle findings emerge: (1) up to six morphologically distinct cell types compose forebrain and sensory niches, and are devoid of ependymal cells; (2) heterogeniety in the phenotype of the stem/progenitor cell exists across niches; some having radial glial characteristics; (3) active populations of proliferating stem/progenitor cells reside within primary sensory structures of the adult brain, forming a “sensory neurogenic niche”; different from other models of adult neurogenesis; (4) changes in the social environment induce neurogenic plasticity in sensory niches more readily than integrative niches of the forebrain, and occur independently of cortisol levels; (5) modality-specific stimulation influences stages of adult neurogenesis exclusively in corresponding primary sensory niches as a result of sensory-dependent neurogenic plasticity. Additionally, I have shown that Fibroblast Growth Factor signalling may not be involved in maintaining cell proliferation in sensory niches. These studies showcase the diverse properties of forebrain and sensory neurogenic niches and provide a new perspective concerning the functional role of adult neurogenesis.

Parkinson’s disease can be caused by A53T or A30P mutations in the α-synuclein (SNCA) gene, or by multiplication of the gene locus. Patients often experience depression and anxiety. We investigated affect, serotonin content and bioenergetic homeostasis of mice expressing human wild-type (WT), A53T, A30P or A53T+A30P (DM) SNCA transgenes. A30P-Tg mice displayed altered affect, increased serotonin turnover and reduced ATP and complex I+III activity. To determine whether murine α-synuclein (Snca) might mask effects SNCA transgenes we re-examined effects of SNCA transgenes in Snca-/- mice. SNCA transgenes rescued anxiety, serotonin levels and ATP content in Snca-/- mice. Only A53T SNCA abrogated behavioural despair associated with decreased norepinephrine in Snca-/- brains. The A53T residue is the natural sequence of murine Snca, and appears to be important for synuclein function in mice. The Snca-/- mouse provides a means to study the effects of SNCA mutants, and the physiologic roles of Snca in vivo.

Throughout adulthood, the brain continuously generates new neurons in two neurogenic regions: the subgranular zone of the hippocampus and the subventricular zone on the lateral wall of the lateral ventricles. These neurons have been shown to integrate into hippocampal and olfactory bulb circuitry, respectively. Nevertheless, their specific contribution to hippocampal or olfactory function remains unclear. Previous studies have tried to assess adult born neuron contribution to memory function by suppressing neurogenesis and examining the impact on memory acquisition. Although ablation of neurogenesis has been shown to impair performance in hippocampus dependent and olfactory tasks, many studies fail to see an effect. Compensation from residual cells in either system after ablation may underlie these contradictory findings. Thus, a more direct approach to answer this question would be to ablate adult born neurons after their incorporation into the memory trace. To do this, we established a double transgenic strategy to tag and selectively ablate adult born neurons with temporal control. Ablation of a population of predominantly mature, adult generated dentate granule cells did not prevent acquisition of contextual fear conditioning or Morris Water Maze memories. Removal of that same population of cells after training, however, led to memory degradation in three hippocampus dependent tasks. Similarly, post-training ablation of a population of adult generated olfactory interneurons iii impaired performance in an associative odour memory task, whereas pre-training ablation had no impact. Together, these data show that adult generated neurons form a crucial component of both hippocampal and olfactory memory traces.

Early-onset major depressive disorder (MDD) is associated with significant morbidity in adolescence. The interview-dependent diagnostic process used in psychiatry leaves a subset of adolescents with MDD undiagnosed. Sleep disturbances are a central feature of depression and adolescence is a period of rapid change in sleep physiology. The aim of this study was to test physiological features of sleep and circadian rhythms as markers of adolescent MDD. Adolescents completed a two-week protocol that included a formal psychiatric interview, polysomnographic (PSG) assessment, actigraphy, salivary melatonin sampling, and holter monitoring. Depressed adolescents (n = 18) differed from controls (n = 15) on features of sleep macroarchitecture measured by PSG, and on autonomic nervous system functioning measured by 24-hour heart rate variability. Depressed adolescents had shorter REM latency and decreased stage 4 sleep. Adolescents with MDD also showed decreased parasympathetic activity over 24-hours and during the day, and decreased sympathetic activity during the night.

One of the central questions of neuroscience research has been how the cellular and molecular components of the brain give rise to complex behaviours. Three major breakthroughs from the past sixty years have made the study of learning and memory central to our understanding of how the brain works. First, the psychologist Donald Hebb proposed that information storage in the brain could occur through the strengthening of the connections between neurons if the strengthening were restricted to neurons that were co-active (Hebb, 1949). Second, Milner and Scoville (1957) showed that the hippocampus is required for the acquisition of new long-term memories for consciously accessible, or declarative, information. Third, Bliss and Lømo (1973) demonstrated that the synapses between neurons in the dentate gyrus of the hippocampus could indeed be potentiated in an activity-dependent manner. Long-term potentiation (LTP) of the glutamatergic synapses in area CA1, the primary output of the hippocampus, has since become the leading model of synaptic plasticity due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals, and its robust pathway specificity. Using whole-cell recording in hippocampal slices from adult rats, I find that the efficacy of synaptic transmission from CA3 to CA1 can in fact be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, I show that the induction of GABAergic plasticity at feedforward inhibitory inputs in CA1 results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials which is dependent on NMDAR activation and is pathway specific. The sharing of these fundamental properties with classic LTP suggests the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.

Causality analysis is an approach to time series analysis that is being used increasingly to investigate neuroimaging data. The reason for its popularity is the useful perspective it provides in describing the ordered operations of various brain regions using indirectly and passively measured neurophysiological signals. Although there are numerous frameworks with which causality analysis can be performed, one concept in particular – termed Granger causality (GC) – is receiving much of the attention because of its ease of implementation and interpretability. GC makes use of the fact that a predictive relationship between the history of one signal and the future of another signal provides evidence for there being a causal relationship between the two signals, and as a result, the physical events underlying those signals. If such a relationship can be established across neural time series, causal dependencies between neural pathways can be inferred and their contribution to brain function can be studied. Several analysis frameworks exist for applying GC to neurophysiological questions but many of these frameworks have deficiencies that impede their application to large and highly multivariate neuroimaging datasets. To address some of these concerns, this study develops the theory and methods for a novel neural time series classification procedure – referred to as GC classification – based on concepts in GC analysis. Validation of this method in neuroimaging research is provided by showing that it can be applied to heterogeneous datasets, that it makes use of many parallel sources of information about causal relationships, and that it can be adapted to different types of preprocessing steps to uncover causal relationships in multivariate neural time series data. Application of this analysis method to human behavioural MEG data revealed that, during a cued button-pressing task, distinct causal relationships exist between sensory cortices and their downstream targets preceding the initiation of actions that differ by whether or not they were the result of a decision being made. These results provide evidence that the GC classification procedure is a useful and robust technique for studying causal relationships in neurophysiological time series.

A persistent unanswered question in cognitive neuroscience has been what are the neural origins of human brain lateralization? Language is strongly lateralized to the left-hemisphere, however, lateralization varies with language experience. Bilinguals demonstrate a greater extent and variability of right-hemisphere involvement for language relative to monolinguals. Here, bilingualism is used as a lens into the conditions that drive brain lateralization. Why does bilingual language processing yields more robust bilateral neural activation relative to monolingual language processing? Neural activation and functional connectivity were measured to test hypotheses about the temporal dynamics of hemispheric recruitment during language processing in monolingual and bilingual children with varying ages of first bilingual language exposure. Hypothesis (1), The human brain is strongly left-hemisphere lateralized for language, but, when faced with the demands of two languages, additional right-hemisphere resources are recruited. Hypothesis (2), The human brain has the potential for enhanced dual hemispheric language processing that can be either potentiated or not based on early life bilingual versus monolingual language experience. If dual language experience places increased cognitive demands on the bilingual brain requiring additional right-hemisphere resources, asynchronous neural activation in left and right hemispheres was predicted. If dual language experience potentiates dual hemispheric language processing, synchronous neural activation in left and right hemispheres was predicted. Furthermore, only early-exposed bilinguals but not later-exposed bilinguals or monolinguals, would show synchronous neural activation across the hemispheres. Early experience with one language (monolinguals) or two languages at different times during a child's development (early-exposed bilinguals, later-exposed bilinguals) revealed differences in the time-course of activation across the two hemispheres' language areas, supporting Hypothesis (2). Monolinguals and later-exposed bilinguals showed asynchronous activation between the hemispheres. Early-exposed bilinguals showed synchronous activation between the hemispheres. The results provide a new view on how different experiences can drive lateralization in development and reveal the neural basis of bilateral activation in the bilingual brain. Synchronous temporal accessing of the hemispheres in bilinguals suggests early life bilingual language experience may support more equal and efficient hemispheric involvement, and, in turn, constitute the brain-based mechanism that makes possible the widely observed linguistic and cognitive advantages in young bilinguals.