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.

The first stage of mammalian auditory processing occurs within the dorsal and ventral divisions of the cochlear nucleus. The dorsal cochlear nucleus (DCN) is remarkable in that it shares striking similarities with the cerebellum in terms of its development, gene expression patterns, and anatomical organization. Notably, principal cells of the DCN integrate auditory nerve input with a diverse array of signals conveyed by a mossy fiber- granule cell system. Yet how the elaborate cerebellum-like circuitry of DCN contributes to early auditory processing has been a longstanding puzzle. The work in this thesis shows that, in mice, that the DCN functions to cancel responses to self-generated sounds. While the DCN and ventral cochlear nucleus (VCN) neurons respond similarly to externally-generated acoustic stimuli, sounds generated by licking behavior evoke much weaker responses in DCN than in VCN. Recordings in deafened mice revealed non- auditory signals related to licking in Purkinje-like neurons of DCN. Moreover, silencing somatosensory mossy fiber inputs revealed prominent DCN responses to sounds generated by licking, suggesting that these inputs normally function to cancel responses to self-generated sounds. Finally, I show that this cancellation is not fixed, but involves an adaptive process whereby neural responses correlated with the animal’s own behavior are gradually reduced. Together, these findings suggest that the fundamental process of distinguishing self-generated from external stimuli begins at the very first stage of mammalian auditory processing. Related adaptive filtering functions have been described for cerebellum-like sensory structures in fish and hypothesized for the mammalian cerebellum. Hence our findings also suggest that, despite their wide phylogenetic separation, different cerebellum-like structures and the cerebellum itself may all perform a similar computation.

The study of cerebellum-like circuits allows many points of entry. These circuits are often involved in very specific systems not found in all animals (for example electrolocation in weakly electric fish) and thus can be studied with a neuroethological approach in mind. There are many cerebellum-like circuits found across the animal kingdom, and so studies of these systems allow us to make interesting comparative observations. Cerebellum-like circuits are involved in computations that touch many domains of theoretical interest - the formation of internal predictions, adaptive filtering, cancellation of self-generated sensory inputs. This latter is linked both conceptually and historically to philosophical questions about the nature of perception and the distinction between the self and the outside world. The computation thought to be performed in cerebellum-like structures is further related, especially through studies of the cerebellum, to theories of motor control and cognition. The cerebellum itself is known to be involved in much more than motor learning, its traditionally assumed function, with particularly interesting links to schizophrenia and to autism. The particular advantage of studying cerbellum-like structures is that they sit at such a rich confluence of interests while being involved in well-defined computations and being accessible at the synaptic, cellular, and circuit levels. In this thesis we present work on two cerebellum-like structures: the electrosensory lobe (ELL) of mormyrid fish and the dorsal cochlear nucleus (DCN) of mice. Recent work in ELL has shown that a temporal basis of granule cells allows the formation of predictions of the sensory consequences of a simple motor act - the electric organ discharge (EOD). Here we demonstrate that such predictions generalize between electric organ discharge rates - an ability crucial to the ethological relevance of such predictions. We develop a model of how such generalization is made possible at the circuit level. In a second section we show that the DCN is able to adaptively cancel self-generated sounds. In the conclusion we discuss some differences between DCN and ELL and suggest future studies of both structures motivated by a reading of different aspects of the machine learning literature.

Duchenne muscular dystrophy (DMD) and congenital muscular dystrophy 1A (MDC1A) are the two most common forms of muscular dystrophy in humans, caused by mutations in dystrophin and laminin α2 genes respectively. Both are severe forms of the disease that lead to premature death due and are both now known to have a significant effect on the central nervous system. This project investigated the role of both proteins involved in each of these diseases in cerebellar Purkinje cells of two murine models of disease: the mdx mouse a dystrophin-deficient model of DMD and the dy2J a laminin α2-deficient murine model of MDC1A. In the case of dystrophin further studies were undertaken in order to determine if increasing age had any effects on cerebellar function. It was found that there is no difference in electrophysiological characteristics (RMP, IR, eEPSP) of the cells when compared to appropriate control groups, nor was there any difference when young and aged dystrophin-deficient mdx groups were compared. Evoked IPSP characteristics were examined in young mdx cerebellar Purkinje cells and again no difference was found when compared to wildtype. There was a significant difference in response to the GABAA antagonist bicuculline, with wildtype increasing eEPSP amplitude by almost double that found in mdx. There was no difference in short term plasticity as measured by paired pulse facilitation in any of these groups. There was no difference in paired pulse depression at the inhibitory interneuron- Purkinje cell synapse of young wildtype and mdx cerebellar Purkinje cells. There a significant blunting of long term depression (LTD, (a form of long term synaptic plasticity) between young wildtype and mdx. When young wildtype animals were compared to aged wildtype animals LTD was found to be similar, when young mdx was compared to aged mdx, there was a recovery of LTD seen in the aged population. There was also significant differences in LTD found when littermate controls were compared to dy2J (laminin α2 mutants). A third of the phenotypic animals (dy2J) potentiated. Finally when rebound potentiation (a GABA-ergic form of long term synaptic plasticity in the cerebellum) was compared in young wildtype and mdx mice, mdx mice displayed depression, rather than the expected potentiation in contrast to potentiation (or no change) as seen in all wildtype cells.

Maternal alcohol abuse during pregnancy can result in a range of structural and functional abnormalities that include lifelong physical, mental, behavioral and learning disabilities, now collectively termed as Fetal Alcohol Spectrum Disorders (FASD). The incidence of FASD is now estimated be as high as 10 per 1000 live births. Each year, 40,000 babies are born with FASD in the United States at an estimated cost of $1.4 million per individual and total cost of $6 billion. Because of the magnitude of this problem and because the incidence has not decreased in spite intensive efforts to educate women to not abuse alcohol during pregnancy, ways to prevent or mitigate the effects of prenatal alcohol exposure must be explored in addition to education. Therefore, we wished to identify the precise mechanisms by which alcohol mediates the neurodevelopmental damage in order to develop intervention/amelioration strategies. The present study was conducted using an ovine model system. The large body mass of the ovine fetus, the longer gestation that is more similar to that of humans, and that all three trimester equivalents occur in utero, make the sheep an excellent model to study the effects of alcohol on the developing fetus. Our study establishes that maternal alcohol exposure does not result in fetal cerebral hypoxia. Instead, alcohol results in hypercapnea and acidemia leading to a cascade of events in the maternal and fetal compartments that include deficits in the levels of glutamine and glutamine-related amino acids, alterations in endocrine axes, oxidative stress, alteration in cardiovascular homeostasis and fetal neuronal loss. Further, we demonstrate that inhibiting the novel two-pore domain acid sensitive potassium channel (TASK) expressed in the cerebellar granule cells and the peripheral and central chemoreceptors may prove to a be potential therapeutic strategy. Preventive strategies that are safe to use in pregnant women and that involve glutamine-related pathways are also suggested. Finally, the study also establishes the beneficial effects of moderate alcohol consumption on the fetal skeletal system.

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: NF-1 -- granule cell neuron. Includes bibliographical references (p. 38-39).

The current study characterizes a novel isoform of the Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP), herein NOS1APc. NOS1APc was identified in a proteomic screen for Scribble interacting proteins. Northern blot analysis revealed a 7kb transcript that was present in a number of different tissues and cell lines. Highest levels were detected in the cerebellum. In situ hybridization studies revealed NOS1APc mRNA throughout the cortex and hippocampus. In addition, cerebellar Purkinje cells and different brainstem nuclei also contained NOS1APc mRNA. Antibodies directed against NOS1APc revealed a 100 kDa protein, while immunohistochemical staining revealed high levels of this protein within the molecular layer of the cerebellum. Finally, immunocytochemical studies using isolated primary astrocytes revealed a subset of BrdU positive nuclei that co-expressed NOS1APc, suggesting that this protein may function in some capacity in cell-cycle progression.

Our behaviour is guided by the ability to predict future events. The predictive saccade paradigm has been shown to be a valuable tool that uses eye movements to measure the control of predictive behaviour. In this task, subjects follow a visual target that alternates or “steps” between two fixed locations at either predictable or unpredictable inter-stimulus time intervals (ISIs). Response times can be measured by subtracting the time of saccade initiation from the time of target appearance. When the ISI is predictable, saccadic reaction times (SRTs) become predictive (SRT <100ms) within 3-4 target steps, but when the ISI is unpredictable, the SRTs remain reactive to target appearance (SRT >100ms). The goal of our study was to investigate neural mechanisms controlling prediction by contrasting areas in the brain that were more active for predictive (PRED) versus reactive (REACT) saccades in young healthy adults using functional magnetic resonance imaging (fMRI). fMRI analysis revealed two distinct neural networks more recruited for REACT and PRED tasks. We observed greater activation for the REACT task compared to the PRED task in oculomotor network areas including the frontal, supplementary, parietal eye fields, dorsolateral prefrontal cortex, thalamus, and putamen. These structures are all involved with the control of saccades. We also observed greater activation for the PRED task compared to the REACT task in default network areas, including the medial prefrontal cortex, posterior cingulate cortex, inferior parietal lobule, and hippocampus. These structures are known to be involved with passive thinking when subjects are not focused on their external environments. We also observed greater activation for the PRED task in the cerebellum (crus I), which may serve as the internal clock that drives the regular rhythmic behaviour observed for predictive saccades. In summary, our findings suggest brain activation in the PRED task reflects automated and motor-timed responses, while that for the REACT task reflects externally-driven responses. Therefore, the predictive saccade task is an excellent tool for measuring prediction involving fast internally-guided responses. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-08-12 10:21:37.744

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