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The notion that learning and memory processes are highly dependent on central cholinergic neurotransmission has been widely accepted. However, studies documenting the importance of Acetylcholine (ACh) in attention have led some to suggest that attention impairments may underlie the deficits in learning and memory resulting from cholinergic disruptions. Using a visual discrimination task, I attempted to discern whether performance impairments by Scopolamine were predominantly due to the importance of muscarinic receptor integrity in attention, or memory consolidation in learning. Rats were trained in a visual discrimination task using a Y-shaped water maze apparatus. To successfully navigate to a hidden platform located in one of the two goal arms, rats learned to discriminate between 2 distinct visual cues, indicating the platform’s presence (CS+) or absence (CS-), respectively. Following task acquisition, testing continued using a combination of Regular trials (RT; both CS+ and CS- present) and Probe trials (PT; only one of the cues present). Results indicated that performance on PT was impaired due to greater task difficulty under conditions of reduced information, while Scopolamine (1 mg/kg) further impacted PT performance without affecting RTs. In a second experiment, PTs were administered with the platform present to provide reinforcement and a learning opportunity. Animals still exhibited poorer PT performance, but rapidly learned to rely on a single cue for accurate platform localization. Interestingly, this learning was not apparent under conditions of Scopolamine treatment (1 mg/kg), even though RT performance was completely unaffected. To examine experience-dependent changes in neuronal responding after visual discrimination learning, a subset of animals were anesthetised and visual evoked potentials (VEPs) in V1 and area CA1 of the hippocampus were recorded in response to CS+, CS-, and novel stimuli. In both the V1 and CA1, the VEP amplitudes elicited to familiar and novel stimuli were not significantly different. First, these experiments demonstrate the importance of the cholinergic system in sustaining visual attention and acquiring a new single-cue strategy. Furthermore, the null electrophysiology findings do not rule out the plastic response properties of the mature V1 and CA1, but remind us of the complex nature of memory encoding in the brain. / Thesis (Master, Psychology) -- Queen's University, 2011-09-16 13:50:24.045

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The thesis presents a new paradigm for studying the importance of interactions between an organism and its environment using a combination of biology and technology: embodying cultured cortical neurons via robotics. From this platform, explanations of the emergent neural network properties leading to cognition are sought through detailed electrical observation of neural activity. By growing the networks of neurons and glia over multi-electrode arrays (MEA), which can be used to both stimulate and record the activity of multiple neurons in parallel over months, a long-term real-time 2-way communication with the neural network becomes possible. A better understanding of the processes leading to biological cognition can, in turn, facilitate progress in understanding neural pathologies, designing neural prosthetics, and creating fundamentally different types of artificial cognition. Here, methods were first developed to reliably induce and detect neural plasticity using MEAs. This knowledge was then applied to construct sensory-motor mappings and training algorithms that produced adaptive goal-directed behavior. To paraphrase the results, most any stimulation could induce neural plasticity, while the inclusion of temporal and/or spatial information about neural activity was needed to identify plasticity. Interestingly, the plasticity of action potential propagation in axons was observed. This is a notion counter to the dominant theories of neural plasticity that focus on synaptic efficacies and is suggestive of a vast and novel computational mechanism for learning and memory in the brain. Adaptive goal-directed behavior was achieved by using patterned training stimuli, contingent on behavioral performance, to sculpt the network into behaviorally appropriate functional states: network plasticity was not only induced, but could be customized. Clinically, understanding the relationships between electrical stimulation, neural activity, and the functional expression of neural plasticity could assist neuro-rehabilitation and the design of neuroprosthetics. In a broader context, the networks were also embodied with a robotic drawing machine exhibited in galleries throughout the world. This provided a forum to educate the public and critically discuss neuroscience, robotics, neural interfaces, cybernetics, bio-art, and the ethics of biotechnology.

[Truncated abstract] Alzheimer’s disease (AD) is a progressive neurodegenerative disease which manifests clinically as personality changes and global cognitive decline resulting in a loss of function, ultimately leading to death. Whilst causal genetic mutations have been identified, accounting for a small proportion of familial cases, the vast majority of all AD cases are late onset and idiopathic. However, a number of risk factors have been identified, including age associated changes in the reproductive hormones – estrogen and the gonadotropins. Previous in vitro and in vivo studies have implicated both estrogen and the gonadotropins in the regulation of the neurotoxic beta amyloid (Aß) peptide, accumulation of which is thought to be a key pathogenic event in the development of AD, but the role of these hormones in the etiology and pathogenesis of AD remains contentious. The aim of this thesis was to further understanding of the role of female reproductive hormones in modulating susceptibility to AD. The role of menopausal hormone dysregulation in behavior, cognitive decline and Aß-related neuropathology was examined in vivo in 4 studies using animal models of AD and menopause. The first two studies used a mouse model of AD expressing a human PS1 mutation (PS1KI) to examine the effects of ovariectomy as a model of menopause on cognition and neuropathology. Ovariectomy was found to selectively impair learning on a spatial working memory task without affecting working memory recall or reference memory performance. However, this cognitive impairment was not associated with any changes in Aß accumulation or oxidative stress. ... However, these findings cannot explain the lack of effect of estrogen supplementation on Aß levels. It is possible that supra-physiological doses of estrogen are necessary to yield anti-amyloidogenic and anti-oxidative benefits in ovariectomized sheep. It is becoming clear that the relationship between hormone changes at menopause and risk of AD may be more complicated than previously conceived. This study has begun to tease apart the relative contributions of estrogen and the gonadotropin hormones in the modulation of Aß, accumulation of which may confer susceptibility to AD. The findings presented indicate that the gonadotropins may play an important role in the regulation of AD-related behavior and cognition. The observed functional effects of the gonadotropins may also have implications for our understanding of behavioral and cognitive changes occurring during reproductive events. Based on the evidence presented here, combined with previous literature, it is clear that both estrogen and the gonadotropins are involved in the modulation of Aß accumulation, however, elucidation of the circumstances necessary to elicit these effects and their clinical relevance to humans will require further investigation. These findings contribute to a more sophisticated understanding of the post-menopausal hormonal milieu, recognizing the role of the gonadotropin hormones and that gonadal estrogen depletion does not necessarily result in brain estrogen depletion.

Les variations du nombre de copies (CNVs) incluent les délétions et les duplications de régions chromosomiques d’une taille variant de 50 pb à plusieurs Mb. Depuis 2005, les études d’association pangénomiques (GWAS) ont permis d’associer certains larges CNVs à des maladies syndromiques associées à la déficience intellectuelle incluant les syndromes de DiGeorge, Williams, Angelman, etc. En fonction de la densité génique de la région d’intérêt et de la variabilité des phénotypes associés, l’étude de la physiopathologie des syndromes peut être extrêmement complexe. La modélisation murine offre de nombreux avantages pour l’identification des gènes candidats et la compréhension des mécanismes moléculaires associés à ces pathologies.Les travaux présentés dans ce manuscrit consistent en la caractérisation des modèles murins pour cinq maladies syndromiques associées aux CNVs : la monosomie 21 partielle ainsi que les réarrangements des régions 16p11.1 et 17q21.31. Les caractérisations anatomiques, métaboliques et comportementales des animaux nous ont permis d’évaluer un grand nombre de paramètres associés à la symptomatique humaine. Nous avons également réalisé des analyses électrophysiologiques et transcriptomiques en ciblant nos investigations sur l’hippocampe, structure cérébrale qui joue un rôle central dans les processus de mémoire et d’apprentissage. Ce projet de recherche s’inscrit dans une perspective plus large qui est l’identification des gènes candidats pour les phénotypes observés et le développement de premières stratégies thérapeutiques pouvant potentiellement aboutir à l’amélioration des capacités cognitives des patients. / Copy number variations (CNVs) include deletions and duplications of chromosomal regions ranging in size from 50bp to several Mb. Since 2005, genome-wide association studies (GWAS) have associated some large CNVs to syndromic diseases linked to intellectual disability including DiGeorge, Williams, Angelman syndroms, etc. Depending on the gene density of the region of interest and the variability of symptoms, the study of the pathophysiology of syndromes can be extremely complex. Mouse modeling show many advantages for the identification of candidate genes and the understanding of molecular mechanisms associated with these diseases.The work presented in this manuscript consists of the characterization of mouse models of five syndromic diseases associated with CNVs: partial monosomy 21 and rearrangements of 16p11.2 and 17q21.31 regions. Anatomical, metabolic and behavioral characterizations of animals allowed us to evaluate a broad number of parameters associated with human phenotypes. We also performed electrophysiological and transcriptomic analysis focusing our investigation on the hippocampus which has a major role in learning and memory processes. This project is part of a wider perspective which is the identification of candidate genes for the different phenotypes we observe in the mouse and the development of first treatment strategies which can potentially lead to the improvement of cognitive capacity of patients.

Depression occurs in about one third of patients with stroke and cardiac arrest. Hyperactivity of the stress system is the most commonly observed neuroendocrine change in major depressive disorder (MDD), which involves elevated levels in the cerebrospinal fluid of corticotropin-releasing hormone (CRH), a key stress neurohormone. Substantial evidence suggests that normalization of the stress system may be a requirement for successful treatment of MDD through region-specific changes in the mesocorticolimbic circuitry. Thus, alteration in the stress system may underlie the emotional and functional impairments observed following brain ischemic events. In addition, recent findings suggest that ischemic brain injury triggers a restorative process, creating a cerebral environment similar to that of early brain development, a period characterized by rapid neuronal growth and neuroplasticity, critical to optimize functional recovery of individuals post stroke. In particular brain-derived neurotrophic factor (BDNF), has been shown to play an important role in the pathophysiology of major depression and cerebral ischemia. However, whether CRH can mediate the expression of BDNF in the reparative process triggered by ischemic injury remains to be characterized. Therefore, the purpose of the current thesis is to characterize the effect of pharmacological blockade of CRH signaling at the onset of a global ischemic stroke, on emotional and cognitive behaviors, alteration in the neuroendocrine stress system, and markers of neuroplasticity including BDNF. To do this, an animal model of global cerebral ischemia with subsequent behavioral testing and postmortem brain analysis was used to determine underlying biochemical and behavioral changes modulated by CRH signaling following brain ischemia. This doctoral work will help elucidate the relationship between CRH and BDNF in the context of cerebral ischemia, and may provide insights for therapies targeting the stress system. These studies address considerations such as: the interplay between stress, neuroplasticity and emotionality, and whether global ischemia can affect mood via changes in the HPA axis response.

Introduction: Schizophrenia is a neuropsychiatric illness characterized by impairments in cognition and positive and negative symptoms. As currently used antipsychotics do not treat all symptoms of the disease, further research of the therapeutic potential of various drugs in the treatment of this disease is crucial. Psychosis is a condition or a mental state that usually accompany schizophrenia, as well as other disorders. We used MK-801, a non-competitive antagonist of NMDA receptors to induce an experimental model of psychosis in rats. By binding to the NMDA subtype of glutamate receptors located on inhibitory interneurons, MK-801 has been shown to elicit an overactivation of cortical and hippocampal pyramidal neurons, leading to behaviors such as hyperlocomotion, stereotypy or cognitive impairments. LY 379268, an agonist of group II metabotropic glutamate receptors, binds to both presynaptic and postsynaptic receptors on pyramidal neurons. It has been suggested that it could alleviate the MK-801-induced hyperactivity of the principal neurons. In this study, we sought to demonstrate the effects of LY 379268 in the MK-801 animal model of psychosis and hypothesized that LY 379268 will ameliorate deficits in the reversal learning induced by MK-801. Materials and methods: Long Evans rats received...

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