Compared to other structures, such as the amygdala, the lateral septum’s (LS) role in the regulation of anxiety and/or behavioural defense is relatively understudied. Thus, the overarching goal of this thesis was to further investigate its contribution to rats’ anxiety-related behaviours. In Chapter 2, we demonstrate, for the first time, that while the dorsal LS does not mediate rats’ appetitive motivation or anxiety in the novelty induced suppression of feeding (NISF) paradigm, it does modulate their defensive behaviours in the elevated plus maze (EPM) and shock probe burying tests (SPBT). In Chapter 3, we are the first to show that bilateral infusions of histamine, a neurochemical previously linked to anxiety, into the LS reduce rats’ anxiety-related behaviours in the EPM and NISF. In addition, we report a novel double dissociation between lateral septal H1 and H2, and H3 receptors in their regulation of rats’ defensive behaviours in those two paradigms. More specifically, the H1 and H2 receptors contribute to rats’ hyponeophagia in the NISF but not their open arm exploration in the EPM, while the H3 receptors modulate rats’ defensive behaviors in the EPM but not in the NISF. Finally, in Chapter 4, we report for the first time that infusions of histamine into the LS, which produce behavioural anxiolysis, increase rather than decrease the frequency of reticular-elicited hippocampal theta activity, a putative neurophysiological correlate of anxiolytic-drug action. Altogether, the data in this thesis increase our understanding of how the LS contributes to rats’ defensive behaviours and adds to the existing literature regarding the neurobiology of fear/anxiety. More importantly though, the data presented here could ultimately aid in the development of novel drugs to treat anxiety disorders in humans. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2013-12-17 17:27:34.014

Compared to other structures, such as the amygdala, the lateral septum’s (LS) role in the regulation of anxiety and/or behavioural defense is relatively understudied. Thus, the overarching goal of this thesis was to further investigate its contribution to rats’ anxiety-related behaviours. In Chapter 2, we demonstrate, for the first time, that while the dorsal LS does not mediate rats’ appetitive motivation or anxiety in the novelty induced suppression of feeding (NISF) paradigm, it does modulate their defensive behaviours in the elevated plus maze (EPM) and shock probe burying tests (SPBT). In Chapter 3, we are the first to show that bilateral infusions of histamine, a neurochemical previously linked to anxiety, into the LS reduce rats’ anxiety-related behaviours in the EPM and NISF. In addition, we report a novel double dissociation between lateral septal H1 and H2, and H3 receptors in their regulation of rats’ defensive behaviours in those two paradigms. More specifically, the H1 and H2 receptors contribute to rats’ hyponeophagia in the NISF but not their open arm exploration in the EPM, while the H3 receptors modulate rats’ defensive behaviors in the EPM but not in the NISF. Finally, in Chapter 4, we report for the first time that infusions of histamine into the LS, which produce behavioural anxiolysis, increase rather than decrease the frequency of reticular-elicited hippocampal theta activity, a putative neurophysiological correlate of anxiolytic-drug action. Altogether, the data in this thesis increase our understanding of how the LS contributes to rats’ defensive behaviours and adds to the existing literature regarding the neurobiology of fear/anxiety. More importantly though, the data presented here could ultimately aid in the development of novel drugs to treat anxiety disorders in humans. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2013-12-17 17:27:34.014

Diese Arbeit beschäftigt sich mit den Auswirkungen der Herz-Lungen-Maschine auf das Gewebe des Hippocampus in einem Ferkelmodell. Die Tiere untereilte man in 5 Gruppen: „Kontrolle“, „Kontrolle mit Minozyklin“, „HLM pulsatil“, „HLM nicht-pulsatil“, sowie „HLM nicht-pulsatil mit Minozyklin“. Es wurde untersucht, ob eine pulsatile Perfusion Schäden in den Zellen des Hippocampus gegenüber eines nicht-pulsatilen Blutflusses während der extrakorporalen Zirkulation abmildern kann. Des Weiteren überprüfte man neuroprotektive Effekte des Tetrazyklin-Derivates Minozyklin während eines kardiochirurgischen Eingriffes mit Herz-Lungen-Maschine. Während der Operation wurde bei allen Ferkeln eine Hypothermie von 28 °C durchgeführt und die HLM-Zeit betrug 90 Minuten. Die Rekonvaleszenzzeit umfasste 120 Minuten. Minozyklin verabreichte man in den entsprechenden Gruppen sowohl zu Beginn des Versuches (4 mg/kg KM) und nach Abkopplung von der Herz-Lungen-Maschine (2 mg/kg KM) intravenös. Hauptbestandteil der Arbeit waren histologische und immunhistochemische Färbemethoden zur Untersuchung des Hippocampus. Mithilfe eines Mikroskops wurden Veränderungen auf zellulärer Ebene im CA1- und CA3-Areal des Cornu ammonis im Hippocampus ausgewertet. Für die Ergebnisse betrachtet man die Pyramidenzellen des Stratum pyramidale. In der Hämatoxylin-Eosin-Färbung wurden Zellen mit den Eigenschaften „Ödem“, „Eosinophilie“ und „Pyknose“ für jedes Versuchstier gezählt. Mit den immunhistochemischen Färbungen sollten Faktoren für den programmierten Zelltod, für Hypoxie (HIF 1-alpha) und für oxidativen Stress (3-Nitrotyrosin) detektiert werden. Als Marker für Apoptose wählte man den Apoptose-induzierenden Faktor (AIF), cleaved Caspase 3 und Poly(ADP)Ribose (PAR).

Notre vision de l'épilepsie du lobe temporal avec sclérose hippocampique a beaucoup évolué grâce aux techniques de neuroimagerie multimodale. Initialement perçue comme maladie restreinte à la lésion, à savoir la sclérose hippocampique (SH), elle est aujourd'hui considérée comme un modèle de pathologie en réseau. Cette thèse a pour but d'approfondir les caractéristiques du réseau sous tendant cette épilepsie.Nous avons pour cela recueilli des données de connectivité structurelle, d'EEG et de données cognitives chez une cohorte de 44 patient avec SH unilatérale (22 droite, 22 gauche) et chez 28 sujets contrôle. Nous avons déterminé les régions d'intérêt corticales et le volume hippocampique avec Freesurfer et la connectivité structurelle (locale ou en réseau) avec MRtrix ou FSL.Trois principaux résultats émergent de ces études :1. La connectivité globale montre un pattern de déconnexion très marqué de l'hémisphère gauche en cas de SH gauche. La SH semble donc s'accompagner d'une atteinte de réseau plus importante lorsqu'elle se situe dans l'hémisphère dominant pour le langage.2. La connectivité hippocampo-thalamique est augmentée du côté de la SH. Cette augmentation semble dysfonctionnelle, car corrélée avec une baisse de fonctions cognitives exécutives. 3.L'EEG de ces patients révèle des anomalies interictales ipsi-latérales qui sont corrélées avec une diminution de fonctions cognitives exécutives. Nos données confirment ainsi le concept de l'épilepsie du lobe temporal en tant que pathologie de réseau. L'atteinte structurelle, mais également cognitive s'étend sur des régions à distance de l'hippocampe et affecte notamment les réseaux de langage de l'hémisphère dominant / Our vision of temporal lobe epilepsy (TLE) with hippocampal sclerosis has much evolved in recent years. Initially regarded as a disease centered on a single lesion, it is now perceived as a genuine network disease, which we intended to explore with a multimodal approach. We examined structural connectivity, fMRI, EEG and cognitive dysfunction in a cohort of 44 patients with unilateral hippocampal sclerosis (HS, 22 with right, 22 with left HS) and 28 healthy age and gender matched control participants. Cortical regions of interest and hippocampal volumes were determined with Freesurfer, structural connectivity with MRtrix (pairwise disconnections and component effects with Network Based Statistics), or for hippocampal-thalamic connections with FSL. We found a pronounced pattern of disconnections most notably in the left hemisphere of patients with left TLE. Network Based Statistics showed large bi hemispheric clusters lateralized to the diseased side in both left and right temporal lobe epilepsy. We suggest that hippocampal sclerosis is associated with widespread disconnections if situated in the dominant hemisphere. We then determined streamline connections between hippocampus and thalamus and found an increase in connections in relation to the HS. This increase was seemingly dysfunctional as the number of hippocampal-thalamic connections was negatively correlated with performance in executive tasks. EEG analysis revealed predominantly ipsilateral epileptic discharge. The number of sharp waves was highly correlated with a number of executive functions depending on the frontal lobe, hence at distance of the HS. Our data thus confirms the concept of temporal lobe epilepsy as a network disease that finds its expression both in widespread, though lateralized alterations of structural connectivity and in neuropsychological dysfunction way beyond the hippocampus.

De acordo com Gray (1982) o sistema nervoso monitora o ambiente e o comportamento continuamente, sendo capaz de inibir o comportamento em curso quando se depara com novidades ou com discrepâncias entre expectativas geradas com base em memórias de regularidades passadas e a informação sensorial presente, de modo a explorar a fonte de novidade ou discrepância e, assim, obter informações que possibilitem gerar previsões melhores no futuro. O sistema septo-hipocampal compararia estímulos presentes com informações antecipadas (ou previstas). Tal sistema envolve um comparador, o subículo, que receberia informações do presente através de aferências neocorticais, via córtex entorrinal, e informações \"previstas\" geradas em um \"circuito gerador de previsões\". Gray (1982) propôs que esse circuito gerador de previsões inclui o subículo, os corpos mamilares, o tálamo anteroventral, o córtex cingulado e, novamente, o subículo. Destas estruturas, o tálamo anteroventral encontra-se em posição privilegiada, do ponto de vista hodológico e experimental, para investigar este postulado circuito gerador de previsões. O objetivo do presente trabalho foi investigar o efeito da lesão seletiva no tálamo anteroventral, pela aplicação tópica de ácido N-metil-D-aspártico (NMDA), sobre a habilidade de ratos extrapolarem a partir de padrões seriais de estímulos. Tampão fosfato foi aplicado em sujeitos controle. Ratos da linhagem Wistar, machos, foram treinados a correr em uma pista reta para receberem reforço ao seu final. Em cada sessão (uma sessão por dia), os animais correram 4 tentativas sucessivas, recebendo quantidades diferentes de sementes de girassol em cada tentativa. No padrão monotônico decrescente os sujeitos receberam 14, 7, 3 e 1 sementes de girassol, enquanto os sujeitos expostos ao padrão não-monotônico receberam 14, 3, 7 e 1 sementes de girassol. Os animais foram treinados ao longo de 31 sessões. No 32° dia do experimento, uma quinta tentativa, nunca antes experienciada pelos animais, foi adicionada à sessão. Como esperado, os tempos de corrida na quinta tentativa dos animais controle expostos ao padrão monotônico decrescente foram substancialmente maiores se comparados aos animais controle expostos ao padrão não-monotônico, indicando a ocorrência de extrapolação. Em contraste, os sujeitos lesados expostos ao padrão monotônico não exibiram esse aumento de latência na quinta corrida, indicando que esses animais não extrapolaram. Em conclusão, os resultados indicam que extrapolação a partir de padrões seriais de estímulos é prejudicada pela lesão seletiva do tálamo anteroventral / According to Gray (1982) the brain continuously monitors environment and behavior, being capable of inhibiting ongoing behaviors when facing novelty or detecting discrepancies involving predictions generated from memories of past regularities and the actual sensorial information, in order to explore the source of novelty and/or discrepancy, and thus to gather information for generating better predictions in the future. The septo-hippocampal system compares anticipated and present information. The comparator would be the subiculum. This brain structure would receive present information from neocortical afferents, via the entorhinal cortex, and expected information from a \"generator of predictions system\" including the subiculum, mammillary bodies, anteroventral thalamus, cingulate cortex and, again, the subiculum. The anteroventral thalamus is in a privileged position, both hodologically and experimentally, to allow investigation of this postulated generator of predictions system. This study investigated the effect of selective damage to the anteroventral thalamus, by topical application of N-Methyl-D-Aspartic acid (NMDA), on the ability of rats to extrapolate relying on serial stimulus patterns. Control subjects were injected with phosphate buffer. Male Wistar rats were trained to run through a straight alleyway to get rewarded. In each session (one session per day) the animal run four successive trials, one immediately after the other, receiving different amounts of sunflower seeds in each trial. While subjects exposed to the monotonic decremental schedule received 14, 7, 3, 1 sunflower seeds along trials, subjects exposed to the non-monotonic schedule received 14, 3, 7, 1 sunflower seeds. Subjects were trained along 31 sessions. Then, on the 32nd testing session, a fifth trial never experienced before by all subjects was included immediately after the fourth trial. As expected, running times on the fifth trial for Control subjects exposed to the monotonic schedule were significantly longer as compared to the corresponding scores of Control subjects exposed to the non-monotonic schedule, thus indicating the occurrence of extrapolation. In contrast, lesioned subjects exposed to the monotonic schedule did not exhibit this increase in running times on the fifth trial thus indicating that these subjects did not extrapolate. In conclusion, results indicate that extrapolation relying on serial stimulus patterns is disrupted following selective damage to the anteroventral thalamus

With the technical advances in neuroscience experiments in the past few decades, we have seen a massive expansion in our ability to record neural activity. These advances enable neuroscientists to analyze more complex neural coding and communication properties, and at the same time, raise new challenges for analyzing neural spiking data, which keeps growing in scale, dimension, and complexity. This thesis proposes several new statistical methods that advance statistical analysis approaches for neural spiking data, including sequential Monte Carlo (SMC) methods for efficient estimation of neural dynamics from membrane potential threshold crossings, state-space models using multimodal observation processes, and goodness-of-fit analysis methods for neural marked point process models. In a first project, we derive a set of iterative formulas that enable us to simulate trajectories from stochastic, dynamic neural spiking models that are consistent with a set of spike time observations. We develop a SMC method to simultaneously estimate the parameters of the model and the unobserved dynamic variables from spike train data. We investigate the performance of this approach on a leaky integrate-and-fire model. In another project, we define a semi-latent state-space model to estimate information related to the phenomenon of hippocampal replay. Replay is a recently discovered phenomenon where patterns of hippocampal spiking activity that typically occur during exploration of an environment are reactivated when an animal is at rest. This reactivation is accompanied by high frequency oscillations in hippocampal local field potentials. However, methods to define replay mathematically remain undeveloped. In this project, we construct a novel state-space model that enables us to identify whether replay is occurring, and if so to estimate the movement trajectories consistent with the observed neural activity, and to categorize the content of each event. The state-space model integrates information from the spiking activity from the hippocampal population, the rhythms in the local field potential, and the rat's movement behavior. Finally, we develop a new, general time-rescaling theorem for marked point processes, and use this to develop a general goodness-of-fit framework for neural population spiking models. We investigate this approach through simulation and a real data application.

Place cells in the hippocampus fire in specific locations within an environment. The aim of this thesis is to investigate the different inputs to the hippocampus and what they contribute to place cell activity and performance of hippocampus-dependent tasks. Place cell activity can also be modulated by relevant features of a task such as a future destination or trajectory. Initial experiments investigated the origin and function of this trajectory-dependent activity and later experiments targeted the medial entorhinal cortex inputs to the hippocampal formation and investigated what they contributed to place cell activity and behaviour. The purpose of the first study was to determine whether trajectory dependent activity occurs in CA3 in a hippocampus-dependent serial-reversal task on the double-Y-maze and to compare it with that seen in CA1. Place cells in both CA3 and CA1 were recorded in rats trained on a serial-reversal task on a double-Y-maze. Rats were trained to run from a start box through two Y-junctions to one of four goal locations. After 10 trials the reward was moved to a new location, until all the boxes had been rewarded. Previous research has found that 44% of CA1 place cells with fields in the start areas of the maze show trajectory-dependent activity in rats trained on the task. This study found that a similar proportion of CA3 place cells also show trajectory-dependent activity in rats trained on this task and that this activity develops at the same time point as the task is learned. This result suggests that trajectory-dependent activity may be generated earlier in the circuit than CA1. Secondly, the contribution of the nucleus reuniens (N.Re) to spatial tasks was investigated. Previously, trajectory-dependent activity has been found to reach the hippocampus via N.Re, however this was shown in a hippocampus-independent task. To investigate the possible role that this input may play in behaviour, N.Re was lesioned and animals were tested on acquisition and performance of the double-Y-maze serial-reversal task described previously. Surprisingly, lesions had no effects on either learning or performance. Taken together with previous data from other studies, this suggests that trajectory dependent activity is not one unique phenomenon but is rather multiple similar phenomena which may originate in different brain regions and fulfil different roles in navigation depending on the demands of the task. In addition, animals were tested on tasks involving allocentric or egocentric navigation. Results suggest that N.Re may have a role in the selection or performance of allocentric navigation but not egocentric navigation. Thirdly, the role of inputs from the medial entorhinal cortex (MEC) to place cells was investigated. Consistent with previous research, MEC lesions resulted in larger, less precise place fields in CA1 place cells. By performing cue-rotation experiments using either distal or proximal cues it was observed that place fields in the MEC lesion animals were not anchored to distal cues but were either stable or anchored to other aspects of the environment. However, place cells in the MEC lesion group still followed proximal cues suggesting that the deficit is restricted to distal landmarks. This suggests that the MEC may process distal landmark information allowing the use of distal landmarks for orientation and self-location within an environment. This thesis contributes a better understanding of the role and origins of trajectory dependent activity as well as a novel finding that the MEC contributes information about distal landmarks to the hippocampus.

Dementia is a clinical state caused by neurodegeneration and characterized by a loss of function in cognitive domains and behavior. Alzheimer’s disease (AD) is the most common form of dementia. Although the amyloid β (Aβ) protein and hyperphosphorylated tau aggregates in the brain are considered to be the key pathological hallmarks of AD, the exact cause of AD is yet to be identified. In addition, clinical diagnoses of AD can be error prone. Many previous studies have compared the clinical diagnosis of AD against the gold standard of autopsy confirmation and shown substantial AD misdiagnosis Hippocampal sclerosis of aging (HS-Aging) is one type of dementia that is often clinically misdiagnosed as AD. AD and HS-Aging are controlled by different genetic architectures. Familial AD, which often occurs early in life, is linked to mainly mutations in three genes: APP, PSEN1, and PSEN2. Late-onset AD (LOAD) is strongly associated with the ε4 allele of apolipoprotein E (APOE) gene. In addition to the APOE gene, genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) in or close to some genes associated with LOAD. On the other hand, GRN, TMEM106B, ABCC9, and KCNMB2 have been reported to harbor risk alleles associated with HS-Aging pathology. Although GWAS have succeeded in revealing numerous susceptibility variants for dementias, it is an ongoing challenge to identify functional loci and to understand how they contribute to dementia pathogenesis. Until recently, rare variants were not investigated comprehensively. GWAS rely on genotype imputation which is not reliable for rare variants. Therefore, imputed rare variants are typically removed from GWAS analysis. Recent advances in sequencing technologies enable accurate genotyping of rare variants, thus potentially improving our understanding the role of rare variants on disease. There are significant computational and statistical challenges for these sequencing studies. Traditional single variant-based association tests are underpowered to detect rare variant associations. Instead, more powerful and computationally efficient approaches for aggregating the effects of rare variants have become a standard approach for association testing. The sequence-kernel association test (SKAT) is one of the most powerful rare variant analysis methods. A recently-proposed scan-statistic-based test is another approach to detect the location of rare variant clusters influencing disease. In the first study, we examined the gene-based associations of the four putative risk genes, GRN, TMEM106B, ABCC9, and KCNMB2 with HS-aging pathology. We analyzed haplotype associations of a targeted ABCC9 region with HS-Aging pathology and with ABCC9 gene expression. In the second study, we elucidated the role of the non-coding SNPs identified in the International Genomics of Alzheimer’s Project (IGAP) consortium GWAS within a systems genetics framework to understand the flow of biological information underlying AD. In the last study, we identified genetic regions which contain rare variants associated with AD using a scan-statistic-based approach.

Alzheimer's disease (AD) is an irreversible neurodegenerative brain disease distinguished by progressive impairment of memory and decline in cognitive abilities. The hippocampus is widely recognized to play essential roles in forming and gradually transferring information from short-term memory into long-term memory, and it is involved in the onset of the neuropathological pathways of the brain to suffer neuron loss in the rise of AD. Thus, hippocampal information obtained from magnetic resonance imaging (MRI) scans have been established as crucial AD biomarkers. The hippocampus is composed of multiple subfields, and the neuron loss is not uniformly distributed on the whole hippocampus. However, this critical subfield information is not addressed by the existing surface-based morphometry (SBM) and voxel-based morphometry (VBM) studies. Due to the size, complexity, heterogeneity, and folding anatomy of the hippocampus, acquiring volumetric and morphometric measures of hippocampal subfields usually presents not only technical challenges in quantitative neuroimaging but also analytical challenges. To address these challenges and deeply understand the relationships between hippocampal shape changes and brain disorders, especially to examine the degeneration of hippocampal subfields, this thesis focuses on constructing a hippocampal subfield morphometric analysis framework including the following aspects: 1) hippocampal subfield segmentation; 2) 3D shape modeling; 3) feature formulation; 4) diffeomorphic surface registration; 5) surface shape reconstruction; and 6) association analytics. The goals include developing accurate hippocampal subfield guided registration methods, extracting useful features and identifying significant subfields on the hippocampus that are highly related to cognitive disabilities, and using such information to assist early detection of AD.

Previous research into the communication of people with amnesia found that they, and their familiar communication partners, used verbal play less frequently than pairs without amnesia (Duff et al., 2009). This study attempts to analyze an additional dimension of playful language use: partner response to verbal play. A rubric was developed to rate verbal play response on a 0-5 scale. The rubric was used to rate partner response in four communication pairs containing one partner with amnesia and one familiar communication partner; and four healthy pairs for comparison. The responses of the experimenter participating in the conversations were also rated. While the study found no differences between the two groups in terms of the familiar communication partners or the experimenter, the participants with amnesia received significantly lower overall scores than participants without amnesia. The participants with amnesia also produced a significantly lower proportion of responses with multiple turns than did healthy participants. This result adds to the body of evidence that memory disorders can affect social interaction. The rubric developed for this study suggests a possible direction for including partner response in analyses of conversational discourse.