Thesis (PhD (Biomedical Sciences. Medical Physiology))--University of Stellenbosch, 2006. / Early life trauma leads to behavioural abnormalities later in life. These include mood and anxiety disorders such as depression and posttraumatic stress disorder (PTSD). This association may be due in part to the effects of trauma on brain development. Data from basic and clinical experiments suggest that alterations in the hippocampus may be fundamental to the development of these disorders. Here we used an animal model of early life trauma to investigate its effects on the behaviour and neurochemistry of the adult rat. Adolescent rats were subjected to time-dependent sensitization stress consisting of a triple stressor (2 hours restraint, 20 min swim stress and exposure to ether vapour) on post-natal day (PND) 28, a single re-stress on PND 35 (20 min swim stress), and a second re-stress in adulthood (PND 60, 20 min swim stress). The rationale was that the frequency of exposure to situational reminders contributes to the maintenance over time of fear-related behavioural disturbances. The effects of trauma on the hypothalamus-pituitary-adrenal-axis, hippocampal and plasma neurotrophin levels, behaviour and phosphoinositide-3 kinase (PI-3 kinase) signaling proteins were initially investigated. In addition, proteomic technologies such as protein arrays and 2D-SDS PAGE combined with liquid chromatography tandem mass spectrometry (LC-MS/MS) were employed to study trauma-induced effects on the hippocampus. Traumatized animals showed a decrease in glucocorticoid receptors in the dentate gyrus of the hippocampus and an increase in basal corticosterone levels 24 hours after adulthood re-stress. These effects were reversed by pretreatment with the serotonin selective reuptake inhibitor, escitalopram. A decrease in the neurotrophins, BDNF and NT-3 were evident 8 days, but not 24 hours after adulthood re-stress. This decrease was not accompanied by decreases in plasma neurotrophin or PI-3 kinase, protein kinase B (PKB), phosphatase and tensin homologue (PTEN), phospho-forkhead and phospho-AFX protein levels. In addition, traumatized animals showed increased rearing in both the elevated plus maze and open field. Proteomic analysis of trauma-induced changes in the hippocampus show increases in Ca2+ homeostasis / signaling proteins such as S-100B, phospho-JNK and calcineurin. Apoptotic initiator proteins, including caspase 9, -10 and -12 were increased and there was evidence of cytoskeletal protein dysregulation. Furthermore, cell cycle regulators and energy metabolism proteins were decreased. These effects indicate to a cellular state of cell cycle arrest after increased calcium influx to avoid apoptosis. Our data suggest that adolescent trauma with adulthood re-stress may affect numerous systems at different levels. These include neuroendocrine-, protein systems and behaviour, and confirmed that a systems biology approach is needed for a better understanding of the neurobiology of mental disorders.

Background: The hippocampus and corpus callosum have been shown to be vulnerable in head injury. Various neuroimaging modalities and quantitative measurement techniques have been employed to investigate pathological changes in these structures. Cognitive and behavioural deficiencies have also been well documented in head injury. Aims: The aim of this research project was to investigate structural changes in the hippocampus and corpus callosum. Two different quantitative methods were used to measure physical changes and neuropsychological assessment was performed to determine cognitive and behavioural deficit. It was also intended to investigate the relationship between structural change and neuropsychology at 1 and 6 months post injury. Method: Forty-seven patients with head injury (ranging from mild to severe) had undergone a battery of neuropsychological tests and an MRI scan at 1 and 6 months post injury. T1-weighted MRI scans were obtained and analysis of hippocampus and corpus callosum was performed using region-of-interest techniques and voxel-based morphometry which also included comparison to 18 healthy volunteers. The patients completed neuropsychological assessment at 1 and 6 months post injury and data obtained was analysed with respect to each assessment and with structural data to determine cognitive decline and correlation with neuroanatomy. Results: Voxel-based morphometry illustrated reduced whole scan signal differences between patients and controls and changes in patients between 1 and 6 months post injury. Reduced grey matter concentration was also found using voxel-based morphometry and segmented images between patients and controls. A number of neuropsychological aspects were related to injury severity and correlations with neuroanatomy were present. Voxel-based morphometry provided a greater number of associations than region-of-interest analysis. No longitudinal changes were found in the hippocampus or corpus callosum using region-of-interest methodology or voxel-based morphometry. Conclusions: Decreased grey matter concentration identified with voxel-based morphometry illustrated that structural deficit was present in the head injured patients and does not change between 1 and 6 months. Voxel-based morphometry appears more sensitive for detecting structural changes after head injury than region- of-interest methods. Although the majority of patients had suffered mild head injury, cognitive and neurobehavioural deficits were evidenced by a substantial number of patients reporting increased anxiety and depression levels. Also, the findings of relationships between reduced grey matter concentration and cognitive test scores are indicative of the effects of diffuse brain damage in the patient group.

Establishing appropriate animal models for the study of human memory is paramount to the development of memory disorder treatments. Damage to the hippocampus, a medial temporal lobe brain structure, has been implicated in the memory loss associated with Alzheimer’s disease and other dementias. In humans, the role of the hippocampus is largely defined; yet, its role in rodents is much less clear due to conflicting findings. To investigate these discrepancies, an extensive review of the rodent literature was conducted, with a focus on studies that used the Novel Object Recognition (NOR) paradigm for testing. The total amount of time the objects were explored during training and the delay imposed between training and testing seemed to determine hippocampal recruitment in rodents. Male C57BL/6J mice were implanted with bilateral dorsal CA1 guide cannulae to allow for the inactivation of the hippocampus at discrete time points in the task. The results suggest that the rodent hippocampus is crucial to the encoding, consolidation and retrieval of object memory. Next, it was determined that there is a delay-dependent involvement of the hippocampus in object memory, implying that other structures may be supporting the memory prior to the recruitment of hippocampus. In addition, when the context memory and object memory could be further dissociated, by altering the task design, the results imply a necessary role for the hippocampus in the object memory, irrespective of context. Also, making the task more perceptually demanding, by requiring the mice to perform a two-dimensional to three-dimensional association between stimuli, engaged the hippocampus. Then, in the traditional NOR task, long and short training exploration times were imposed to determine brain region activity for weak and strong object memory. The inactivation and immunohistochemistry findings imply weak object memory is perirhinal cortex dependent, while strong object memory is hippocampal-dependent. Taken together, the findings suggest that mice, like humans, process object memory on a continuum from weak to strong, recruiting the hippocampus conditionally for strong familiarity. Confirming this functional similarity between the rodent and human object memory systems could be beneficial for future studies investigating memory disorders. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

Xie, Hui. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 91-116). / Abstracts in English and Chinese. / CONTENTS --- p.I / ACKNOWLEDGEMENTS --- p.i / ABSTRACT --- p.ii / 中文摘要 --- p.v / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Overview of the Study --- p.1 / Chapter 1.2 --- Obstructive Sleep Apnea --- p.4 / Chapter 1.2.1 --- Epidemiology --- p.5 / Chapter 1.2.1.1 --- Prevalence --- p.5 / Chapter 1.2.1.2 --- Risk Factors --- p.6 / Chapter 1.2.2 --- Pathogenesis --- p.8 / Chapter 1.2.3 --- Pathophysiologic Consequences --- p.9 / Chapter 1.2.4 --- Diagnosis --- p.12 / Chapter 1.2.5 --- Treatment --- p.13 / Chapter 1.3 --- Memory and Long-term Potentiation --- p.15 / Chapter 1.3.1 --- Memory --- p.15 / Chapter 1.3.1.1 --- Classification of Memory --- p.15 / Chapter 1.3.1.1 --- Physiology of Memory --- p.17 / Chapter 1.3.2 --- Hippocampus --- p.18 / Chapter 1.3.2.1 --- Anatomy --- p.18 / Chapter 1.3.2.2 --- Hippocampus and Memory --- p.20 / Chapter 1.3.3 --- Long-term Potentiation (LTP) --- p.20 / Chapter 1.3.3.1 --- Discovery of LTP --- p.21 / Chapter 1.3.3.2 --- Types of LTP --- p.22 / Chapter 1.3.3.3 --- Properties of NMDA-LTP --- p.23 / Chapter 1.3.3.4 --- Early Phase LTP and Mechanism --- p.24 / Chapter 1.3.3.5 --- Late Phase LTP and Mechanism --- p.28 / Chapter 1.3.3.6 --- Important Factors in Long-term Potentiation --- p.29 / Chapter 1.4 --- Brain-derived Neurotrophic Factor (BDNF) --- p.33 / Chapter 1.4.1 --- Neurotrophins --- p.33 / Chapter 1.4.2 --- Structure and Expression of BDNF --- p.36 / Chapter 1.4.3 --- BDNF and Synaptic Plasticity --- p.37 / Chapter 1.4.3.1 --- BDNF and E-LTP --- p.38 / Chapter 1.4.3.2 --- BDNF and L-LTP --- p.39 / Chapter CHAPTER 2 --- METHODS --- p.43 / Chapter 2.1 --- Animal model of Obstructive Sleep Apnea --- p.43 / Chapter 2.1.1 --- Chronic Intermittent Hypoxia --- p.43 / Chapter 2.1.2 --- Bodyweight During Hypoxia Treatment --- p.47 / Chapter 2.2 --- Electrophysiological Experiments --- p.47 / Chapter 2.2.1 --- Brain Slice Preparation --- p.47 / Chapter 2.2.2 --- Multi-electrode Recording Setup (MED64) --- p.48 / Chapter 2.2.3 --- Slice Superfusion --- p.51 / Chapter 2.3.4 --- Field Potential Recordings --- p.53 / Chapter 2.3.5 --- LTP Induction Protocol --- p.55 / Chapter 2.3 --- Stereotaxic Surgery --- p.57 / Chapter 2.4 --- Drugs and Data Analysis --- p.58 / Chapter CHAPTER 3 --- RESULTS --- p.59 / Chapter 3.1 --- Validation of the OSA model --- p.59 / Chapter 3.2 --- Optimization for Studies of Early and Late-phase LTP by MED64 --- p.60 / Chapter 3.2.1 --- Optimization of Brain Slices --- p.60 / Chapter 3.2.2 --- Optimization of Field Potential Recording --- p.62 / Chapter 3.2.3 --- Optimization for LTP Study --- p.65 / Chapter 3.3 --- Effect of Intermittent Hypoxia on Hippocampal LTP --- p.68 / Chapter 3.3.1 --- Early-phase LTP (E-LTP) --- p.68 / Chapter 3.3.2 --- Late-phase LTP (L-LTP) --- p.71 / Chapter 3.4 --- Effect of BDNF on Intermittent Hypoxia-induced LTP Impairment --- p.75 / Chapter 3.4.1 --- BDNF Rescues LTP Impairment --- p.75 / Chapter 3.4.2 --- BDNF prevents LTP Impairment --- p.78 / Chapter CHAPTER 4 --- DISCUSSION --- p.80 / Chapter 4.1 --- Chronic Intermittent Hypoxia Model of OSA in Mice --- p.80 / Chapter 4.2 --- Impairment of LTP Induced by Intermittent Hypoxia --- p.82 / Chapter 4.3 --- The role of BDNF in IH-induced Impairment in Hippocampal Synaptic Plasticity --- p.84 / Chapter 4.4 --- Future Studies --- p.89 / REFERENCE --- p.91

Leung, Yeung Yeung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 134-154). / Abstracts in English and Chinese. / CONTENTS --- p.i / ACKNOWLEDGEMENTS --- p.iv / ABSTRACT --- p.v / 論文摘要 --- p.viii / LIST OF FIGURES --- p.x / LIST OF TABLES --- p.xiv / LIST OF ABBREVIATIONS --- p.xv / Chapter 1. --- INTRODUCTION --- p.1 / Chapter 1.1 --- Brain iron function and diseases --- p.1 / Chapter 1.1.1 --- Function of iron in the brain --- p.1 / Chapter 1.1.2 --- Iron involved oxidative damage --- p.2 / Chapter 1.1.3 --- Role of iron in neurodegenerative diseases --- p.6 / Chapter 1.1.4 --- Role of iron in Alzheimer's disease --- p.7 / Chapter 1.1.5 --- Deleterious effects of iron in memory function --- p.9 / Chapter 1.2 --- Iron regulation in the brain --- p.10 / Chapter 1.2.1 --- Transport and storage of brain iron --- p.10 / Chapter 1.2.2 --- Iron homeostasis in the brain --- p.14 / Chapter 1.2.3 --- Transport of iron in axon and synapse --- p.17 / Chapter 1.3 --- The hippocampus --- p.19 / Chapter 1.3.1 --- Hippocampus and memory function --- p.19 / Chapter 1.3.2 --- Structure of the hippocampus --- p.20 / Chapter 1.3.3 --- Cell composition in the hippocampus --- p.26 / Chapter 1.3.4 --- Wiring in the hippocampus --- p.28 / Chapter 1.4 --- Synaptic plasticity and long term potentiation --- p.30 / Chapter 1.4.1 --- Basic theory of synaptic plasticity --- p.30 / Chapter 1.4.2 --- Types of synaptic plasticity --- p.30 / Chapter 1.4.3 --- The discovery of long term potentiation --- p.31 / Chapter 1.4.4 --- Long term potentiation --- p.32 / Chapter 1.4.5 --- Cellular mechanism of long term potentiation --- p.33 / Chapter 1.4.6 --- Role of reactive oxygen species in long term potentiation --- p.36 / Chapter 1.5 --- Aim of the study --- p.38 / Chapter 2. --- MATERIALS AND METHODS --- p.39 / Chapter 2.1 --- Rat model of iron overload --- p.39 / Chapter 2.2 --- Multi-electrode field potential measurement --- p.40 / Chapter 2.2.1 --- Acute preparation of hippocampal slices --- p.40 / Chapter 2.2.2 --- Multi-electrode array recording system --- p.41 / Chapter 2.2.3 --- Recording of field excitatory postsynaptic potentials --- p.42 / Chapter 2.2.4 --- Induction of LTP --- p.47 / Chapter 2.2.5 --- Recording of paired-pulse ratio --- p.48 / Chapter 2.3 --- Whole cell patch-clamp recordings --- p.50 / Chapter 2.4 --- Biochemical assays --- p.57 / Chapter 2.4.1 --- Preparation of brain homogenate --- p.57 / Chapter 2.4.2 --- Total iron measurement --- p.57 / Chapter 2.4.3 --- Protein carbonyl measurement --- p.58 / Chapter 2.4.4 --- Determination of reactive oxygen species --- p.60 / Chapter 2.5 --- Drugs and data analysis --- p.61 / Chapter 3. --- RESULTS --- p.62 / Chapter 3.1 --- The acute effects of extracellular iron on synaptic transmission and long-term synaptic plasticity in the hippocampus in vitro --- p.63 / Chapter 3.1.1 --- Effects of ferric ion on basal synaptic transmission --- p.63 / Chapter 3.1.1.1 --- Effect of FAC on basal fEPSPs --- p.63 / Chapter 3.1.1.2 --- Comparison with the effect of AC on basal fEPSPs --- p.69 / Chapter 3.1.2 --- Effects of ferric ion on long-term synaptic plasticity --- p.72 / Chapter 3.1.2.1 --- Effect of acute FAC treatment on LTP --- p.72 / Chapter 3.1.2.2 --- Comparison with the effect of AC on LTP --- p.75 / Chapter 3.1.3 --- Effects of ferric chloride --- p.78 / Chapter 3.1.4 --- Effects of ascorbic acid on the action of FAC --- p.81 / Chapter 3.2 --- "The acute, in vitro effect of extracellular iron on the membrane properties and excitability of hippocampal CA1 neurons" --- p.86 / Chapter 3.2.1 --- Membrane input resistance --- p.86 / Chapter 3.2.2 --- Voltage-Current relationship --- p.88 / Chapter 3.2.3 --- Membrane excitability --- p.90 / Chapter 3.2.3.1 --- Threshold current --- p.90 / Chapter 3.2.3.2 --- Action potential firing frequency --- p.92 / Chapter 3.2.4 --- Action potential characteristics --- p.95 / Chapter 3.2.4.1 --- "Action potential amplitude, area and width" --- p.95 / Chapter 3.2.4.2 --- Rise and decay kinetics of action potential --- p.98 / Chapter 3.3 --- The chronic effects of iron-loading in the brain on hippocampal long-term synaptic plasticity --- p.100 / Chapter 3.3.1 --- Validation of the iron-overload model --- p.100 / Chapter 3.3.1.1 --- Short-term (1 week) treatment --- p.100 / Chapter 3.3.1.2 --- Long-term (4 weeks) treatment --- p.103 / Chapter 3.3.2 --- Effects of chornic iron-overloading on LTP --- p.105 / Chapter 3.3.2.1 --- Short term iron treatment --- p.105 / Chapter 3.3.2.2 --- Long term iron treatment --- p.108 / Chapter 3.3.3 --- Oxidative stress measurement --- p.111 / Chapter 3.3.3.1 --- Protein oxidation --- p.111 / Chapter 3.3.3.2 --- Reactive oxidative species level --- p.116 / Chapter 4. --- DISCUSSION --- p.120 / Chapter 4.1 --- "Acute, in vitro effects" --- p.121 / Chapter 4.2 --- "Chronic, in vivo effects" --- p.125 / Chapter 5. --- REFERENCES --- p.134

Tesi realitzada a l'Equip de Neurociència de Sistemes - IDIBAPS / The generation of cognitive maps is influenced by different senses such as vision, audition or smell. However, the tactile information system -a highly developed system in the rat- and its influence on spatial processing, has hardly been studied. The availability of precise tactile information in the hippocampus (Pereira et al., 2007) is highly suggestive of a possible influence of tactile information on spatial processing. In this study we aimed to test if somatosensory information contributes to the cognitive map creation and spatial representation. The deprivation of the tactile sense without the possibility of using other senses (total darkness, homogeneous odour and uniform white noise), should then affect the coding of spatial information and could be detected as an alteration in place cell properties such as firing rate, location and/or extension of the firing fields. These types of changes would demonstrate that somatosensory inputs are involved in the cognitive map creation. To carry out this study we developed three kinds of experiments. First, we developed a paradigm (Gener et al., 2009) to temporarily deprive the tactile input using locally applied local anaesthesia (lidocaine). In a second part, we demonstrate that this deprivation was effective in the awake animal, altering the behaviour during tactile discrimination protocols and reducing successful trials from 88% to chance (48%). Finally, we applied the deprivation technique to characterise the cognitive map creation. With that purpose, we first demonstrated that place cells recorded in a controlled environment were sensitive to tactile cues, such that the rotation of the cues induce the rotation of the firing fields. Next, when tactile information was deprived, the place cells’ fields showed changes in their compactness and size. The results of this study suggest that somatosensory input information transduced by the whiskers contributes to the cognitive map creation. Those findings respond to some of the questions about hippocampus integration’s of sensory information.

Tesi realitzada a l'Equip de Neurociència de Sistemes - IDIBAPS / Since the discovery of the place cells in 1971 by John O’Keefe and colleagues an extensive work over the hippocampus has been developed as the mammal model of spatial navigation. Place cells are rodents’ hippocampal neurons whose firing is associated to certain locations of the environment. A majority of studies have focused on how the place fields (the area where the firing of a neuron is restricted) are generated in relation to the static cues of the environment (O'Keefe and Conway, 1978; Muller et al., 1987; Gothard et al., 1996). The present work assessed a similar question but regarding the dynamic cues surrounding the subject, and with the hypothesis that the hippocampus is also representing the position of other moving objects. In order to demonstrate if that was the case, we developed a behavioural protocol in which rats learnt to discriminate the movements of a robot in order to obtain reward, an Operant Position Discrimination Task (OPDT). Once the protocol was validated, the subjects were chronically implanted with tetrodes in the CA1 region of the hippocampus. In this way the activity of single hippocampal cells could be isolated off-line and the LFP of the area stored during the recordings. Using this method, the relationship between the firing of the cells and the field activity with the spatial parameters of the robot could be evaluated. The results showed a modulation by the dynamic cue of the theta oscillation. While the locomotor activity of the subjects is directly related to the power of theta in natural conditions (Vanderwolf, 1969), during the movement of the robot such relationship was disrupted and the band power between 4-12 Hz showed a trough at this time. The analysis of the single cells’ activity showed neurons locked to several spatial features of the dynamic cue. First, the position of the rat and the robot where analysed by information content parameters. Skaggs Index and Positional information (Markus et al., 1994; Olypher et al., 2003) showed neurons locked to the position of the subject as expected in CA1 and also other neurons locked to the positions of the robot. Second, moving from the spatial analysis to the temporal one, we found responses to the movement of the robot like OFF/ON variations of the basal activity of the neurons. Such changes in the firing patterns where quantified by the Mutual Information index (Nelken and Chechik, 2007) demonstrating that a large fraction of the neurons have a significant differential pattern of activity during the movement of the robot towards one side or the other. The use of the same index, MI, for the evaluation of the static or dynamic condition of the robot, also resulted in a set of neurons spiking with significant disparity during such epochs. In conclusion, the present work has demonstrated the existence of neural correlates locked to a dynamic cue in the hippocampus. Both the field activity at the theta range, LFP between 4 and 12 Hz, and the activity of the hippocampal neurons were found to reflect and/or encode the spatial features of a dynamic cue. The present work has in this way enlarged the limited evidence present in the prior literature about the role of the hippocampus in the tracking and localization of dynamic cues with the use of a behavioural protocol where both the spatial and temporal dynamics could be assessed. / La correcta localización y seguimiento de las pistas dinámicas que se encuentran en el ambiente es una tarea crucial para el individuo. Comportamientos fundamentales como la caza, el apareamiento o el escape necesitan una correcta identificación de la posición de presas, congéneres y depredadores para su correcta realización. El sistema cerebral encargado de localizar al propio sujeto en el ambiente se sabe que se encuentra en la formación hipocampal después de que diversos estudios hayan demostrado la necesidad del mismo para una correcta orientación (Morris et al., 1982) y, aún más importante, tras el descubrimiento en roedores de neuronas que disparan únicamente en espacios restringidos del entorno, las células de lugar (O'Keefe and Dostrovsky, 1971). Si bien se conoce que estos procesos están fundados en una correcta representación de la posición de las pistas estáticas del ambiente (O'Keefe and Conway, 1978; Muller et al., 1987; Gothard et al., 1996), que sirven de referencia para la propia localización, poco se sabe acerca de cómo se integra la información relativa a los objetos y/o sujetos móviles que se encuentran en el mismo ambiente. Este trabajo tiene como objetivo principal intentar responder a esta pregunta, es decir, ¿en qué modo el hipocampo procesa la información relativa a las pistas dinámicas? Para el desarrollo del estudio, primero, se diseñó una tarea comportamental que asegurara el hecho de que la pista dinámica resultase relevante para los sujetos de forma que los mismos prestaran atención a sus movimientos. Con este fin elegimos utilizar un robot cuyos desplazamientos pueden ser finamente controlados y asociar una recompensa a determinados patrones de navegación del robot. Después de probar con diferentes tareas de discriminación se llegó a una configuración (Operant Position Discrimination Task, OPDT) que permitía a los animales seguir los movimientos del robot desde un espacio separado en el cual recibían la recompensa en caso de discernir correctamente los desplazamientos de la pista. Una vez validada la tarea comportamental, a los sujetos que alcanzaron altas tasas de rendimiento se les implantaron tetrodos en la zona CA1 del hipocampo, lugar en el que se encuentran las células de lugar más estables. Una vez hecho el implante se procedió a registrar la actividad cerebral durante la ejecución de la tarea. Por una parte se aislaron los potenciales de acción pertenecientes a neuronas únicas y el potencial de campo de la zona, LFP. Respecto a la actividad de campo, LFP, se observó una disminución significativa de la potencia en la banda theta, 4-12 Hz, relacionada generalmente con la actividad locomotora del sujeto (Vanderwolf, 1969) durante el movimiento del robot. Durante el resto del registro la relación entre velocidad y potencia de theta se mantuvo y sólo en el periodo de discriminación del movimiento del robot esta relación se vio alterada con un mínimo de potencia observado en diferentes sujetos y registros. La actividad de las neuronas se analizó en función de los parámetros espaciales y dinámicos de la rata y el robot. Mirando la especificidad espacial del disparo de las neuronas a través de los parámetros Skaggs Index y Positional information (Markus et al., 1994; Olypher et al., 2003) se encontraron células significativamente ligadas en su actividad a la posición del sujeto o del robot. La actividad de las neuronas también se analizó de forma temporal, tomando como referencia el inicio de los estímulos, es decir el movimiento del robot hacia un lado u otro. Utilizando como índice la Mutual Information (Nelken and Chechik, 2007) se encontró que una larga proporción de las neuronas tienen respuestas diferenciales durante el movimiento del robot hacia uno de los lados. A su vez, el mismo análisis, pero en esta ocasión comparando los periodos en los que la pista se encuentra inmóvil con los que está en movimiento, determinó que otra fracción de las neuronas tiene patrones de disparo diferenciales según sea la condición dinámica de la pista. El conjunto de los resultados obtenidos indica claramente que el hipocampo se encuentra involucrado activamente en la localización y el seguimiento de las pistas dinámicas, siendo esto reflejado tanto en la actividad de sus neuronas como en la actividad de campo global. Los parámetros espaciales de la pista que resultaron modulados durante la tarea fueron su posición, la dirección de su movimiento y el hecho en sí de permanecer inmóvil o en desplazamiento.

In this thesis we use computational neural network models to examine the dynamics and functionality of the CA3 region of the mammalian hippocampus. The emphasis of the project is to investigate how the dynamic control structures provided by inhibitory circuitry and cellular modification may effect the CA3 region during the recall of previously stored information. The CA3 region is commonly thought to work as a recurrent auto-associative neural network due to the neurophysiological characteristics found, such as, recurrent collaterals, strong and sparse synapses from external inputs and plasticity between coactive cells. Associative memory models have been developed using various configurations of mathematical artificial neural networks which were first developed over 40 years ago. Within these models we can store information via changes in the strength of connections between simplified model neurons (two-state). These memories can be recalled when a cue (noisy or partial) is instantiated upon the net. The type of information they can store is quite limited due to restrictions caused by the simplicity of the hard-limiting nodes which are commonly associated with a binary activation threshold. We build a much more biologically plausible model with complex spiking cell models and with realistic synaptic properties between cells. This model is based upon some of the many details we now know of the neuronal circuitry of the CA3 region. We implemented the model in computer software using Neuron and Matlab and tested it by running simulations of storage and recall in the network. By building this model we gain new insights into how different types of neurons, and the complex circuits they form, actually work. The mammalian brain consists of complex resistive-capacative electrical circuitry which is formed by the interconnection of large numbers of neurons. A principal cell type is the pyramidal cell within the cortex, which is the main information processor in our neural networks. Pyramidal cells are surrounded by diverse populations of interneurons which have proportionally smaller numbers compared to the pyramidal cells and these form connections with pyramidal cells and other inhibitory cells. By building detailed computational models of recurrent neural circuitry we explore how these microcircuits of interneurons control the flow of information through pyramidal cells and regulate the efficacy of the network. We also explore the effect of cellular modification due to neuronal activity and the effect of incorporating spatially dependent connectivity on the network during recall of previously stored information. In particular we implement a spiking neural network proposed by Sommer and Wennekers (2001). We consider methods for improving associative memory recall using methods inspired by the work by Graham and Willshaw (1995) where they apply mathematical transforms to an artificial neural network to improve the recall quality within the network. The networks tested contain either 100 or 1000 pyramidal cells with 10% connectivity applied and a partial cue instantiated, and with a global pseudo-inhibition.We investigate three methods. Firstly, applying localised disynaptic inhibition which will proportionalise the excitatory post synaptic potentials and provide a fast acting reversal potential which should help to reduce the variability in signal propagation between cells and provide further inhibition to help synchronise the network activity. Secondly, implementing a persistent sodium channel to the cell body which will act to non-linearise the activation threshold where after a given membrane potential the amplitude of the excitatory postsynaptic potential (EPSP) is boosted to push cells which receive slightly more excitation (most likely high units) over the firing threshold. Finally, implementing spatial characteristics of the dendritic tree will allow a greater probability of a modified synapse existing after 10% random connectivity has been applied throughout the network. We apply spatial characteristics by scaling the conductance weights of excitatory synapses which simulate the loss in potential in synapses found in the outer dendritic regions due to increased resistance. To further increase the biological plausibility of the network we remove the pseudo-inhibition and apply realistic basket cell models with differing configurations for a global inhibitory circuit. The networks are configured with; 1 single basket cell providing feedback inhibition, 10% basket cells providing feedback inhibition where 10 pyramidal cells connect to each basket cell and finally, 100% basket cells providing feedback inhibition. These networks are compared and contrasted for efficacy on recall quality and the effect on the network behaviour. We have found promising results from applying biologically plausible recall strategies and network configurations which suggests the role of inhibition and cellular dynamics are pivotal in learning and memory.

This study sought to determine whether the DG, CA3, and CA1 regions contain uniformly excitable populations and test the hypothesis that rapid addition of new, more excitable, granule cells in prepubescence results in a low activation probability (P1) in the DG. The immediate-early gene Homer1a was used as a neural activity marker to quantify activation in juvenile (P28) and adult (~5 mo) rats during track running. The main finding was that P1 in juveniles was substantially lower not only the DG, but also CA3 and CA1. The P1 for a DG granule cell was close to 0 in juveniles, versus 0.58 in adults. The low P1 in juveniles indicates that sparse, but non-overlapping, subpopulations participate in encoding events. Since sparse, orthogonal coding enhances a network’s ability to decorrelate input patterns (Marr, 1971; McNaughton & Morris, 1987), the findings suggest that juveniles likely possess greatly enhanced pattern separation ability. / ix, 51 leaves : ill. ; 29 cm

Development of a three dimensional (3D) HYBROT model with targeted in vivo like intact cellular circuitry in thick brain slices for multi-site stimulation and recording will provide a useful in vitro model to study neuronal dynamics at network level. In order to make this in vitro model feasible, we need to develop several associated technologies. These technologies include development of a thick organotypic brain slice culturing method, a three dimensional (3D) micro-fluidic multielectrode Neural Interface system (µNIS) and the associated electronic interfaces for stimulation and recording of/from tissue, development of targeted stimulation patterns for closed-loop interaction with a robotic body, and a deep-tissue non-invasive imaging system. To make progress towards this goal, I undertook two projects: (i) to develop a method to culture thick organotypic brain slices, and (ii) construct a multiphoton imaging system that allows long-term and deep-tissue imaging of two dimensional and three dimensional cultures. Organotypic brain slices preserve cytoarchitecture of the brain. Therefore, they make more a realistic reduced model for various network level investigations. However, current culturing methods are not successful for culturing thick brain slices due to limited supply of nutrients and oxygen to inner layers of the culture. We developed a forced-convection based perfusion method to culture viable 700µm thick brain slices. Multiphoton microscopy is ideal for imaging living 2D or 3D cultures at submicron resolution. We successfully fabricated a custom-designed high efficiency multiphoton microscope that has the desired flexibility to perform experiments using multiple technologies simultaneously. This microscope was used successfully for 3D and time-lapse imaging. Together these projects have contributed towards the progress of development of a 3D HYBROT. ----- 3D Hybrot: A hybrid system of a brain slice culture embodied with a robotic body.