Electrophysiological recordings are a valuable tool for neuroscience in order to monitor the activity of multiple or even single neurons. Significant insights into the nervous system have been gained by analyses of resulting data; in particular, many findings were gained from spike trains whose correlations can give valuable indications about neural interplay. But detecting, specifying, and representing neural interactions is mathematically challenging. Further, recent advances of recording techniques led to an increase in volume of collected data, which often poses additional computational problems. These developments call for new, improved methods in order to extract crucial information. The matter of this thesis is twofold: It presents a novel method for the analysis of neural spike train data, as well as a generic framework in order to assess the new and related techniques. The new computational method, the Snap Shot Score, can be used to inspect spike trains with respect to temporal dependencies, which are visualised as an information flow network. These networks can specify the relationships in the data, indicate changes in dependencies, and point to causal interactions. The Snap Shot Score is demonstrated to reveal plausible networks both in a variety of simulations and for real data, which indicate its value for understanding neural dynamics. Additional to the Snap Shot Score, a neural simulation framework is suggested, which facilitates the assessment of neural network inference techniques in a highly automated fashion. Due to a new formal concept to rate learned networks, the framework can be used to test techniques under partial observability conditions. In the presence of hidden units quantification of results has been a tedious task that had to be done by hand, but which can now be automated. Thereby high throughput assessments become possible, which facilitate a comprehensive simulation-based characterisation of new methods.

Spontaneous activity in neuronal networks in vitro is common and has been well documented. However, alteration of spontaneous activity in such networks via conditioning electrical stimulation has received much less experimental attention. Two different patterns of electrical stimulation were used to enhance or depress the level of spontaneous activity in spinal cord cultures. High-frequency stimulation (HFS), a method routinely shown to increase the efficacy of synaptic transmission, was employed to augment spontaneous activity. Low-frequency stimulation (LFS), the technique often applied to depress synaptic efficacy, was employed to decrease spontaneous activity. In addition, LFS was used to reverse the effect of HFS on spontaneous activity. Likewise, HFS was applied to counter the effect of LFS. Because these networks were grown on multi-microelectrode plates (MMEPs), this allowed the simultaneous stimulation of any combination of the 64 electrodes in the array. Thus, the possible differences in response to single versus multi-electrode stimulation were also addressed. Finally, test-pulses were delivered before and after the conditioning stimulation on the same stimulation electrode(s) in order to assess the change in mean evoked action potentials (MEAPs). Dissociated spinal tissue from embryonic mice was allowed to mature into self-organized networks that exhibited spontaneous bursting activity after two weeks of incubation. Spontaneous activity was monitored from up to 14 recording channels simultaneously. Although uniform responses to stimulation across all recording electrodes were rarely observed, a large majority of the recording channels had similar responses. Spontaneous activity was increased in 52% of 89 HFS trials, whereas activity was decreased in 35% of 75 LFS trials. The duration of most of these increases was less than 5 minutes. When there were substantial and long-term (> 15 min) changes in spontaneous activity, the opposing stimulation pattern successfully reversed the effect of the previous stimulation. The percent change in MEAPs following conditioning stimulation suggested that synaptic modification had taken place in 75% of all test-pulse stimulation trials.

A "complex" system typically has a relatively large number of dynamically interacting components and tends to exhibit emergent behavior that cannot be explained by analyzing each component separately. A biological neural network is one example of such a system. A multi-agent model of such a network is developed to study the relationships between a network's structure and its spike train output. Using this model, inferences are made about the synaptic structure of networks through cluster analysis of spike train summary statistics A complexity measure for the network structure is also presented which has a one-to-one correspondence with the standard time series complexity measure sample entropy.

There are differences today amongst psychoanalysts regarding if psychoanalysis should limit itself to being exclusively a hermeneutic discipline or if psychoanalysis should find points of contact with neurobiology. The purpose of this essay is to touch upon the larger issue that creates the different points of view: Can psychoanalysis become enriched by finding points of contact with neurobiology, and should psychoanalysis be regarded as belonging to a broader scientific field than being exclusively a human science? The question at issue is: Can modern neurobiology contribute to a development of the psychoanalytic concepts; compulsion to repeat, transference/countertransference and talking cure? The method used is a literature study. The result shows that: Freud’s theories regarding traumatic compulsion to repeat can be linked with LeDoux’s theory of "emotional memory". Freud’s theory of the death instinct as an explanation to the compulsion to repeat can be replaced by a modern neurobiological theory of "emotional memory". The part of the countertransference that is an emotion transferred from the patient to the analyst can happen with the assistance of mirror neurons through "embodied simulation". This suggests that the phenomenon of the analyst being able to experience the patients emotion in himself does not have to imply that projection or intersubjective pressure have played a part in it. To be able to include this phenomenon in the concepts of transference and countertransference these need to be broadened or revised. It is possible to link and develop Freud’s theory of the talking cure with Deacon’s theory about symbolic communication. The results clinical implications are: Understanding of the traumatic compulsion to repeat as an expression of "emotional memory" demands work with this as an expression of memory processes. Understanding of the transference of emotion in transference/countertransference as possible through reflexive simulation processes, implies that projection or interpersonal pressure should not be preconceived in an emotion transference situation. It also implies that the emotional activation in the analyst should not by necessity be seen as an activation of the analyst’s internal objects together with emotions towards these. Deacon’s theory of symbolic communication implies that the talking cure should be used with awareness of its negative tendencies, visual thinking should not necessarily be considered non-symbolic and focus should be put on multiple ways of communication in the clinical situation.

Les circuits neuronaux peuvent générer une panoplie de rythmes. Nous pouvons séparer les mécanismes de création de ces rythmes en deux grands types. Le premier consiste de circuits contrôlés par des cellules « pacemakers », ayant une activité rythmique intrinsèque, comme dans le ganglion stomatogastique des crustacés. Le deuxième consiste de circuits multi-neuronaux connectés par un réseau synaptique qui permet une activité rythmique sans la présence de neurones pacemakers, tel que démontré pour les circuits de la nage chez plusieurs vertébrés. Malgré nos connaissances des mécanismes de rhythmogénèse chez les vertébrés adultes, les mécanismes de la création et la maturation de ces circuits locomoteurs chez les embryons restent encore inconnus. Nous avons étudié cette question à l’aide du poisson-zébré où les embryons débutent leur activité motrice par des contractions spontanées alternantes à 17 heures post-fertilisation (hpf). Des études ont démontré que cette activité spontanée n’est pas sensible aux antagonistes de la transmission synaptique chimique et ne requiert pas le rhombencéphale. Après 28 hpf, les embryons commencent à nager et se propulser en réponse au toucher. Des études antérieures on démontré que l’apparition de la nage nécessite le rhombencéphale et la transmission synaptique chimique. Cette thèse explore la possibilité que ces changements comportementaux représentent la progression d’un circuit contrôle par un pacemaker à un circuit ou le rythme provient d’un circuit distribué. En mesurant le groupement des contractions de l’activité spontanée, plutôt que la fréquence moyenne, nous avons découvert une nouvelle forme d’activité spontanée qui débute à 22 hpf. Cette activité consiste de deux contractions alternantes à succession très rapide. Contrairement à l’activité spontanée présente dès 17 hpf cette nouvelle forme d’activité requiert le rhombencéphale et la transmission synaptique chimique, comme démontré pour la nage qui apparait à 28 hpf. Cette forme de comportement intermédiaire représente potentiellement une étape transitoire lors de la maturation des circuits moteurs. / Neuronal circuits are capable of generating diverse forms of rhythmic activity. Mechanisms underlying rhythmogenesis can be separated into two main groups. First, pacemaker central pattern generators (CPGs) are composed of neurons that have intrinsic oscillatory properties, such as the lobster stomatogastric ganglion. Second, CPGs driven by network-based dynamics rely on synapse-mediated cell properties, such as locomotion in aquatic vertebrates. Despite an existing wealth of knowledge obtained through studying frog and lamprey swimming CPGs, the means by which a locomotor CPG develops remains elusive. Here, we propose to address this question using the zebrafish embryo, for its rapid development, optical transparency and stereotyped behaviour. Motor activity in zebrafish embryos begins with spontaneous activity around 17 hours post-fertilization (hpf). Studies have shown that this activity is not sensitive to antagonists of chemical neurotransmission, and does not require the hindbrain. By 28 hpf, they become able to swim, and generate low-amplitude alternating contractions at a rate of 30 Hz. This study explores the developmental window between the onset of motility and the onset of a mature locomotor output, such as swimming, with the objective of uncovering key steps in motor network maturation. By measuring the grouping of contractions rather than overall frequency of spontaneous activity, we uncovered a novel form of spontaneous activity, starting around 22 hpf. This activity consists of two alternating contractions in rapid succession. In contrast to early spontaneous activity, this motor activity requires glutamatergic neurotransmission and input from the hindbrain, as previously shown for swimming at 28 hpf. This intermediate behavior may reveal an important step in the maturation of the motor network.

Exposure to interparental conflict has been implicated in children's development. Research suggests that underlying mechanisms, such as neuropsychological indicators of cognitive processes, may shed light on how exposure to interparental conflict differentially influences children's outcomes over time. Event-related potentials (ERP), extracted from electroencephalogram data, allow for examination of neuropsychological markers of cognition based on precise timing and scalp topography of electrical activity in the brain. For example, the late positive potential (LPP) ERP component has been implicated in the timing and magnitude of sustained attention and emotion regulation processes elicited in response to emotionally salient stimuli. LPP amplitudes and peak latencies were compared for a community sample of 23 children (9-11 years of age, 12 females) during an oddball task, which used images of couples looking angry, happy, and neutral toward each other. Linear mixed models were used to analyze whether children's perceptions of interparental conflict, and whether they were from high- compared to low-conflict homes, influenced their level of neuropsychological resources directed toward angry compared to happy emotionally-charged interpersonal images. Significant results were found for when children were directed to respond to angry images. Differences emerged in LPP amplitudes for all children in the sample, with the greatest amplitudes produced for happy images compared to neutral and angry images. Regarding conflict exposure and perceptions of conflict, children from homes with greater levels of conflict and children who blamed themselves for conflicts they witnessed between parents produced greater LPP amplitudes when happy trials were presented compared to neutral trials. Finally, females reached their maximum LPP amplitude faster than males for neutral trials compared to angry trials. Results are discussed in terms of the implications for children's processing of interpersonal emotions as it is related to underlying neuropsychological mechanisms for sustained attention and emotion regulation.

Endogenous bioelectric fields guide morphogenesis during embryonic development and regeneration by directly regulating the cellular functions responsible for these phenomena. Although this role has been extensively explored in many peripheral tissues, the ability of electric fields to regulate wound repair and stimulate regeneration in the mammalian central nervous system (CNS) has not been convincingly established. This dissertation explores the role of electric fields in regulating the injury response and controlling the regenerative potential of the mammalian CNS. We place particular emphasis on their influence on astrocytes, as specific differences in their injury-induced behaviors have been associated with differences in the regenerative potential demonstrated between mammalian and non-mammalian vertebrates. For example, astrocytes in both mammalian and non- mammalian vertebrates begin migrating towards the lesion within hours and begin to proliferate after an initial delay of two days; subsequently, astrocytes in non-mammalian vertebrates support neurogenesis and assume a bipolar radial glia-like morphology that guides regenerating axons, whereas astrocytes in mammals do not demonstrate robust neurogenesis and undergo a hypertrophic response that inhibits axon sprouting. To test whether injury-induced electric fields drive the astrocytic response to injury, we exposed separate populations of purified astrocytes from the rat cortex and cerebellum to electric field intensities associated with intact and injured mammalian tissues, as well as to those electric field intensities measured in regenerating non-mammalian vertebrate tissues. Upon exposure to electric field intensities associated with uninjured tissue, astrocytes showed little change in their cellular behavior. However, cortical astrocytes responded to electric field intensities associated with injured mammalian tissues by demonstrating dramatic increases in migration and proliferation, behaviors that are associated with their formation of a glial scar in vivo; in contrast, cerebellar astrocytes, which do not organize into a demarcated glial scar, did not respond to these electric fields. At electric field intensities associated with regenerating tissues, both cerebellar and cortical astrocytes demonstrated robust and sustained responses that included morphological changes consistent with a regenerative phenotype. These results support the hypothesis that physiologic electric fields drive the astrocytic response to injury, and that elevated electric fields may induce a more regenerative response among mammalian astrocytes.

Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years after injury. In this study we investigate the chronic consequences of TBI on adult neurogenesis and the possible involvement of chronic-inflammation in regulating adult neurogenesis. We used two popular TBI animal models, Control Cortical Impact (CCI) and Lateral Fluid Percussion Injury (LFPI) models, to examine focal and diffuse injury responses respectively. Adult rats received CCI, LFPI, or sham injury and were sacrificed at either 15 days or 3 months after injury to examine either subacute or chronic TBI-induced responses respectively. We found no change in levels of proliferation activity at both time points in both TBI models compared to sham animals. Using Doublecortin immunolabeling we found an enhanced generation of new neurons at 15 days after injury and by 3 months this activity was significantly reduced in both TBI models compared to sham animals. We also found persistent inflammation in the injured brains at both time points. Morphological assessment showed that LFPI model of TBI causes shrinkage of the ipsilateral hippocampus. Our results show that moderate TBI induced hippocampal neurogenesis in both models at the early time post-injury. However, at chronic stage, reduced hippocampal neurogenesis is observed in both models and this is accompanied by chronic inflammation. These results suggest that persistent inflammatory responses maybe detrimental to normal neurogenic activity, leading to cognitive impairment and neurodegeneration in long-term TBI survivors.

Inhalants are a loosely defined diverse group of volatile substances which people abuse. Despite widespread misuse of inhalants, there are limited preclinical methods available to study the reinforcement-like properties of inhalants. One procedure which has demonstrated substantial promise as a tool to investigate inhalant pharmacology is the intracranial self-stimulation (ICSS) procedure. ICSS utilizes pulses of electrical stimulation to the mesolimbic reward pathway to serve as a temporally defined and controlled operant reinforcer with a highly adjustable efficacy. The first aim of the project was to characterize the effects of commonly abused inhalants: including toluene, trichloroethane, nitrous oxide, isoflurane and R134a in ICSS. The second aim was to attenuate inhalant-facilitated ICSS by utilization of compounds which would attenuate the pharmacological actions of toluene on GABAA receptors. The low efficacy benzodiazepine negative modulator Ro15-4513 significantly attenuated the ability of toluene to facilitate ICSS without itself significantly altering baseline ICSS responding. Pretreatment with Ro15-4513 also attenuated methamphetamine ICSS even though there is no evidence of methamphetamine interacting with GABAA receptors. Given these unexpected results, I employed a microdialysis procedure to examine the effect of Ro15-4513 on methamphetamine stimulated dopamine release in the nucleus accumbens. Pretreatment with Ro15-4513 significantly attenuated methamphetamine stimulated dopamine release while having a negligible effect on dopamine release when administered alone. These results suggest that a modest level of benzodiazepine-site negative modulation can reduce the reinforcement enhancing effects of abused drugs regardless of their primary mechanism of action through allosteric modulation of GABAergic neurons within the mesolimbic pathway. Further, these results may have implications for expanding the examination of GABAA negative modulator medications beyond those trials currently being conducted with alcohol. Finally, the effects of chronic intermittent toluene exposure on ICSS and nesting behaviors were examined. Subjects were systemically exposed to air, chronic intermittent toluene (CIT), or escalating chronic intermittent (ECIT) toluene for 15 min at 3300 PPM toluene vapor per exposure. The results show that ECIT resulted in decreased overall responding in ICSS relative to air control and showed a tolerance-like effect to facilitatory effects of 3300 ppm toluene during ICSS compared to CIT group. These results indicate that escalating use of toluene produces reductions in its reward-like effects and may contribute to escalation to other drugs of abuse.

Stress has been widely shown to directly influence people’s emotional and behavioral processing as well as their underlying biological systems. This project examined physiological and behavioral responses as indicators of stress and coping in the context of a psychosocial stressor in a controlled laboratory setting. We examined the association between indicators of behavioral coping and underlying physiological reactivity within participants while experiencing stress. Participants included 68 emerging adults. Physiological measures include autonomic biomarkers (e.g., heart-rate, skin conductance) at rest and during the stressor while behavioral indicators that were coded include acute verbal and non-verbal actions exhibited by participants during the stressor. Results supported the efficacy of a modified social stressor at eliciting stress responding in participants. In addition, behavioral coping was found to be associated with autonomic responding to the stressor. Exploring these associations has important implications for understanding the interaction between biological and behavioral responding to stress.