Stroke is a leading cause of neurological disability, often resulting in long-term motor impairments due to damage to the striatum and/or motor cortex. While both humans and animals show spontaneous recovery following stroke, little is known about how the injury location affects recovery and what causes recovery to plateau. This information is essential in order to improve current rehabilitation practice and develop new therapies to enhance recovery. In this thesis, we used endothelin-1 (ET-1), a potent vasoconstrictor, to produce focal infarcts in the forelimb motor cortex (FMC), the dorsolateral striatum (DLS) or both the FMC and DLS in male Sprague-Dawley rats. In the first experiment, the spontaneous recovery profile of animals was followed over an 8-week period using multiple behavioural tasks assessing motor function and limb preference to identify how recovery varies depending on injury location. Infarct volumes were measured to determine the association between injury and behavioural outcome. All three groups had significant functional impairments on the Montoya staircase, beam traversal, and cylinder tests following stroke, with the combined group having the largest and most persistent impairments. Importantly, spontaneous recovery was not simply dependent on lesion volume but on the lesion location and the behavioural test employed. In the second experiment, we focused on a potential cellular mechanism thought to underlie post-stroke plasticity and functional recovery. In a separate cohort of animals, we assessed how plasticity-limiting perineuronal nets (PNNs) and associated parvalbumin-positive (PV) GABAergic interneurons change following similar ET-1 strokes as in the prior experiment. A significant reduction in the density of PNNs was observed in the perilesional cortex of animals that received a cortical-only or combined stroke but not a striatal-only injury. Although there were no significant differences in the density of PV interneurons between sham and stroked groups, a significant negative correlation existed between cortical infarct volume and the density of PV interneurons in the perilesional cortex. Taken together these results demonstrate that lesion location influences motor recovery and neuroplastic changes following stroke. This supports the idea that a “one size fits all” approach for stroke rehabilitation may not be effective and treatment needs to be individualized to the patient.

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Des preuves convergentes ont attribué aux interneurones de l’inhibition périsomatique (IIPs) un rôle clé dans la production des oscillations gamma (OG). J’ai sondé optogénétiquement l'effet de l'inhibition périsomatique réduite sur les OG et l'apprentissage associatif dans le cortex auditif des souris se comportant librement. Contrairement aux expectatives, je n'ai pas observé une réduction des OG pendant l'inhibition des IIPs, mais plutôt une forte augmentation de l'amplitude dans les OG. L'amplification du potentiel évoqué auditif (PEA) N15, ainsi que l'absence d'une augmentation de la synchronisation entre le cortex et le thalamus, suggèrent que la diminution de l'inhibition périsomatique désinhibe le cortex auditif et favorise la génération intracorticale des OG. Dans une autre expérience, j’ai montré que l'inhibition des IIPs a détérioré l'apprentissage et a produit une réduction liée à l'expérience dans le PEA N15. Enfin, j’ai trouvé que l'abaissement de l'inhibition optogénétique livré à IIP et le réapprentissage des souris ont renforcé les OG auditivement induites. / Convergent evidence has attributed to perisoma-inhibiting interneurons (PIIs) a key role in the generation of gamma oscillations (GO). I optogenetically probed the effect of reduced perisomatic inhibition on GO and associative learning in the auditory cortex of freely behaving mice. Contrary to expectations, I did not observe a reduction in GO during inhibition of PIIs, but rather a strong increase in the amplitude of GO. The amplification of the auditory-evoked potential (AEP) N15, together with the absence of an increase in synchrony between the cortex and the thalamus, suggest that decreased perisomatic inhibition disinhibits the auditory cortex and promotes the intracortical generation of GO. In a different experiment, I showed that inhibition of PIIs impaired learning and produced an experience-related reduction in the AEP N15. Lastly, I found that lowering the optogenetic inhibition delivered to PIIs and retraining mice enhanced auditory-induced GO.

Genetic studies have sought to identify subtypes or endophenotypes of schizophrenia in an effort to improve the reliability of findings. A number of chromosomal regions or genes have now been shown to have had replicated linkage to schizophrenia susceptibility. Molecules involved in neurodevelopment or neurotransmitter function are coded by many of the genes that have been implicated in schizophrenia. Studies of neurotransmitter function have identified, among others, a possible role for GABA, glutamate and dopamine in animal models of schizophrenia. GABA neurons that co-express the calcium binding protein parvalbumin have been implicated as have glutamatergic metabotropic receptors and dopamine D3 receptors. Stress influences glutamate and dopamine providing another environmental factor that may interact with the influence of genes on neurotransmitter function. Neurotransmitter interactions include influences on signaling molecules and these too have been implicated in forms of learning thought to be affected in schizophrenia. Results continue to unravel the interplay of genes and environment in the etiology of schizophrenia and other psychotic disorders.

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Eine einzigartige experimentelle Beobachtung, welche die Basis für eine ganzheitliche, neurowissentschafliche Theorie für Gedächtnis darstellen könnte, sind sharp wave-ripples (SWRs). SWRs werden in lokalen Neuronennetzwerken erzeugt und sind wichtig für Gedächtniskonsolidierung; SWRs sind charakteristische Ereignisse der lokalen Feldpotentiale im Hippocampus des Säugetiers, die in Phasen von Schlaf und Ruhe vorkommen. Eine SWR besteht aus einer sharp wave, einer ≈ 100 ms langen Auslenkung des Feldpotentials, welche mit ripples, 110–250 Hz Oszillationen, überlagert ist. Jüngste Experimente bekräftigen die Theorie, dass ripples in Netzwerken inhibitorischer Interneurone (INT-INT) erzeugt werden, die aus parvalbumin-positive basket cells (PV+BCs) bestehen. PV+BCs sind untereinander über rekurrente inhibitorische Synapsen und Gap Junctions (GJs) gekoppelt. In dieser Arbeit untersuche ich die spezifische Funktion von interneuronalen Gap Junctions in ripples. Im Hauptteil dieser Arbeit demonstriere ich, dass GJs in INT-INT Netzwerken die neuronale Synchronität und die Feuerrate während ripples erhöhen, die ripple-Frequenz sich hingegen nur leicht verändert. Zusätzlich zeige ich, dass diese rippleunterstützenden Effekte nur dann auftreten, wenn die GJ-Transmission schnell genug ist (≈< 0.5 ms), was wiederum somanahe Kopplung voraussetzt (≈< 100 µm). Darüber hinaus zeige ich, dass GJs die oszillatorische Stärke der ripples erhöhen und so die minimale für ripples notwendige Netzwerkgröße verringern. Abschließend zeige ich, dass ausschließlich mit Gap Junctions gekoppelte INT-INT Netzwerke zwar mit ripple Frequenz oszillieren können, aber wahrscheinlich nicht der Erzeuger von experimentell beobachteten ripple-artigen Oszillationen sind. Zusammengenommen zeigen meine Resultate, dass schnelle Gap Junction-Kopplung von Interneuronen die Entstehung von ripples begünstigt und somit SWRs unterstützt, welche einen wichtigen Beitrag zur Bildung unserers Gedächtnisses leisten. / A unique experimental observation that opens ways for a holistic, bottom-up theory for memory generation are sharp-wave ripples (SWRs). SWRs are generated in local neuronal networks and are important for memory consolidation. SWRs are prominent features of the extracellular field potentials in the mammalian hippocampus that occur during rest and sleep; they are characterized by sharp waves, ≈ 100 ms long voltage deflections, that are accompanied by ripples, i.e., 110–250 Hz oscillations. Recent experiments support the view that ripples are clocked by recurrent networks of inhibitory interneurons (INT-INT), which are likely constituted by networks of parvalbumin-positive basket cells (PV+BCs). PV+BCs are not only recurrently coupled by inhibition but also by gap junctions (GJs). In this thesis, I investigate the specific function of interneuronal GJs in hippocampal ripples. Consequently, I simulate INT-INT networks and demonstrate that gap junctions increase the neuronal synchrony and firing rates during ripple oscillations, while the ripple frequency is only affected mildly. I further show that GJs only have these supporting effects on ripples when they are sufficiently fast (≈< 0.5 ms), which requires proximal GJ coupling (≈< 100 µm). Additionally, I find that gap junctions increase the oscillatory power of ripple oscillations and by this means reduce the minimal network size required for INT-INT networks to generate ripple oscillations. Finally, I demonstrate that exclusively GJ-coupled INT-INT networks can oscillate at ripple frequency, however, are unlikely the generator of experimentally observed ripple-like oscillations. In sum, my results show that fast interneuronal gap junction coupling promotes the emergence of ripples and hereby supports SWRs, which are important for the formation of memory.

How do circuits in the mammalian cerebral cortex encode properties of the sensory environment in a way that can drive adaptive behavior? This question is fundamental to neuroscience, but it has been very difficult to approach directly. Various computational and theoretical models can explain a wide range of phenomena observed in the primary visual cortex (V1), including the anatomical organization of its circuits, the development of functional properties like orientation tuning, and behavioral effects like surround modulation. However, so far no model has been able to bridge these levels of description to explain how the machinery that develops directly affects behavior. Bridging these levels is important, because phenomena at any one specific level can have many possible explanations, but there are far fewer possibilities to consider once all of the available evidence is taken into account. In this thesis we integrate the information gleaned about cortical development, circuit and cell-type specific interactions, and anatomical, behavioral and electrophysiological measurements, to develop a computational model of V1 that is constrained enough to make predictions across multiple levels of description. Through a series of models incorporating increasing levels of biophysical detail and becoming increasingly better constrained, we are able to make detailed predictions for the types of mechanistic interactions required for robust development of cortical maps that have a realistic anatomical organization, and thereby gain insight into the computations performed by the primary visual cortex. The initial models focus on how existing anatomical and electrophysiological knowledge can be integrated into previously abstract models to give a well-grounded and highly constrained account of the emergence of pattern-specific tuning in the primary visual cortex. More detailed models then address the interactions between specific excitatory and inhibitory cell classes in V1, and what role each cell type may play during development and function. Finally, we demonstrate how these cell classes come together to form a circuit that gives rise not only to robust development but also the development of realistic lateral connectivity patterns. Crucially, these patterns reflect the statistics of the visual environment to which the model was exposed during development. This property allows us to explore how the model is able to capture higher-order information about the environment and use that information to optimize neural coding and aid the processing of complex visual tasks. Using this model we can make a number of very specific predictions about the mechanistic workings of the brain. Specifically, the model predicts a crucial role of parvalbumin-expressing interneurons in robust development and divisive normalization, while it implicates somatostatin immunoreactive neurons in mediating longer range and feature-selective suppression. The model also makes predictions about the role of these cell classes in efficient neural coding and under what conditions the model fails to organize. In particular, we show that a tight coupling of activity between the principal excitatory population and the parvalbumin population is central to robust and stable responses and organization, which may have implications for a variety of diseases where parvalbumin interneuron function is impaired, such as schizophrenia and autism. Further the model explains the switch from facilitatory to suppressive surround modulation effects as a simple by-product of the facilitating response function of long-range excitatory connections targeting a specialized class of inhibitory interneurons. Finally, the model allows us to make predictions about the statistics that are encoded in the extensive network of long-range intra-areal connectivity in V1, suggesting that even V1 can capture high-level statistical dependencies in the visual environment. The final model represents a comprehensive and well constrained model of the primary visual cortex, which for the first time can relate the physiological properties of individual cell classes to their role in development, learning and function. While the model is specifically tuned for V1, all mechanisms introduced are completely general, and can be used as a general cortical model, useful for studying phenomena across the visual cortex and even the cortex as a whole. This work is also highly relevant for clinical neuroscience, as the cell types studied here have been implicated in neurological disorders as wide ranging as autism, schizophrenia and Parkinson’s disease.

本研究は、線条体パルブアルブミン発現ニューロン(PVニューロン)が受け取るグルタミン酸作動性軸索投射を順行性ウィルストレーサーを用い形態学的に調べた。その結果、運動皮質および視床腹側部からのグルタミン酸作動性軸索入力はいずれもPVニューロン樹状突起の広範囲に投射を行っているものの、視床腹側部の投射のみが細胞体から20µｍ程度の近位樹状突起に高密度な分布を示すことが明らかとなった。 / Using bacterial artificial chromosome transgenic mice expressing somatodendritic membrane–targeted green fluorescent protein in striatal parvalbumin (PV) interneurons, we demonstrate that glutamatergic inputs originating from the ventral anterior/ventral lateral motor thalamus preferentially contact on proximal dendrites, while inputs from motor cortex are uniformly distributed on PV neurons. These results were confirmed using a combination of vesicular glutamate transporter immunoreactions. Collectively, these findings suggest that PV neurons produce fast and reliable inhibition of medium spiny neurons in response to thalamic inputs. In contrast, excitatory inputs from motor cortices modulate PV dendrite excitability, possibly in concert with other glutamatergic, GABAergic, and dopaminergic inputs. / 博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University

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