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Working memories have long been thought to be maintained by persistent spiking. However, mounting evidence from multiple-electrode recording (and single-trial analyses) shows that the underlying spiking is better characterized by intermittent bursts of activity. A counterargument suggested this intermittent activity is at odds with observations that spike-time variability reduces during task performance. However, this counterargument rests on assumptions, such as randomness in the timing of the bursts, which may not be correct. Thus, we analyzed spiking and LFPs from monkeys’ prefrontal cortex (PFC) to determine if task-related reductions in variability can co-exist with intermittent spiking. We found that it does because both spiking and associated gamma bursts were task-modulated, not random. In fact, the task-related reduction in spike variability could largely be explained by a related reduction in gamma burst variability. Our results provide further support for the intermittent activity models of working memory as well as novel mechanistic insights into how spike variability is reduced during cognitive tasks.

Dissertation, RWTH Aachen University, 2019; Aachen 1 Online-Ressource (179, xxxvi Seiten) : Illustrationen, Diagramme (2019). = Dissertation, RWTH Aachen University, 2019, Durch die Anordnung von weichen filamentösen Strukturen stellt die Natur die extrazelluläre Matrix (EZM) her, die die Zellen in Geweben umgibt. Die EZM ist oftmals anisotrop und interagiert dynamisch mit den Bioeinheiten. Mit dem Ziel die natürliche EZM zu imitieren und Strukturen von unten nach oben anzuordnen (bottom-up), wurde ein injizierbares Biomaterial entwickelt, das eine anisotrope Matrix ausbildet, die mit hoher Präzision angeordnet werden kann. Mikroskopisch kleine Gelstäbchen wurden mit superparamagnetischen Eisenoxidnanopartikeln versetzt, um eine ultrahohe magnetische Orientierbarkeit zu erreichen. Die magnetische Mikrogelorientierung wurde eingehend untersucht und ein Model entwickelt und verifiziert, dass eine Vorhersage der Orientierung erlaubt, indem die spezifischen Parameter einfach eingelesen werden (Aspektverhältnis, Volumen, Nanopartikelanteil, Viskosität des umgebenen Fluids, Magnetfeldstärke und -richtung). Entsprechend kann - unter Beibehaltung der hohen Kontrolle der magnetischen Mikrogelanordnung - ein breites Spektrum an Mikrogelparametern variiert werden. Zur Erstellung einer stabilen anisotropen Matrix werden nach der Ausrichtung die Mikrogelorientierung und -position durch ein umgebendes, enzymatisch-vernetzendes Hydrogel fixiert. Das entstandene “Anisogel” stellt ein sehr geeignetes injizierbares Biomaterial zur Regeneration von empfindlichen, ausgerichteten Geweben dar, wie beispielweise dem Rückenmarks-, Herz- und Gehirngewebe. In vitro Experimente haben gezeigt, dass selbst bei geringen Mikrogelanteilen von, Published by Aachen

Diese Dissertation beinhaltet experimentelle Arbeiten zu Verhalten, Neuropharmakologie, Einzelzellableitungen und komputationaler Modellierung sowie einige methodische Arbeiten. Die zentrale Fragestellung ist hierbei, welche Rolle dopaminerge Belohnungssignale für das Lernen und die Verhaltenssteuerung spielen. In meiner Arbeit konnte ich zeigen, dass die Lerngeschwindigkeit von der abhängigen Belohnungsgröße und damit durch Dopamin moduliert wird. Dieser Effekt lässt sich durch das TD-Modell quantifizieren. Außerdem konnte ich zeigen, dass sich durch TD-Lernen Verhaltenskategorien entwickeln und einzelne Zellen im Taubenhirn diese Kategorien repräsentieren. Im austrainierten Tier wird die dopaminerge Antwort dann dazu verwendet Aufmerksamkeit und Arbeitsgedächtnis zu kontrollieren und gegen Störung zu stabilisieren.

Biomaterials 163, 128-141 (2018). doi:10.1016/j.biomaterials.2018.02.001, Published by Elsevier Science, Amsterdam [u.a.]

Biomacromolecules 20(11), 4075-4087 (2019). doi:10.1021/acs.biomac.9b00891, Published by American Chemical Soc., Columbus, Ohio

An enzymatically cross-linked polyethylene glycol (PEG)-based hydrogel was engineered to promote and align nerve cells in a three-dimensional manner. To render the injectable, otherwise bioinert, PEG-based material supportive for cell growth, its mechanical and biochemical properties were optimized. A recombinant fibronectin fragment (FNIII9*-10/12-14) was coupled to the PEG backbone during gelation to provide cell adhesive and growth factor binding domains in close vicinity. Compared to full-length fibronectin, FNIII9*-10/12-14 supports nerve growth at similar concentrations. In a 3D environment, only the ultrasoft 1 w/v% PEG hydrogels with a storage modulus of ∼10 Pa promoted neuronal growth. This gel was used to establish the first fully synthetic, injectable Anisogel by the addition of magnetically aligned microelements, such as rod-shaped microgels or short fibers. The Anisogel led to linear neurite extension and represents a large step in the direction of clinical translation with the opportunity to treat acute spinal cord injuries.

Directing cells is essential to organize multi-cellular organisms that are built up from subunits executing specific tasks. This guidance requires a precisely controlled symphony of biochemical, mechanical, and structural signals. While many guiding mechanisms focus on 2D structural patterns or 3D biochemical gradients, injectable material platforms that elucidate how cellular processes are triggered by defined 3D physical guiding cues are still lacking but crucial for the repair of soft tissues. Herein, a recently developed anisotropic injectable hybrid hydrogel (Anisogel) contains rod-shaped microgels that orient in situ by a magnetic field and has propelled studying 3D cell guidance. Here, the Anisogel is used to investigate the dependence of axonal guidance on microgel dimensions, aspect ratio, and distance. While large microgels result in high material anisotropy, they significantly reduce neurite outgrowth and thus the guidance efficiency. Narrow and long microgels enable strong axonal guidance with maximal outgrowth including cell sensing over distances of tens of micrometers in 3D. Moreover, nerve cells decide to orient inside the Anisogel within the first three days, followed by strengthening of the alignment, which goes along with oriented fibronectin deposition. These findings demonstrate the potential of the Anisogel to tune structural and mechanical parameters for specific applications. �� 2020 The Authors. Published by Wiley-VCH GmbH

Advanced healthcare materials 9(21), e2000886 (2020). doi:10.1002/adhm.202000886, Published by Wiley-VCH, Weinheim

Working memory is thought to result from sustained neuron spiking. However, computational models suggest complex dynamics with discrete oscillatory bursts. We analyzed local field potential (LFP) and spiking from the prefrontal cortex (PFC) of monkeys performing a working memory task. There were brief bursts of narrow-band gamma oscillations (45–100 Hz), varied in time and frequency, accompanying encoding and re-activation of sensory information. They appeared at a minority of recording sites associated with spiking reflecting the to-be-remembered items. Beta oscillations (20–35 Hz) also occurred in brief, variable bursts but reflected a default state interrupted by encoding and decoding. Only activity of neurons reflecting encoding/decoding correlated with changes in gamma burst rate. Thus, gamma bursts could gate access to, and prevent sensory interference with, working memory. This supports the hypothesis that working memory is manifested by discrete oscillatory dynamics and spiking, not sustained activity., National Institute of Mental Health (U.S.) (Grant 5R01MH091174-05), National Institute of Mental Health (U.S.) (Grant 5R37MH087027-07)

In this review, we provide a brief overview over the current knowledge about the role of dopamine transmission in the prefrontal cortex during learning and memory. We discuss work in humans, monkeys, rats, and birds in order to provide a basis for comparison across species that might help identify crucial features and constraints of the dopaminergic system in executive function. Computational models of dopamine function are introduced to provide a framework for such a comparison. We also provide a brief evolutionary perspective showing that the dopaminergic system is highly preserved across mammals. Even birds, following a largely independent evolution of higher cognitive abilities, have evolved a comparable dopaminergic system. Finally, we discuss the unique advantages and challenges of using different animal models for advancing our understanding of dopamine function in the healthy and diseased brain.

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