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Echoortende Fledermäuse verfügen über ein hochauflösendes Gehör. Sie können anhand einer geringen Zeitverzögerung zwischen ausgesendetem Echoortungsruf und dem Echo die Entfernung von Objekten bestimmen. Je nach Spezies und deren spezifischer Ortungsstrategie gibt es unterschiedliche Typen von Ortungslauten. Die meisten Fledermäuse verwenden frequenzmodulierte (FM) Ortungssignale und zählen zu den FM-Fledermäusen. CF-FM-Fledermäuse verwenden dagegen zusätzlich zu FM-Komponenten konstantfrequente Signalelemente (CF-FM). Diese sind besonders zur Detektion flügelschlagender Beuteinsekten in dichter Vegetation von Vorteil. Im auditorischen Kortex (AC) von Fledermäusen existieren so genannte FM-FM-Neurone, die auf die Auswertung der Verzögerungszeiten zwischen Rufaussendung (FM-Ruf) und Echo (FM-Echo) spezialisiert sind. Eine Besonderheit von FM-FM-Neuronen ist, dass sie bei CF-FM-Fledermäusen systematisch, entsprechend ihrer bevorzugten Echoverzögerungen, im AC angeordnet sind. Somit sind die FM-FM-Neurone chronotop entlang einer rostro-kaudalen Achse organisiert. Solche FM-FM-Neurone wurden bislang auch in FM-Fledermäusen nachgewiesen, jedoch waren sie nicht chronotop organisiert. Ein Ziel dieser Promotionsarbeit war es, FM-FM-Neurone bei der FM-Fledermaus Carollia perspicillata hinsichtlich ihrer Eigenschaften und ihrer räumlichen Anordnung im AC zu untersuchen. Die Befunde der vorliegenden Studie an C. perspicillata zeigen, dass alle untersuchten Neurone im dorsalen AC sowohl auf hochfrequente Reintöne als auch auf FM-FM-Stimulation reagierten. Die Echoverzögerungen, auf welche die Neurone im Areal reagierten, lagen zwischen 1 und 32 ms, was einer Distanz zwischen Fledermaus und Objekt von 16 cm bis 5,3 m entspricht. Überraschenderweise waren die kortikalen FM-FM-Neurone bei C. perspicillata chronotop organisiert, ähnlich wie bei insektenfressenden CF-FM-Fledermäusen. Warum eine chronotope Anordnung von FM-FM-Neuronen im AC bei CF-FM-Fledermäusen von Nutzen sein kann, ist nicht geklärt. Bislang wurde vermutet, dass eine systematische Anordnung die Zeitverarbeitungsprozesse optimiert und vor allem beim Insektenjagen in dichter Vegetation vorteilhaft sein könnte. Der vorliegende Befund ist außergewöhnlich, da er zeigt, dass auch bei der überwiegend frugivoren Fledermaus C. perspicillata FM-FM-Neurone chronotop angeordnet sind, und damit verdeutlicht, dass der funktionelle Rückschluss hinsichtlich des Beutefangs neu diskutiert werden muss. Neben der Charakterisierung von FM-FM-Neuronen bei adulten C. perspicillata war Ziel der vorliegenden Arbeit, die postnatale Entwicklung des AC im Hinblick auf die Frequenzrepräsentation zu untersuchen. Während der Entwicklung von C. perspicillata wurden drei wichtige Veränderungen festgestellt: (1) Das Audiogramm zeigt, dass der Hörbereich von Neugeborenen charakteristische Frequenzen (CF) zwischen 15 und 80 kHz aufweist. Dieser Frequenzbereich entspricht etwa 72% des Hörbereichs von Adulten. Während der ersten vier postnatalen Entwicklungswochen findet eine Frequenzverschiebung um etwa 0,4 Oktaven hin zu höheren Frequenzen statt. Insgesamt erhöhen sich die CF der Neurone im dorsalen AC von Neugeborenen bis hin zu Adulten um 30 kHz. (2) Die Sensitivität der hochfrequenten Neurone nimmt während der ersten postnatalen Woche um 15 dB zu und bleibt ab dieser Entwicklungsphase relativ konstant. (3) Die Sensitivität der tieffrequenten Neurone im ventralen AC nimmt im Laufe der Entwicklung um etwa 30 dB zu. Die CF der tieffrequenten Neurone sinken unerwartet während der postnatalen Entwicklung von Juvenilen zu Adulten um etwa 10 kHz. Diese Ergebnisse könnten auf eine bidirektionale Ausreifung der Cochlea hinweisen. Eine dritte ontogenetische Teilstudie der vorliegenden Arbeit befasste sich erstmalig mit den FM-FM-Neuronen und deren Organisation während der postnatalen Entwicklung. Die Befunde zeigen, dass während der Ontogenese drei wichtige Modifikationen auftreten: (1) Bereits bei Neugeborenen liegt der Anteil an FM-FM-Neuronen bei 21% im Vergleich zur Aktivität auf Reintöne. Dieser Anteil nimmt in der ersten Entwicklungswoche auf 56% zu und steigt einhergehend mit der beginnenden Flugtüchtigkeit der Tiere in der dritten Entwicklungswoche abrupt auf 84%. (2) Bei Neugeborenen werden im Vergleich zu älteren Entwicklungsphasen ausschließlich Entfernungen zwischen Fledermaus und Objekt von 50 cm bis 2,5 m auf neuronaler Ebene mittels FM-FM-Neurone codiert. Bereits nach der ersten postnatalen Woche sind die CD ähnlich verteilt wie bei adulten Tieren. Die Sensitivität an den CD nimmt während der Entwicklung vom Neugeborenen zum Adulten um etwa 20 dB zu. (3) Bereits bei Neugeborenen sind die FM-FM-Neurone im dorsalen AC chronotop angeordnet und über alle Altersgruppen hinweg bleibt die Chronotopie bestehen. Die Befunde der vorliegenden Studie zeigen erstmalig, dass die kortikalen Zeitverarbeitungsareale und die Chronotopie pränatal angelegt werden.
Im Rahmen der hier vorliegenden Arbeit wurde der Einfluss sowohl akuter als auch chronischer Aufnahme subletaler Mengen des Insektizids Thiacloprid auf Einzelbienen und Bienenvölker untersucht. Anlass für diese Art an Untersuchungen gibt ein seit Jahren in Nordamerika und Europa auftretendes unerklärliches Phänomen, „Colony Collapse Disorder“ genannt, bei dem Bienenvölker durch einen plötzlichen Verlust der Flugbienen zusammenbrechen. Als Ursache für das Völkersterben stehen neben anderen Faktoren wie Parasiten, Pathogenen und Umweltfaktoren die Insektizide aus der Gruppe der Neonikotinoide und deren Auswirkungen auf Bienen in subletalen Mengen im Verdacht. Basierend auf Studien der Europäischen Behörde für Lebensmittelsicherheit (EFSA) wurde der zugelassene Einsatz der drei Neonikotinoide Clothianidin, Imidacloprid und Thiamethoxam im Pflanzenschutz für zunächst zwei Jahre durch die EU-Kommission stark eingeschränkt.
Thiacloprid, ein weiteres Insektizid, welches zur Gruppe der Neonikotinoide gehört, ist weiterhin für den Einsatz im Pflanzenschutz zugelassen. Es wirkt in ähnlicher Weise wie die zuvor genannten Neonikotinoide als Agonist am nikotinischen Acetylcholinrezeptor, wobei es jedoch als weniger toxisch für Bienen gilt. Trotzdem sind subletale Auswirkungen dieses Neonikotinoids auf Bienen denkbar, die sich in Verhaltensänderungen der Bienen äußern und als Folge Einfluss auf das gesamte Bienenvolk nehmen könnten.
In der hier vorliegenden Arbeit wurden in chronisch mit Thiacloprid eingefütterten Völkern über mehrere Monate regelmäßige Populationsschätzungen durchgeführt, um die Entwicklung der Bienenvölker unter Aufnahme von Thiacloprid festzustellen. In einem weiteren Versuch wurde die Entwicklung der Brut unter chronischer Fütterung mit Thiacloprid beobachtet. Zusätzlich wurde eine große Zahl an Bienen mit RFID-Transpondern ausgestattet, um das Flugverhalten zu dokumentieren. Insbesondere wurden hier der Zeitpunkt des ersten Ausflugs und die Lebensdauer der Bienen zu Vergleichen herangezogen. Nach akuter Fütterung einer subletalen Einzeldosis Thiacloprid wurden Versuche zum Heimkehrvermögen von Bienen durchgeführt.
Unter feldrelevanten und bis zu zehnfach höheren Thiacloprid-Konzentrationen wurden keine beeinträchtigenden Einflüsse auf die Volksentwicklung beobachtet. Bei Konzentrationen, die um ein 25faches bzw. ein 40faches höher als die feldrelevante Konzentration waren, wurde festgestellt, dass die Brutzellenanzahl im Verhältnis zur Bienenanzahl verringert war. Bienen aus chronisch mit Thiacloprid eingefütterten Völkern starteten mit höherem Alter zu ihrem ersten Flug aus dem Bienenstock. Die Zeit, die die Bienen als Sammlerinnen verbrachten, änderte sich nicht. Durch Beobachtungen der Brutflächen konnte festgestellt werden, dass sich die Brut in Thiacloprid-gefütterten Völkern entsprechend der Brut in Kontrollvölkern entwickelte. Aufgrund weiterer Ergebnisse wurde eine Störung der olfaktorischen Wahrnehmung von Bienen aus Thiacloprid-gefütterten Völkern vermutet. Die akut verabreichte subletale Dosis an Thiacloprid führte zu einem erheblichen Verlust an heimkehrenden Bienen und deutet auf eine Beeinträchtigung des Orientierungs- bzw. Navigationsvermögens der Bienen hin.
In den durchgeführten Versuchen wurden sowohl direkte Auswirkungen von chronischer und akuter Aufnahme subletaler Mengen an Thiacloprid, als auch indirekte Auswirkungen auf Honigbienen beobachtet. Da teilweise erst bei hohen, nicht feldrelevanten Konzentrationen in den Versuchen Effekte beobachtet wurden, kann nur bedingt durch die Verhaltensänderung von Einzelbienen auf daraus resultierende Auswirkungen auf ein gesamtes Bienenvolk unter realistischen Bedingungen geschlossen werden.
Using walls to navigate the room: egocentric representations of borders for spatial navigation
(2021)
Spatial navigation forms one of the core components of an animal’s behavioural repertoire. Good navigational skills boost survival by allowing one to avoid predators, to search successfully for food in an unpredictable world, and to be able to find a mating partner. As a consequence, the brain has dedicated many of its resources to the processing of spatial information. Decades of seminal work has revealed how the brain is able to form detailed representations of one’s current position, and use an internal cognitive map of the environment to traverse the local space. However, what is much less understood is how neural computations of position depend on distance information of salient external locations such as landmarks, and how these distal places are encoded in the brain.
The work in this thesis explores the role of one brain region in particular, the retrosplenial cortex (RSC), as a key area to implement distance computations in relation to distal landmarks. Previous research has shown that damage to the RSC results in losses of spatial memory and navigation ability, but its exact role in spatial cognition remains unclear. Initial electrophysiological recordings of single cells in the RSC during free exploration behaviour of the animal resulted in the discovery of a new population of neurons that robustly encode distance information towards nearby walls throughout the environment. Activity of these border cells was characterized by high firing rates near all boundaries of the arena that were available to the animal, and sensory manipulation experiments revealed that this activity persisted in the absence of direct visual or somatosensory detection of the wall.
It quickly became apparent that border cell activity was not only modulated by the distance to walls, but was contingent on the direction the animal was facing relative to the boundary. Approximately 40% of neurons displayed significant selectivity to the direction of walls, mostly in the hemifield contra-lateral to the recorded hemisphere, such that a neuron in left RSC is active whenever a wall occupies proximal space on the right side of the animal. Using a cue-rotation paradigm, experiments initially showed that this egocentric direction information was invariant to the physical rotation of the arena. Yet this rotation elicited a corresponding shift in the preferred direction of local head-direction cells, as well as a rotation in the firing fields of spatially-tuned cells in RSC. As a consequence, position and direction encoding in RSC must be bound together, rotating in unison during the environmental manipulations, as information about allocentric boundary locations is integrated with head-direction signals to form egocentric border representations.
It is known that the RSC forms many anatomical connections with other parts of the brain that encode spatial information, like the hippocampus and para-hippocampal areas. The next step was to establish the circuit mechanisms in place for RSC neurons to generate their activity in respect to the distance and direction of walls. A series of inactivation experiments revealed how RSC activity is inter-dependent with one of its communication partners, the medial entorhinal cortex (MEC). Together they form a wider functional network that encodes precise spatial information of borders, with information flowing from the MEC to RSC but not vice versa. While the conjunction between distance and heading direction relative to the outer walls was the main driver of neural activity in RSC, border cells displayed further behavioural correlates related to movement trajectories. Spiking activity in either hemisphere tended to precede turning behaviour on a short time-scale in a way that border cells in the right RSC anticipated right-way turns ~300 ms into the future.
The interpretation of these results is that the RSC’s primary role in spatial cognition is not necessarily on the early sensory processing stage as suggested by previous studies. Instead, it is involved in computations related to the generation of motion plans, using spatial information that is processed in other brain areas to plan and execute future actions. One potential function of the RSC’s role in this process could be to act correctly in relation to the nearby perimeter, such that border cells in one hemisphere are involved in the encoding of walls in the contralateral hemifield, after which the animal makes an ipsilateral turn to avoid collision. Together this supports the idea that the MEC→RSC pathway links the encoding of space and position in the hippocampal system with the brain’s motor action systems, allowing animals to use walls as prominent landmarks to navigate the room.
Neurodevelopmental psychiatric disorders (NPDs) like attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia, affect millions of people worldwide. Despite recent progress in NPD research, much remains to be discovered about their underpinnings, therapeutic targets, effects of biological sex and age. Risk factors influencing brain development and signalling include prenatal inflammation and genetic variation. This dissertation aimed to build upon these findings by combining behavioural, molecular, and neuromorphological investigations in mouse models of such risk factors, i.e. maternal immune activation (MIA), neuron-specific overexpression (OE) of the cytoplasmatic isoforms of the RNA-binding protein RBFOX1, and neuronal deletion of the small Ras GTPase DIRAS2.
Maternal infections during pregnancy pose an increased risk for NPDs in the offspring. While viral-like MIA has been previously established elsewhere, this study was the first in our institution to implement the model. I validated NPD-relevant deficits in anxiety- and depression-like behaviours, as well as dose- and sex-specific social deficits in mouse offspring following MIA in early gestation. Proteomic analyses in embryonic and adult hippocampal (HPC) synaptoneurosomes highlighted novel and known targets affected by MIA. Analysis of the embryonic dataset implicated neurodevelopmental disruptions of the lipid, polysaccharide, and glycoprotein metabolism, important for proper membrane function, signalling, and myelination, for NPD-pertinent sequelae. In adulthood, the observed changes encompassed transmembrane trafficking and intracellular signalling, apoptosis, and cytoskeletal organisation pathways. Importantly, 50 proteins altered by MIA in embryonic and adult HPC were enriched in the NPD-relevant synaptic vesicle cycle. A persistently upregulated protein cluster formed a functional network involved in presynaptic signalling and proteins downregulated in embryos but upregulated in adults by MIA were correlated with observed social deficits. 49/50 genes encoding these proteins were significantly associated with NPD- and comorbidity-relevant traits in human phenome-wise association study data for psychiatric phenotypes. These findings highlight NPD-relevant targets for future study and early intervention in at-risk individuals. MIA-evoked changes in the neuroarchitecture of the NPD-relevant HPC and prefrontal cortex (PFC) of male and female mice highlighted sex- and region-specific alterations in dendritic and spine morphology, possibly underlining behavioural phenotypes.
To further investigate genetic risk factors of NPDs, I performed a study based on the implications of RBFOX1’s pleiotropic role in neuropsychiatric disorders and previous preclinical findings. Cytoplasmatic OE of RBFOX1, which affects the stability and translation of thousands of targets, was used to disseminate its role in morphology and behaviour. RBFOX1 OE affected dendritic length and branching in the male PFC and led to spine alterations in both PFC and HPC. Due to previously observed ASD-like endophenotypes in our Rbfox1 KO mice and the importance of gene × environment effects on NPD susceptibility, I probed the interaction of cytoplasmatic OE and a low-dose MIA on offspring. Both RBFOX1 OE alone and with MIA led to increased offspring loss during the perinatal period. Preliminary data suggested that RBFOX1 OE × MIA might increase anxiety- and anhedonia-like behaviours. Morphological changes in the adult male OE HPC and PFC suggested increased spine density and reduced dendritic complexity. A small post-mortem study in human dorsolateral PFC of older adults did not reveal significant effects of a common risk variant on RBFOX1 abundance.
To expand upon NPD genetic risks, I evaluated the effects of a homo- (KO) or heterozygous (HET) Diras2 deletion in a novel, neuron-specific mouse model. DIRAS2’s function is largely unknown, but it has been associated with ADHD in humans and neurodevelopment in vitro. In adult mice, there were subtle sex-specific effects on behaviour, i.e. more pronounced NPD-relevant deficits in males, in keeping with human data. KO mice had subtly improved cognitive performance, while HET mice exhibited behaviours in line with core ADHD symptoms, e.g. earning difficulties (females), response inhibition deficits and hyperactivity (males), suggesting Diras2 dose-sensitivity and sex-specificity. The morphological findings revealed multiple aberrations in dendritic and spine morphology in the adult PFC, HPC, and amygdala of HET males. KOs changes in spine and dendritic morphology were exclusively in the PFC and largely opposite to those in HETs and NPD-like phenotypes. Region- and genotype-specific expression changes in Diras2 and Diras1 were observed in six relevant brain regions of adult HET and KO females, also revealing differences in the survival and morphology regulator mTOR, which might underlie observed differences.
In conclusion, the effects of MIA and partial Diras2 knockdown resembled each other in core, NPD-associated behavioural and morphological phenotypes, while cytoplasmatic RBFOX1 OE and full Diras2 KO differed from those. My findings suggest complex dose- and sex-dependent relationships between these prenatal and genetic interventions, whose NPD-relevant influences might converge onto neurodevelopmental molecular pathways. An assessment of such putative overlap, based on available data from the MIA proteomic analyses of embryonic and adult HPC, suggested the three models might be linked via downstream targets, interactions, and upstream regulators. Future studies should disseminate both distinct and shared aspects of MIA, RBFOX1, and DIRAS2 relevant to NPDs and build upon these findings.
The human brain is one of the most complex biological systems. More than 100 billion neurons build networks that control basic body functions and highly coordinated movements, enable us to express emotions, feelings and thoughts and to store memories over years and even throughout life time. Ultimately, “We are who we are because of what we learn and what we remember” (Kandel 2006). Under pathological conditions, the brain function is challenged. Most if not all neurological diseases have in common that they are either triggered and/or accompanied by inflammatory processes of brain tissue, referred to as neuroinflammation. Such inflammatory processes directly affect an elementary neural mechanism relevant for learning and memory: synaptic plasticity. Indeed, neurons are highly dynamic structures and able to respond to specific stimuli with morphological, functional and molecular adaptations that modify the strength and number of neuronal contact sides (synapses). Hence, the main motivation of this thesis was to identify the neural targets through which inflammation affects brain function and synaptic plasticity in particular. The principles of synaptic plasticity have been studied intensively in the hippocampus, an anatomical structure localized within the temporal lobes that is essential for the consolidation of memories and spatial navigation. Synaptic plasticity is coordinated by complex interactions of thousands of molecules and proteins. Among those proteins, synaptopodin (SP) is localized at a strategic position within excitatory synapses and has been shown to be fundamentally involved in the regulation of synaptic plasticity.
To induce neuroinflammation and to study its effects on SP as well as synaptic plasticity, the classic model of lipopolysaccharide (LPS) was applied. This thesis discloses that inflammatory processes impair the ability of neurons to express hippocampal synaptic plasticity in vivo, which is accompanied by a downregulation of SP-mRNA and protein level in the mouse hippocampus, indicating that SP is one of the cellular targets through which inflammatory signaling pathways affect synaptic plasticity and hence neural function. To learn more about the cellular and molecular mechanisms, an in vitro LPS model was established using entorhino-hippocampal organotypic slice cultures (OTCs).
While confirming the major effect of LPS on SP, this thesis furthermore shows that neuroinflammation crucially involves the cytokine TNFα to transduce its effects on SP, and that microglial cells are the main source of TNFα production under inflammatory conditions. In an attempt to learn more about the mechanisms that are affected under conditions of neuroinflammation effects of retinoic acid (RA), a vitamin A derivate were tested. This is mainly because SP as well as RA have been shown to modulate synaptic plasticity through the accumulation of glutamate receptors at the postsynaptic site: SP via the association with the actincytoskeleton as well as intracellular calcium stores, and RA directly via the modulation of local protein synthesis within dendrites. Indeed, in slice cultures exposed to RA, hippocampal SP cluster size is upregulated, both in vitro and in vivo. Intriguingly, a lack of SP prevents RA-induced synaptic strengthening of hippocampal dentate granule cells in OTCs. This suggests a direct contribution of SP in RA-dependent synaptic plasticity. Interestingly, co-immunoprecipitation of SP-mRNA together with the RA-receptor alpha (RARα) further implies that RA directly controls synaptic plasticity via regulation of SP-protein expression. It is therefore interesting to speculate that RA may increase SP expression or prevent its reduction and thus alterations in synaptic plasticity under conditions of neuroinflammation. Taken together, this thesis identifies SP as an important neuronal target of TNFα-mediated alterations in synaptic plasticity. Moreover, the work on RA indicates that SP affects the ability of neurons to express synaptic plasticity by modulating/mediating local protein synthesis. Since neuroinflammatory processes are an elementary concomitant feature and/or cause of neurological diseases, I am confident that future work on the effects of inflammatory processes on brain function may provide the perspective in devising new therapeutic strategies for the treatment of neuropathologies such as Alzheimer’s disease, multiple sclerosis, epilepsy or stroke, by targeting SP expression and SP-mediated synaptic plasticity.
The nucleus reuniens drives hippocampal goal‑directed trajectory sequences for route planning
(2023)
Goal-directed spatial navigation requires accurate estimates of one’s position and destination, as well as careful planning of a route between them to avoid known obstacles in the environment. Despite its general importance across species, the neural circuitry supporting the ability for route planning remains largely unclear. Previous studies described that place cells in the hippocampal CA1 encode the animal's next movement direction (Wood et al., 2000; Ito et al., 2015) and upcoming navigational routes (Pfeiffer & Foster, 2013). However, it has been shown that part of the CA1 activity representing the animal’s future behaviors is not necessarily generated in the hippocampus, but is derived from the medial prefrontal cortex (PFC) via the nucleus reuniens of the thalamus (RE) (Ito et al., 2015). Notably, the importance of the PFC in navigation has been demonstrated in several studies, including the recent finding of a goal map in the orbitofrontal cortex (Basu et al., 2021). Therefore, I hypothesized that information flow from the PFC to CA1 via the RE plays a key role in route planning.
To assess the animals' route planning ability, I designed a new navigation task in which a rat has to navigate to a fixed target location from various starting positions in an arena. Furthermore, by adding an L-shaped wall in the maze and removing all light sources in the experimental room, this task forced the animals to plan a wall-avoiding route without relying on direct sensory perceptions. I confirmed that rats could learn this task successfully, memorizing the wall location and taking a smooth wall-avoidance route. To test the role of the RE, I inactivated RE neurons by expressing the inhibitory opsin SwiChR++, which resulted in a significant deficit in the animal’s route planning ability, taking a longer non-smooth path to the destination. By contrast, this manipulation did not affect navigation performance when a straight goal-directed route was available, suggesting a specific role of the RE in route planning. I further found that DREADDs-mediated inactivation of neurons in the bilateral hippocampi resulted in a similar deficit in route planning ability, implying cooperation between the RE and the hippocampus.
I finally examined the activity of hippocampal CA1 neurons with and without RE inactivation. While neurons in the hippocampus exhibited brief trajectory sequences corresponding to the animal’s subsequent goal-directed journey, I found that this goal-directed bias of trajectory events was significantly reduced by RE inactivation, likely associated with route-planning deficits in these animals.
Altogether, this dissertation demonstrates the role of the RE from both behavioral and neural coding perspectives, identifying a pivotal circuit element supporting the animal’s route-planning ability.
Rhythms, i.e. periodic sequences of events or states, are a ubiquitous feature of physiological systems such as the heart, the lungs or the brain. For the brain in particular, the diversity of rhythms is remarkable, ranging from low frequency rhythms in the slow/delta band (0.5-4 Hz) during sleep to gamma band oscillations (30-120 Hz) rhythms during alert behavior, all expressed in various brain areas and at various spatial scales. To understand whether these rhythms subserve a function for the organism it is important to also understand the underlying mechanisms that generate them. While the generation of some rhythms appear to be well-understood, e.g. sleep spindles, others such as the cortical beta rhythm (13-30 Hz) have remained elusive.
Understanding the generation of a brain rhythm involves multiple spatial scales, from identifying intracellular mechanisms such as the contribution of individual transmembrane currents to studying how specific neuronal populations or areas affect the full physiological rhythm present in the intact, highly interconnected brain. The aim of this work has been to delineate the mechanistic contributions of individual brain areas to the in vivo generation of two particular rhythms present in efferent areas: (1) The first part of this work studies the influence of thalamocortical neurons on cortical slow/delta waves (0.5-4 Hz) of sleep that are sometimes also present in awake animals. (2) The second part is about the contribution of primary visual cortex to the beta rhythm (13-30 Hz) in extrastriate cortex of awake behaving animals.
Eine Einschränkung des Hörvermögens durch Schäden der Sinnesrezeptoren im Innenohr gilt beim Menschen sowie bei allen anderen Säugetieren als irreversibel. Die Hörforschung ist an der Frage interessiert, ob durch Plastizität in zentralen Teilen des auditorischen Systems Kompensationsmechanismen die Folgen mildern können. Die vorliegende Arbeit befasst sich mit der Frage, ob und in welchem Umfang nach peripheren Hörschäden durch zentrale Kompensationsmechanismen eine Erholung des Hörvermögens auftritt auf der Basis von plastischen Änderungen der neuronalen Verarbeitung der Eingangssignale aus dem geschädigten Hörorgan. Schäden des Sinnesepithels im Innenohr, z.B. durch überlaute Beschallung oder ototoxische Substanzen, betreffen in der Regel zunächst die äußeren Haarzellen und führen zu einem Verlust der Empfindlichkeit und Frequenzspezifität des Hörvermögens. Eine primäre selektive Schädigung der inneren Haarzellen (IHZ) tritt im Tiermodell, aus unbekannten Gründen nur bei einer Spezies auf, dem Chinchilla (Chinchilla laniger) und zwar nach Gabe des antineoplastischen Medikament Carboplatin. Das gute Tieffrequenzhören der Chinchillas (0.1-20 kHz) ermöglicht außerdem Aussagen zur akustischen Signalverarbeitung in einem für das menschliche Gehör relevanten Frequenzbereich (0.02-16 kHz). Dieses Tiermodell bietet somit die Gelegenheit, die Veränderungen in zentralen Teilen des auditorischen Systems nach einer definierten sensorischen Schädigung zu untersuchen. Hierfür kommt u.a. das auditorische Mittelhirn, der Colliculus Inferior (IC) in Frage. Der IC wird als Hauptintegrationszentrum der Hörbahn angesehen weil er Eingänge von fast allen vor ihm liegenden auditorischen Kernen (z.B. Nucleus cochlearis, Nucleus olivaris und Leminscus lateralis) bekommt. Ein weiterer Grund für die Wahl des IC als Untersuchungsgebiet der vorliegenden Arbeit ist, die Frage zu beantworten, ob die auf der Ebene des auditorischen Kortex bereits nachgewiesene funktionelle Plastizität auch auf der Ebene des IC schon realisiert oder vorbereitet wird. Die vorliegende Arbeit untersucht das Antwortverhalten der Neurone im ICc an wachen Tieren vor und nach einem selektiven Teilverlust der IHZ bei Erhalt der äußeren Haarzellen. Die Arbeitshypothese ist, dass es nach einem abgeschwächten sensorischen Eingang zu Veränderungen der exzitatorischen und inhibitorischen Antwortfelder kommt, die als funktionelle Plastizität bzw. als Kompensation verstanden werden können. Anhand elektrophysiologischer Ableitungen im ICc von wachen, chronisch implantierten Tieren wurden die exzitatorischen und die inhibitorischen Antwortfelder der Neurone durch Einton- und Zweiton- Stimulation getrennt gemessen und bestimmt. Die Resultate zeigen, dass die exzitatorischen und inhibitorischen Antworteigenschaften im IC bei wachen und narkotisierten Tieren unterschiedlich sind. In wachen Tieren weist die Inhibition generell höhere Variation auf als in narkotisierten Tieren und ist unabhängiger von der Art der Exzitation. Eine Carboplatinbehandlung führte bei allen Tieren nach 3-7 Tagen zu einer Abnahme der Amplituden und einer Erhöhung der Schwellen der akustisch evozierten Hirnstammpotentiale (ABRs). Die histologische Untersuchung des Innenohres (10 Wochen nach Carboplatinbehandlung), zeigte bei allen Tieren Verluste der IHZ (zwischen 20 und 60%) entlang der gesamten Basilarmembran. Es wurden aber keine Verluste von ÄHZ festgestellt. Die Gehirn-Schnitte zeigten, dass die Registrierungen aus dem zentralen Teil des Colliculus Inferior stammen. Die physiologische Untersuchung der Antworteigenschaften der Neurone im IC 4-6 Wochen nach der carboplatinbedingten Schädigung der IHZ zeigte eine Reduktion der Inhibition, die u.a. deutlich an dem Verlauf der Intensitätskennlinien zu beobachten war. Nach dem Teilverlust der IHZ wurden viel weniger nichtmonotone Kennlinien gefunden als vor der Innenohrschädigung. Darüber hinaus beobachteten wir eine Reduzierung der inhibitorischen Regionen und eine signifikante Ausweitung der exzitatorischen Antwortfelder nach dem Teilverlust der IHZ. Die Resultate der vorliegenden Arbeit führen zu der Schlussfolgerung, dass nach einer Teilschädigung der inneren Haarzellen, unter Erhalt der ÄHZ nur ein geringer Sensitivitätsverlust in der zentralen Hörbahn auftritt. Der Verlust von 20-60% der IHZ und der damit einhergehende reduzierte afferente Informationsfluss führt zu physiologischen Veränderungen in der Hörbahn, die im IC von wachen Tieren vor allem durch eine Reduktion der Inhibition hervortritt. Dies deutet daraufhin, dass zentrale Kompensationsmechanismen bei peripheren Hörschäden nicht, wie bisher vermutet, erst in kortikalen sondern zum Teil bereits in subkortikalen Arealen (im Mittelhirn) stattfinden.
The single unit doctrine proposes that each one of our percepts and sensations is represented by the activity of specialized high-level cells in the brain. A common criticism applied to this proposal is the one referred to as the "combinatorial problem". We are constantly confronted with unlimited combinations of elements and features, and yet we face no problem in recognizing patterns and objects present in visual scenes. Are there enough neurons in the brain to singly code for each one of our percepts? Or is it the case that perceptions are represented by the distributed activity of different neuronal ensembles? We lack a general theory capable of explaining how distributed information can be efficiently integrated into single percepts. The working hypothesis here is that distributed neuronal ensembles signal relations present in the stimulus by selectively synchronizing their spiking responses. Synchronization is generally associated with oscillatory activity in the brain. Gamma oscillations in particular have been linked to various integrative processes in the visual system. Studies in anesthetized animals have shown a conspicuous increase in power for the gamma frequency band (30 to 60 Hz) in response to visual stimuli. Recently, these observations have been extended to behavioral studies which addressed the role of gamma activity in cognitive processes demanding selective attention. The initial motivation for carrying out this work was to test if the binding-by-synchronization (BBS) hypothesis serves as a neuronal mechanism for perceptual grouping in the visual system. To this aim we used single and superimposed grating stimuli. Superimposed gratings (plaids) are bi-stable stimuli capable of eliciting different percepts depending on their physical characteristics. In this way, plaids can be perceived either as a single moving surface (pattern plaids), or as two segregated surfaces drifting in different directions (component plaids). While testing the BBS hypothesis, we performed various experiments which addressed the role of both stimulus and cortical architecture on the properties of gamma oscillations in the primary visual cortex (V1) of monkeys. Additionally, we investigated whether gamma activity could also be modulated by allocating attention in time. Finally, we report on gamma-phase shifts in area V1, and how they depend on the level of neuronal activation. ...
The prefrontal cortex (PFC) is considered the cognitive center of the mammalian brain. It is involved in a variety of cognitive functions such as decision making, working memory, goal-directed behavior, processing of emotions, flexible action selection, attention, and others (Fuster, 2015). In rodents, these functions are associated with the medial prefrontal cortex (mPFC). Experiments in mice and rats have shown that neurons in the mPFC are necessary for successful performance of many cognitive tasks. Moreover, measurements of neural activity in the mPFC show excitation or inhibition in different cells in relation to specific aspects of the tasks to be solved. To date, however, it is largely unknown whether prefrontal neurons are stably activated during the same behaviors within a task and whether similar aspects are represented by the same neurons in different tasks. In addition, it is unclear how specifically neurons are activated, for example, whether cells that are activated in response to reward are activated in a different task without reward in a different situation or remain inactive. To address these questions, we recorded the same neurons in the mPFC of mice over the course of several weeks while the animals performed various behaviors.
To do this, we expressed GCaMP6 in pyramidal neurons in the mPFC of mice. A small lens was implanted in the same location and a miniature microscope ("miniscope") was used to record neural activity. Later the extracted neurons got aligned based on their shape and position across multiple days and sessions. The mice performed five different behavioral tests while neural activity was measured: A spatial working memory test in a T-maze, exploration of the elevated plus maze (EPM), a novel object recognition (NO) test including free open field (OF) exploration, a social interaction (SI) test and discriminatory auditory fear conditioning (FC). Each task was repeated at least twice to check for stable task encoding across sessions. Behavioral performance and neural correlates to specific task events were similar to earlier studies across all tasks. We utilized generalized linear models (GLM) to determine which behavioral variables most strongly influence neural activity in the mPFC. The position of the mouse in the environment was found to explain most of the variance in neural activity, together with movement speed they were the strongest predictors of neural activity across all tasks. Reward time points in the working memory test, the conditioned stimulus after fear conditioning, or head direction in general were also strongly encoded in the mPFC.
Many of the recorded neurons showed a stable spatial activity profile across multiple sessions of the same task. Similarly, cells that coded for position in one task tended to code for position in other tasks. Not only did the same cells code for position across multiple tasks, but cells also coded for movement speed and head direction. This indicates that at least these general behavioral variables are each represented by the same neurons in the mPFC. Interestingly, the stability of position or speed coding did not depend on the time between two sessions, but only on whether it was within the same or across different tasks. Within the same task, stability was slightly higher than across different tasks.
To find out whether task-specific behavioral aspects were also stably encoded in the mPFC, difference scores as the difference in neural activity between two task aspects like left- and right-choice trials or exposed and enclosed locations were calculated. Many cells encoded these aspects stably across different sessions of each task. Both the left-right differences in the different phases of the working memory test, the open-closed-arm differences in the elevated plus maze, the different activity between center and corners in the open field, the social target-object differences in the social interaction test, and the differences between the two tones during fear conditioning were all stably encoded across the population of mPFC cells. Only the distinction between the novel and the familiar object during object recognition was not stably encoded, but also the preference for the novel object was not present in the second session of novel object exploration.
There was also an overlap in coding for different aspects within a task across multiple sessions. For example, cells stably encoded left-right differences in the T-maze between different sessions as a function of walking direction across different phases of working memory, an aspect that we could already show within one session (Vogel, Hahn et al., 2022). During fear conditioning, the same cells showed a discrimination between CS+ and CS- that also responded to the start of CS+.
Consistency in the neurons activity across different tasks was also found, but only between tasks with similar demands, the elevated plus-maze and free exploration of the open field. Cells that were more active in the open arms also showed more activity in the center of the open field and vice versa. This could be an indicator that the cells were coding for anxiety or exposure across those tasks, indicating that neurons in the mPFC also stably encode general task aspects independent of the specific environment. However, it remains unclear what exactly these neurons encode; in the case of a general fear signal, one would also expect activation during fear conditioning which could not be found.
Overall, we found that neurons in the mPFC of mice encoded multiple general behavioral variables across multiple tasks and task-specific variables were encoded stably within each of the tested tasks. However, we found little task-specific variables that were systematically encoded by the same neurons with the exception being the elevated plus-maze and open field exploration, two tasks with similar features.