Psychosoziale Einflüsse auf die Dynamik der adulten hippocampalen Neurogenese

The term “adult neurogenesis” describes the continuous generation of cohorts of new neurons in some discrete regions of the adult brain, such as the dentate gyrus of the hippocampus. Adult hippocampal neurogenesis (ahNG) has been shown as relevant for typical functions of this brain areal (e.g. memory consolidation), but also influences social behavior and has medical relevance. The exact dynamics of this neuronal development are still unknown, as are psychosocial impacts on this process. To analyze the temporal pattern of ahNG and quantify the development of the new neurons we analyzed the relative and absolute numbers of cells in all known stages of the neural differentiation, from stem cell phase towards neurons, in mice at different time points after BrdU injection. BrdU permanently labels cells during S-phase of the cell cycle and enabled us to follow a cohort of new cells over time, thus, here a pseudo- longitudinal study was performed. Subsequently, first studies on the relation between social factors and ahNG in mammals are presented. Regulation of the neuronal development is related to, and dependent on inputs from the outer environment. A connection between ahNG and social environment has been demonstrated previously, but detailed information on the altered differentiation process is missing. In the first part of this thesis I present detailed information on the progression of distinct cell types through the differentiation process of ahNG. Transitions over time are observed allowing the estimation of cell cycle length (CCL) for each cell type involved in ahNG. I found, that the individual cell types are more flexible than assumed before. In the second part, I investigate the impact of social housing, (behavioral relevant) auditori stimuli and stress on ahNG. While the positive factors were applied to healthy subjects, I used the stress paradigm in the GR+/- mice model of depression. Flexible adaptations of different stages in ahNG were also found in these studies on social factors. Each single stimulator affected individual differentiation stages in characteristic ways. While group size, music, silence and pup calls increase BrdU cell counts in proliferation analyses, with distinct effects on each mitotic differentiation stage, does only silence increase survival of new neurons. In the GR+/- mouse model I found decreased ahNG, without any effect on the proportion of neurogenesis or gliogenesis. Based on the information obtained about the dynamics of ahNG a new, innovative model of ahNG is proposed, pushing type-1 and type-2a cells in the center of attention, while diminishing the weight of type-3 cells for the process of differentiation. Type-1 cells, previously assumed as origin of neurogenesis in the hippocampus, are here hypothesized as safeguard of the system, while type-2a cells, highly proliferative, giving rise to gliogenesis and neurogenesis, are hypothesized as the origin of ahNG under normal, healthy conditions. The additional studies give some indications for changes of the model caused by different social factors. The aim is to draw attention to the importance and impact of social environment on adult neurogenesis, brain plasticity and mental health. Thus, future studies will focus more on the promising field of ahNG.Der Begriff “Adulte Neurogenese” beschreibt die kontinuierliche Generierung neuer Nervenzellen in bestimmten Arealen des erwachsenen Gehirns, wie zum Beispiel dem Hippocampus. Adulte hippocampale Neurogenese (ahNG) ist im Säugetier stark in regional spezifische Funktionen, wie z.B. dem semantischen Gedächtnis, involviert, kann aber auch soziales Verhalten beeinflussen und besitzt zusätzlich medizinische Relevanz. Der exakte Ablauf der neuronalen Entwicklung im Gyrus Dentatus ist bislang ungewiss und soziale Einflüsse auf diesen Prozess wurden noch wenig untersucht. Um den zeitlichen Verlauf der adulten, hippokampalen Neurogenese zu analysieren und die Generierung neuer Körnerzellen zu quantifizieren, wurden als erstes sowohl relative als auch absolute Werte einzelner Entwicklungsstadien zu verschiedenen Zeitpunkten nach BrdU Administration erhoben. BrdU markiert dabei Zellen in der S-Phase des Zellzyklus und ermöglicht es, einer Kohorte neuer Zellen über einen festgelegten Zeitraum zu folgen. Somit handelt es sich bei diesem Teil der Dissertation um eine Pseudo-longitudinale Studie. Im Anschluss werden erstmals Studien präsentiert, welche den Zusammenhang zwischen ahNG und sozialen Faktoren, wie Gruppenzusammensetzung und (z.T. verhaltensrelevanten) auditiven Stimulationen, in gesunden Mäusen untersuchen und dabei vor allem Bezug auf die verschiedenen Differenzierungsstadien nehmen. Neben Untersuchungen im gesunden Organismus wurde zusätzlich der Effekt von Stress in Mäusen mit reduzierter Expression des Glucocorticoid-Rezeptors erforscht. Dieser Mausstamm stellt ein anerkanntes Depressionsmodel dar, mit für Depression typischen, sozialen Verhaltenswesen. Die Ergebnisse zur Dynamik der ahNG zeigen starke Unterschiede zwischen den Zelltypen der einzelnen Differenzierungsstadien, insbesondere bezüglich der Proliferationsrate und der Zellzykluslänge (CCL). Interessanterweise sind die Unterschiede zwischen den einzelnen Zellstadien noch größer als bisher angenommen, e.g. in Bezug auf den Zellzyklus). Flexible Anpassungen an den Zeitverlauf der ahNG werden auch im Falle sozialer Stimulation aufgezeigt. Während steigende Gruppengröße, Musik, Stille und Rufe isolierter Säuglinge, die Anzahl BrdU-positiver Zellen in Proliferationsanalysen erhöhte, zeigte nur Stille eine Steigerung der Neurogenese in Bezug auf Überlebensraten neugebildeter Nervenzellen. In unserem GR+/- Depressionsmodel fanden wir eine Reduktion der ahNG, ohne Beeinflussung der Neurogenese- oder Gliogenese-Rate. Basierend auf den Ergebnissen zur Dynamic der ahNG wird ein neues Modell der ahNG vorgestellt, dass erstmalig nicht nur Type-1 Zellen als den bisher vermuteten Ursprung der Neurogenese, sondern auch Type-2a Zellen in das Zentrum stellt. Hingegen wird die Bedeutung der Type-3 Zellen zugunsten von Type-2b und unreifen Körnerzellen gemindert. Type-1 Zellen werden hier als Sicherung des Systems propagiert, während stark proliferierende Type-2a Zellen sowohl Gliogenese als auch Neurogenese begründen. Eine hohe Flexibilität zeichnet das System der Neubildung neuer Nervenzellen aus, wie wir auch mit den Ergebnissen der anderen Studien zeigen konnten. Die weiteren Studien lassen vermuten, dass die Dynamik der ahNG, wie im Model dargestellt, durch soziale Faktoren verändert werden kann. Diese Untersuchungen sollen Interesse an einem zukünftigen Forschungsfeld wecken, dessen Zweck es sein wird den Zusammenhang zwischen sozialen Umwelteinflüssen, hippokampaler Neurogenese, Gehirnplastizität und mentaler Gesundheit zu lenken

Is silence golden? Effects of auditory stimuli and their absence on adult hippocampal neurogenesis

We have previously hypothesized that the reason why physical activity increases precursor cell proliferation in adult neurogenesis is that movement serves as non-specific signal to evoke the alertness required to meet cognitive demands. Thereby a pool of immature neurons is generated that are potentially recruitable by subsequent cognitive stimuli. Along these lines, we here tested whether auditory stimuli might exert a similar non-specific effect on adult neurogenesis in mice. We used the standard noise level in the animal facility as baseline and compared this condition to white noise, pup calls, and silence. In addition, as patterned auditory stimulus without ethological relevance to mice we used piano music by Mozart (KV 448). All stimuli were transposed to the frequency range of C57BL/6 and hearing was objectified with acoustic evoked potentials. We found that except for white noise all stimuli, including silence, increased precursor cell proliferation (assessed 24\ua0h after labeling with bromodeoxyuridine, BrdU). This could be explained by significant increases in BrdU-labeled Sox2-positive cells (type-1/2a). But after 7\ua0days, only silence remained associated with increased numbers of BrdU-labeled cells. Compared to controls at this stage, exposure to silence had generated significantly increased numbers of BrdU/NeuN-labeled neurons. Our results indicate that the unnatural absence of auditory input as well as spectrotemporally rich albeit ethological irrelevant stimuli activate precursor cells-in the case of silence also leading to greater numbers of newborn immature neurons-whereas ambient and unstructured background auditory stimuli do not

Maintenance and Representation of Mind Wandering during Resting-State fMRI

International audienceMajor advances in resting-state functional magnetic resonance imaging (fMRI) techniques in the last two decades have provided a tool to better understand the functional organization of the brain both in health and illness. Despite such developments, characterizing regulation and cerebral representation of mind wandering, which occurs unavoidably during resting-state fMRI scans and may induce variability of the acquired data, remains a work in progress. Here, we demonstrate that a decrease or decoupling in functional connectivity involving the caudate nucleus, insula, medial prefrontal cortex and other domain-specific regions was associated with more sustained mind wandering in particular thought domains during resting-state fMRI. Importantly, our findings suggest that temporal and between-subject variations in functional connectivity of above-mentioned regions might be linked with the continuity of mind wandering. Our study not only provides a preliminary framework for characterizing the maintenance and cerebral representation of different types of mind wandering, but also highlights the importance of taking mind wandering into consideration when studying brain organization with resting-state fMRI in the future. Over the past two decades, resting-state functional connectivity measured by functional magnetic resonance imaging (fMRI) has played an essential role in understanding brain functional networks in healthy and patient populations 1–5. Resting-state functional connectivity is measured by the temporal co-activation level of spontaneous fMRI signals between spatially distinct brain regions in the absence of a perceptual or behavioral task 6. Although the participants are not engaged in any particular task, there is increasing evidence that spontaneous thoughts (known as mind wandering, daydreaming, self-generated mental activity or task-unrelated thought) that are minimally constrained by external perception emerge during fMRI scans and may potentially affect resting-state fMRI data 7,8. Mind wandering during resting-state fMRI has been assessed using different approaches. Questionnaires can be administered, following the resting-state fMRI scan, in which participants are asked to report the presence and frequency of spontaneous thoughts across various domains. Resting-state fMRI studies have employed several types of retrospective measures to assess spontaneous thoughts: Amsterdam Resting-State Questionnaire (ARSQ) 9 , New York Cognition Questionnaire (NYC-Q) 10–12 , and Resting-State Questionnaire (ReSQ) 13,14. Alternatively, mind-wandering has been assessed using experience or thought sampling in conjunction with resting-state fMRI scanning 15–20. While regions within the default mode networ