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Adult neurogenesis has been the focus of over 1500 articles in the past 10 years. Evidence for the continuous production of new neurons in the adult brain has raised hopes for new therapeutic approaches. On the other hand, the generation of new neurons is modulated in several neurological diseases and disorders, suggesting the involvement of the adult neurogenesis in their pathogenesis. Therefore, a better understanding of the disease-associated modulation of adult neurogenesis is essential for determining the most effective therapeutic strategy. The purpose of this doctoral project was to investigate long-term adult hippocampal neurogenesis changes in two disease models. BrdU labeling in combination with various cellular markers, and genetic fate-mapping approach were used to reach this goal. In the first experiment, the impact of the BeAN strain of the Theiler’s virus on hippocampal cell proliferation and neuronal progenitors was evaluated in two mouse strains which differ in the disease course. It was shown that Theiler’s murine encephalomyelitis virus can exert delayed effects on the hippocampal neurogenesis with long-term changes evident 90 days following the infection. The hippocampal changes proved to depend on strain susceptibility and might have been affected by microglial cells. In the second experiment, hippocampal neurogenesis was analyzed based on genetic fate mapping of transgenic animals in the amygdala-kindling model of epilepsy. The number of new granule neurons added to the dentate gyrus was increased in kindled animals. A prior seizure history proved to be sufficient to induce a long-term net effect on neuron addition and an ongoing occurrence of seizures did not further increase the number of new neurons. Hypertrophic astrocytes were observed in the kindled animals suggesting that seizures result in structural changes of astrocytes that could be detected long after the termination of the insults. The results of the experiments indicated the importance of methodological considerations in chronic studies of neurogenesis.

Alzheimer’s disease (AD) is a fast growing global problem. AD is a form of dementia characterised by the progressive loss of cognitive abilities. Pathologically, the disease is defined by two neuropathological hallmarks: neurofibrillary tangles and amyloid-β plaques. Plaques appear to be toxic to brain tissue and are surrounded by activated microglia and astrocytes, dystrophic neurites and neurons under oxidative stress. When plaques first develop, they are generally small, but in advanced AD, plaques can be much larger. How small plaques may develop into large plaques is still unclear. A number of studies have shown that small plaques grow uniformly over time to give rise to larger plaques. However, this study investigates an alternative hypothesis: that clusters of multiple small plaques merge over time to form large plaques. This hypothesis was inspired by a study that showed that plaques do not deposit in random locations within the brain parenchyma, but rather form in clusters and that these plaque clusters get bigger over time. The aim was to investigate the clustering of plaques in vivo, and follow these clusters over time to see whether they merge together to form a single, larger plaque. This study employed a 2-stage staining technique to follow individual plaques in APPPS1 transgenic mice over time. The fluorescent, amyloid-binding dye Methoxy-X04 was injected into the mice at Day 0 of the experiment. Methoxy-X04 crosses the blood brain barrier and binds stably to plaques for several months and thus labelled the original plaque population. Following 1 day, 1 month or 4 month incubation periods, acute in vivo plaque imaging was performed or the mice sacrificed for post mortem analysis. Antibodies against amyloid-β labelled the state of the plaques at these later time points. Hence this procedure enabled comparison of individual plaque status at different time points and the identification of new plaques that had developed over the incubation time. Detailed analysis of the new and pre-existing plaques revealed two key results. Firstly, that new plaques are more likely to form very close (< 40 µm) to a pre-existing plaque than at further distances. New plaques depositing very close to other plaques formed clusters of plaques in the tissue. Secondly, that clusters of close plaques can fuse over time to form a single large plaque. These two key results provide compelling evidence for a clustering hypothesis of large plaque formation and growth. Together, these data provide in vivo support for the clustering hypothesis by which clusters of small plaques merge together to form single plaques over time. This work expands our understanding of how plaques form and develop in AD and could inform the understanding of plaque clearance strategies to combat AD pathological changes in the brains of patients.

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The present work examines top-down shielding from distraction in visual attention; that is, under which circumstances can the intentions and goals of an observer counteract the bottom-up salience of irrelevant distractors. Several factors of influence will be considered: First, prior experience with distractors, i.e. did observers previously acquire an effective distractor shielding strategy; second, intra- vs. cross-dimensionality of distractors, i.e. are irrelevant distractors defined in the same feature dimension (e.g., shape, color) as the target or in a different feature dimension; third, time, i.e. how effective is distractor shielding early vs. later in processing; and finally, the incentive for effective distractor shielding.

Abnormalities in social behavior are found in almost all psychiatric disorders, such as anxiety, depression, autism and schizophrenia. Thus, comprehension of the neurobiological basis of social interaction is important to better understand numerous pathologies and improve treatments. Several evidences suggest that an alteration of cannabinoid CB1 receptor function could be involved in the pathophysiology of such disorders. However, the role of CB1 receptor is still unclear and its localization on different neuronal subpopulations may produce distinct outcomes. To dissect the role of CB1 receptor on different neuronal population, male mice were used – knockout mice and their respective control littermates [total deletion (CB1-/-); specific deletion on cortical glutamatergic neurons (GluCB1-/-); on GABAergic neurons of the forebrain (GABACB1-/-); or on dopaminergic D1 receptor expressing neurons (D1CB1-/-)], and wild-type (WT) mice treated with CB1 antagonist/inverse agonist SR141716A (3mg/kg). To elucidate the behavioral effects of specific CB1 receptor deficiency, D1CB1-/- mice were submitted to a battery of behavioral tests which included exploration-based tests, depressive-like behavioral tests, and fear-related memory paradigms. It was demonstrated that D1CB1-/- mice exhibited significantly increased contextual and auditory-cued fear, with attenuated within-session extinction. Also, when all mice lines were submitted to different social tasks, involving male or female as the stimulus subject, GluCB1-/- mice showed reduced interest for the social stimulus, as CB1-/- or WT treated with SR141716A mice. D1CB1-/- showed moderate changes in social interest, and GABACB1-/- mice showed the opposite phenotype by spending more time investigating the social stimulus. In conclusion, specific reduction of endocannabinoid signaling in D1-expressing neurons is able to affect acute fear adaptation. Moreover, CB1 receptors specifically modulate social investigation of female mice in a cell-specific manner. These findings support the involvement of cannabinoid signaling in social alterations in psychiatry disorders.

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