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Improved protocols for the visualization of immature neurons in the human brain provide evidence for generation of neurons in the adult hippocampus and uncover reduced neurogenesis in Alzheimer’s disease.

Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths 1 . Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process 2 – 4 . Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans 5 – 9 , it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of 14 C derived from nuclear testing in genomic DNA 10 , we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques—thinly myelinated lesions that are thought to represent remyelinated areas—were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies. There are no new oligodendrocytes in potentially remyelinated multiple sclerosis shadow plaques, although oligodendrocyte generation is increased in the normal appearing white matter of patients with aggressive disease, informing the development of new therapies.

Conditions affecting the nervous system are collectively the largest contributor to ill health and disability worldwide, and the therapeutic options for many neurological diseases remain limited. For a long time, it was believed that the central nervous system was fixed, with very limited potential for repair after injury. However, studies over the recent decades have demonstrated that the brain exhibits more plasticity than previously understood, which has led to significant efforts to harness these mechanisms for regenerative therapies. In addition, our increased understanding of how the central nervous system interacts with the immune system, opens further possibilities for novel therapeutic strategies. While animal models have provided important insights to brain plasticity and neuroimmune interactions, the involvement of these processes in neurological disease remain largely unexplored in the human brain. This is primarily due to a lack of methods to study cellular dynamics, such as cell generation and immune cell infiltration in brain tissues, without harming the individual. Using two innovative techniques, we have in this thesis explored cellular processes in time and space, in the healthy as well as the pathological human brain.In paper I, we utilized a 14C-based retrospective birth dating method to study how adult neurogenesis, the generation of new neurons in the adult brain, in the hippocampus may be affected in individuals that suffered from alcohol or cocaine addiction. We did not observe any difference in adult hippocampal neurogenesis between healthy controls and the addiction groups, indicating that reduced neurogenesis throughout life does not contribute to addiction vulnerability. Although it was not possible to exclude smaller, yet clinically relevant, changes in cell turnover during the time of abuse, we found that individuals with long-term abuse of alcohol must have similar levels of neuronal generation as many healthy controls during the time of abuse. Furthermore, we found large interindividual variability in neuronal turnover in the healthy control group, suggesting that lifestyle and genetic factors greatly influence adult neurogenesis in the healthy brain.The retrospective birth dating method was also applied in paper IIto investigate the dynamics of oligodendrocyte generation in patients with multiple sclerosis (MS). We specifically examined shadow plaque lesions, which are believed to be remyelinated through the generation of new myelinating oligodendrocytes. Contrary to this belief, we found that oligodendrocytes in shadow plaques are old, indicating that potential remyelination in humans is performed by older oligodendrocytes. However, increased oligodendrocyte generation was found in non-lesion tissue of a few patients, possibly suggesting a heterogeneous reactive cell generation response.MS is generally considered a T cell mediated autoimmune disease. However, the clinical success of B cell-depleting therapies suggest an important role of B cells in MS pathology. The specific T and B cells involved, and their target antigens, are not yet fully characterized. However, the diverse clones can be identified by their highly specific T and B cell receptors, and studying the lymphocyte clonality in a spatial context could shed light on specific clones’ involvement in MS pathology. However, high throughput methods for simultaneous analysis of the spatial distribution B and T cell clones in human tissues were not available.Therefore, in paper III,we developed a spatial transcriptomics method for variable, diversity and joining (VDJ) sequences, called Spatial VDJ, that maps the spatial distribution of T and B cell receptors in tissue sections, while simultaneously capturing the spatial gene expression. This method allows us to study lymphocyte clonal dynamics in a spatial context, link specific lymphocyte clones to local gene expression profiles as well as to lineage trace B cell clones, which can inform us of the development of B cell immune responses.In paper IV,we utilized the Spatial VDJ technique to characterize the spatial distribution of lymphocyte clones in MS lesions, with the goal of identifying candidate clones that may be involved in driving the lesion pathology. We found significant infiltrates of clones of the B cell lineage, possibly terminally differentiated and antibody producing plasma cells, in different lesion types. We identified locally expanded clones that had infiltrated the lesion parenchyma close to vessels and along active lesion borders This potentially suggest a local antigen-driven activity and involvement in driving lesion pathology.

Oligodendrocytes wrap nerve fibers in the central nervous system with layers of specialized cell membrane to form myelin sheaths1. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not appear to contribute to this process2–4. Considering the major differences in oligodendrocyte generation dynamics and adaptive myelination between rodents and humans5–9, it is uncertain how well experimental animals reflect the situation in multiple sclerosis. We have assessed the generation dynamics of oligodendrocytes in multiple sclerosis patients by measuring the integration of nuclear bomb test derived 14C in genomic DNA10. The generation of new oligodendrocytes was increased several-fold in normal appearing white matter in a subset of individuals with very aggressive disease, but not in the majority of subjects with multiple sclerosis, demonstrating an inherent potential to substantially increase oligodendrocyte generation but that this fails in most patients. Oligodendrocytes in shadow plaques, thinly myelinated lesion that are thought to represent remyelinated areas, were old in multiple sclerosis patients. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occur transiently or not at all, or that myelin is regenerated by preexisting, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, which should guide the use of current, and the development of new, therapies.

In this Letter, the vertical error bars were missing from Fig. 3b and 3c. This figure has been corrected online.In this Letter, the vertical error bars were missing from Fig. 3b and 3c. This figure has been corrected online.

Clinical studies on humans with a history of chronic abuse of alcohol or cocaine show cognitive impairments associated with hippocampal atrophy. Adult hippocampal neurogenesis is a process important for memory formation and has been shown to be impaired by alcohol and cocaine in rodent models. It has thus been suggested that a reduction in adult neurogenesis may contribute to cognitive dysfunctions seen in patients with abuse. In addition, reduced adult neurogenesis has been suggested to play a role in the pathology of addiction vulnerability. We have previously demonstrated persistent adult hippocampal neurogenesis throughout life by measuring 14C concentrations in genomic DNA, incorporated during cell division, in a mixed cohort of subjects. In this study, we use the same strategy to assess the extent of cell turnover of neuronal and non-neuronal cells in the hippocampus of humans with known history of alcohol and cocaine abuse and compare these with healthy controls. We find that there is significant neuronal and non-neuronal turnover in healthy controls, as well as in individuals with long term alcohol use orcocaine use. Using mathematical modelling, we compare the extent of cell turnover of neurons and non-neuronal cells and did not find any significant difference between healthy controls and the two addiction groups. While we cannot exclude scenarios of altered adult neurogenesis over shorter periods of time, our data does not support the theory of low neurogenesis as a mechanism of addiction vulnerability.

The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed Spatial Transcriptomics of VDJ sequences (Spatial VDJ), which maps immunoglobulin and TR antigen receptors in human tissue sections. Spatial VDJ captures lymphocyte clones matching canonical T, B, and plasma cell distributions in tissues and amplifies clonal sequences confirmed by orthogonal methods. We confirm spatial congruency between paired receptor chains, develop a computational framework to predict receptor pairs, and link the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity, class switch recombination, and lineage trajectories within their spatial context. Taken together, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, which could have important therapeutic implications.Competing Interest StatementCE, KT, QL, AA, HT, SS, JMo, JLu, and JF are scientific consultants for 10x Genomics Inc, which holds IP rights to the spatial technology. The remaining authors declare no competing interests.Footnotes* https://doi.org/10.5281/zenodo.7326539