The thalamus, a crucial regulator of cortical functions, is composed of many nuclei arranged in a spatially complex pattern. Thalamic neurogenesis occurs over a short period during mammalian embryonic development. These features have hampered the effort to understand how regionalization, cell divisions, and fate specification are coordinated and produce a wide array of nuclei that exhibit distinct patterns of gene expression and functions. Here, we performed in vivo clonal analysis to track the divisions of individual progenitor cells and spatial allocation of their progeny in the developing mouse thalamus. Quantitative analysis of clone compositions revealed evidence for sequential generation of distinct sets of thalamic nuclei based on the location of the founder progenitor cells. Furthermore, we identified intermediate progenitor cells that produced neurons populating more than one thalamic nuclei, indicating a prolonged specification of nuclear fate. Our study reveals an organizational principle that governs the spatial and temporal progression of cell divisions and fate specification and provides a framework for studying cellular heterogeneity and connectivity in the mammalian thalamus.

Over the past decade, research has unveiled the intimate relationship between neuroinflammation and neurodegeneration. Microglia and astrocytes react to brain insult by setting up a multimodal inflammatory state and act as the primary defenders and executioners of neuroinflammatory structural and functional changes. Microglia and astrocytes also play critical roles in the maintenance of normal brain function. This intricate balance of homeostatic and neuroinflammatory functions can influence the onset and the course of neurodegenerative diseases. The emergent role of the microglial-astrocytic axis in neurodegenerative disease presents many druggable targets that may have broad therapeutic benefits across neurodegenerative disease. Here, we provide a brief review of the basal function of both microglia and astrocytes, how they are changed in disease states, the significant differences between mouse and human glia, and use of human induced pluripotent stem cells derived from patients to study cell autonomous changes in human astrocytes and microglia.

No abstract

The thalamus, a crucial regulator of cortical functions, is composed of many nuclei arranged in a spatially complex pattern. Thalamic neurogenesis occurs over a short period during embryonic development. These features have hampered the effort to understand how regionalization, cell divisions and fate specification are coordinated and produce a wide array of nuclei that exhibit distinct patterns of gene expression and functions. Here, we performed an in vivo clonal analysis to track the divisions of individual progenitor cells and spatial allocation of their progeny in the developing thalamus. Quantitative analysis of clone compositions revealed evidence for sequential generation of distinct sets of thalamic nuclei that are associated with the location of the founder cell. Furthermore, we identified intermediate progenitor cells that produced two to four neurons populating more than one thalamic nuclei, indicating a late specification of nuclear fate. Our study reveals an organizational principle that governs the spatial and temporal progression of cell divisions and fate specification, and provides a framework for studying cellular heterogeneity and connectivity in the thalamus.

While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene Ataxin1 (ATXN1). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex, of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1. We found brain region-specific changes in astrocyte density and GFAP expression and area, early in the disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain region-specific manner and correlated with neuronal activity, indicating that astrocytes may compensate or exacerbate neuronal dysfunction. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions, indicating loss of astrocyte functions. We observed no obvious correlation between spatiotemporal changes in microglia and spatiotemporal astrocyte alterations, indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain region and disease stage-specific manner.

Glial cells constitute half the population of the human brain and are essential for normal brain function. Most, if not all, brain diseases are characterized by reactive gliosis, a process by which glial cells respond and contribute to neuronal pathology. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease characterized by a severe degeneration of cerebellar Purkinje cells (PCs) and cerebellar gliosis. SCA1 is caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1). While several studies reported the effects of mutant ATXN1 in Purkinje cells, it remains unclear how cerebellar glia respond to dysfunctional Purkinje cells in SCA1. To address this question, we performed single nuclei RNA sequencing (snRNA seq) on cerebella of early stage Pcp2-ATXN1[82Q] mice, a transgenic SCA1 mouse model expressing mutant ATXN1 only in Purkinje cells. We found no changes in neuronal and glial proportions in the SCA1 cerebellum at this early disease stage compared to wild-type controls. Importantly, we observed profound non-cell autonomous and potentially neuroprotective reactive gene and pathway alterations in Bergmann glia, velate astrocytes, and oligodendrocytes in response to Purkinje cell dysfunction.

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1) and characterized by motor deficits, cognitive decline, changes in affect, and premature lethality. Due to the severe cerebellar degeneration in SCA1, the pathogenesis of Purkinje cells has been the main focus of previous studies. However, mutant ATXN1 is expressed throughout the brain, and pathology in brain regions beyond the cerebellar cortex likely contribute to the symptoms of SCA1. Here, we investigate early-stage SCA1 alterations in neurons, astrocytes, and microglia in clinically relevant brain regions including hippocampus and brain stem of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1 expressing mutant ATXN1 globally. Our results indicate shared and brain region specific astrocyte pathology early in SCA1 preceding neuronal loss. We found reduced expression of homeostatic astrocytic genes Kcnj10, Aqp4, Slc1a2 and Gja1, all of which are key for neuronal function in the hippocampus and brain stem. These gene expression changes did not correlate with classical astrogliosis. Neuronal and microglial numbers were largely unaltered at this early stage of SCA1 with the exception of cerebellar white matter, where we found significant reduction in microglial density, and the brain stem where we detected an increase in microglial cell counts. Brain-derived neurotrophic factor (BDNF) is a growth factor important for the survival and function of neurons with broad therapeutic potential for many brain diseases. We report here that BDNF expression is decreased in cerebellum and medulla of patients with SCA1. Moreover, we found that BDNF had dual effect on SCA1 and wild-type mice. Motor performance, strategy development, hippocampal neurogenesis, and expression of astrocyte homeostatic genes in the hippocampus were ameliorated in BDNF-treated SCA1 mice and further enhanced in BDNF-treated wild-type mice. On the other hand, BDNF had a negative effect on memory recall and expression of homeostatic genes in the brain stem astrocytes both in wild-type and in SCA1 mice.

No abstract