Abstract
The ability of new neurons to promote repair of brain circuitry depends on their capacity to re-establish afferent and efferent connections with the host. In this review article, we give an overview of past and current efforts to restore damaged connectivity in the adult mammalian brain using implants of fetal neuroblasts or stem cell-derived neuronal precursors, with a focus on strategies aimed to repair damaged basal ganglia circuitry induced by lesions that mimic the pathology seen in humans affected by Parkinson’s or Huntington’s disease. Early work performed in rodents showed that neuroblasts obtained from striatal primordia or fetal ventral mesencephalon can become anatomically and functionally integrated into lesioned striatal and nigral circuitry, establish afferent and efferent connections with the lesioned host, and reverse the lesion-induced behavioral impairments. Recent progress in the generation of striatal and nigral progenitors from pluripotent stem cells have provided compelling evidence that they can survive and mature in the lesioned brain and re-establish afferent and efferent axonal connectivity with a remarkable degree of specificity. The studies of cell-based circuitry repair are now entering a new phase. The introduction of genetic and virus-based techniques for brain connectomics has opened entirely new possibilities for studies of graft-host integration and connectivity, and the access to more refined experimental techniques, such as chemo- and optogenetics, has provided new powerful tools to study the capacity of grafted neurons to impact the function of the host brain. Progress in this field will help to guide the efforts to develop therapeutic strategies for cell-based repair in Huntington’s and Parkinson’s disease and other neurodegenerative conditions involving damage to basal ganglia circuitry.
Highlights
The idea that new cells—neurons, neuroblasts, or immature neural precursors—can be used to repair damaged neural circuitry in the brain goes back to the late 1970s
The experiments pursued in our lab here in Lund were focused on the use of tissue dissected from the developing ventral mesencephalon or fetal striatal primordia
The possibility to create transgenic animals and cell lines expressing fluorescent reporters, such as green fluorescent protein (GFP), provided a new set of powerful and versatile tools to trace axonal projections, making it possible to study the connectivity of neural grafts with a sensitivity and specificity that went beyond what had been possible with classic tract-tracing techniques
Summary
The idea that new cells—neurons, neuroblasts, or immature neural precursors—can be used to repair damaged neural circuitry in the brain goes back to the late 1970s These early studies were performed in rodents and made use of neuroblasts obtained from the developing CNS. The early studies used methods that allowed selective visualization of specific neuronal systems, defined by their transmitter content, or on the use of species-specific antibodies that allow immunohistochemical staining of, e.g., mouse, pig or human neurons and their axonal projections in the rodent brain or spinal cord These methods were combined with classic anterograde or retrograde tracers injected into the grafted tissue or selected anatomical targets in the host brain. The purpose of the present review is to summarize the progress made in this field, from the early days to the present, with a focus on the studies performed over the last four decades in our lab here in Lund, and discuss the possibilities and challenges for the development of cell-based therapies for brain circuitry repair
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call