Brain Slices as Models for Neurodegenerative Disease and Screening Platforms to Identify Novel Therapeutics

Abstract

Recent improvements in brain slice technology have made this biological preparation increasingly useful for examining pathophysiology of brain diseases in a tissue context. Brain slices maintain many aspects of in vivo biology, including functional local synaptic circuitry with preserved brain architecture, while allowing good experimental access and precise control of the extracellular environment, making them ideal platforms for dissection of molecular pathways underlying neuronal dysfunction. Importantly, these ex vivo systems permit direct treatment with pharmacological agents modulating these responses and thus provide surrogate therapeutic screening systems without recourse to whole animal studies. Virus or particle mediated transgenic expression can also be accomplished relatively easily to study the function of novel genes in a normal or injured brain tissue context.In this review we will discuss acute brain injury models in organotypic hippocampal and co-culture systems and the effects of pharmacological modulation on neurodegeneration. The review will also cover the evidence of developmental plasticity in these ex vivo models, demonstrating emergence of injury-stimulated neuronal progenitor cells, and neurite sprouting and axonal regeneration following pathway lesioning. Neuro-and axo-genesis are emerging as significant factors contributing to brain repair following many acute and chronic neurodegenerative disorders. Therefore brain slice models may provide a critical contextual experimental system to explore regenerative mechanisms in vitro.

An in vitro spinal cord injury model to screen neuroregenerative materials

“…For example, such tissue arrays are increasingly being used for long term, high throughput assays in experimental neurology [18]. They provide a versatile bridge between isolated cell culture and in vivo experiments wherein the cytoarchitecture and structural relationships of cells are maintained, allowing for parameters 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 of neural regeneration, e.g.…”

“…neuronal survival [19], nerve fiber regeneration [20,21] and collateral axon sprouting to be evaluated [22]. These models offer several advantages including the ease of manipulation/observation of in vitro preparations [18]; several ages, neuroanatomical areas and species, including human foetuses [23] and transgenic models [24,25] can be used as tissue donor sources, offering high flexibility to study neural pathologies and disease mechanisms. Slice cultures are amenable to electrophysiological techniques [26], molecular biology methods [27], time lapse video microscopy [28] and dynamic confocal imaging [10,29,30], which has greatly expanded the translational utility of this approach.…”

Histone Hyperacetylation Up-regulates Protein Kinase Cδ in Dopaminergic Neurons to Induce Cell Death

“…Propidium Iodide Uptake and Fluoro-Jade Staining AssaysThe propidium iodide uptake and Fluoro-Jade staining methods were used to determine the extent of neuronal damage after MPP ϩ treatment in brain slice cultures as described previously (69,70). PI is a fluorescent molecule that is excluded from cells with intact membranes, but it labels nucleic acids in cells that have damaged cell membranes to produce red fluorescence (71,72). Fluoro-Jade is an anionic fluorochrome, which selectively and specifically stains degenerating neurons in brain slices (69,70,72).…”

Image Informatics Strategies for Deciphering Neuronal Network Connectivity

“…However, the methods for acquiring and analysing such datasets are far from standard, the size of the datasets is massive and interpretation, let alone quantification, is non-trivial 12 . For live cell imaging studies, acute or organotypic brain slices circumvent the need for extended animal suffering and monitoring of multiple physiological parameters typically accompanying in vivo manipulation 13 . While maintaining a reasonable level of tissue architecture, this approach improves the experimental access and allows precise control of the extracellular environment.…”