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Encouraging an excitable brain state: mechanisms of brain repair in stroke

Abstract

Stroke induces a plastic state in the brain. This period of enhanced plasticity leads to the sprouting of new axons, the formation of new synapses and the remapping of sensory-motor functions, and is associated with motor recovery. This is a remarkable process in the adult brain, which is normally constrained in its levels of neuronal plasticity and connectional change. Recent evidence indicates that these changes are driven by molecular systems that underlie learning and memory, such as changes in cellular excitability during memory formation. This Review examines circuit changes after stroke, the shared mechanisms between memory formation and brain repair, the changes in neuronal excitability that underlie stroke recovery, and the molecular and pharmacological interventions that follow from these findings to promote motor recovery in animal models. From these findings, a framework emerges for understanding recovery after stroke, central to which is the concept of neuronal allocation to damaged circuits. The translation of the concepts discussed here to recovery in humans is underway in clinical trials for stroke recovery drugs.

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Fig. 1: Endogenous plasticity in subacute stroke.
Fig. 2: Parallels between windows of plasticity in development and stroke.
Fig. 3: Storage of memory in coactive neuronal networks, or engrams.
Fig. 4: Recovery engram in stroke.

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Acknowledgements

The authors thank the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the American Heart Association and the National Institutes of Health (NIH; grant number NS085019) for financial support.

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S.T.C. has received research grant funding from Takeda Phamaceuticals. M.T.J. declares no competing interests.

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Glossary

Stroke

A disease caused by the blockade or rupture of a blood vessel to the brain. Loss of blood flow causes death of brain tissue, resulting in long-term neurological impairments.

Plasticity

Structural or functional changes (or both) within neurons that affect the connectivity of neurons with each other in a network serving a function. These changes are usually in response to a change in neuronal input or firing patterns induced by this input, such as during learning or after injury.

Neuronal circuits

Neurons from either the same brain region or different regions that are connected to each other via synapses to form networks that subserve different brain functions.

Neuronal excitability

Changes in the electrical properties of a neuron in response to a stimulus.

Neuronal allocation

The property by which neurons are selected to integrate into a circuit that stores information on a particular stimulus.

Motor recovery

The return of a motor function where the initial motor patterns prior to injury or a stroke are regained.

Peri-infarct

Brain tissue that borders the infarct.

Infarct

The site of tissue loss in the brain from a stroke.

Dendritic spines

Sub-micrometre protrusions on dendrites of a neuron that receive synaptic input as postsynaptic elements in the synaptic connection.

Axonal sprouting

The growth and extension of a new axon and its connections. This may occur from an injured or damaged axon, or through collateralization or extension from an existing axon. The ability to grow new axons is nearly absent in the adult brain except after injury.

Critical period

A time window during development or after a stroke marked by significant changes in neuronal growth and connectivity shaped by sensory, motor and cognitive experiences.

Engram

A collection of neurons that fire together in response to a stimulus with higher connectivity with each other and store the memory for that stimulus.

Compensation

The return of a motor function using new movement patterns that allow complete or partial execution of a task, often at the expense of higher energy demands and lower movement quality.

Map reorganization

Maps are gross anatomical and functional readouts from the activity of a population of neurons that underlie or respond to movement or sensation, and they can reorganize to take a different spatial location or expand in original territory during learning or in response to injury.

Clinical translation

The transfer of an experimental paradigm identified in an animal or laboratory-based model of disease to a clinical setting in which patients are treated based on these preclinical experimental results.

Neural repair therapy

A therapeutic strategy that targets genes or signalling molecules underlying plasticity such that stroke recovery can be induced through increased connectivity between relevant brain regions to execute lost function. Neural repair therapies do not minimize cell death that occurs in the initial phases of stroke, but rather utilize and enhance inherent plasticity present in the later stages of stroke by manipulating specific genes, allowing for more effective therapies and greater treatment accessibility to patients who do not qualify for clot removal therapies.

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Joy, M.T., Carmichael, S.T. Encouraging an excitable brain state: mechanisms of brain repair in stroke. Nat Rev Neurosci 22, 38–53 (2021). https://doi.org/10.1038/s41583-020-00396-7

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