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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.Stroke initially causes cell injury and death. After these acute events, there is a period of increased plasticity in the brain. Joy and Carmichael review changes in neuronal excitability systems during this period that lead to neural circuit reformation after stroke and how they may be targeted to promote functional recovery.

Mesenchymal stem cells have previously been shown to mediate brain repair after stroke; they secrete 50–100 nm complexes called extracellular vesicles (EVs), which could be responsible for provoking neurovascular repair and functional recovery. EVs have been observed by electron microscopy and NanoSight, and they contain associated proteins such as CD81 and Alix. This purified, homogeneous population of EVs was administered intravenously after subcortical stroke in rats. To evaluate the EVs effects, we studied the biodistribution, proteomics analysis, functional evaluation, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers. We found that a single administration of EVs improved functional recovery, fiber tract integrity, axonal sprouting and white matter repair markers in an experimental animal model of subcortical stroke. EVs were found in the animals’ brain and peripheral organs after euthanasia. White matter integrity was in part restored by EVs administration mediated by molecular repair factors implicated in axonal sprouting, tract connectivity, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery. This novel role for EVs presents a new perspective in the development of biologics for brain repair.

Spinal cord injury (SCI) causes neural disconnection and persistent neurological deficits, so axon sprouting and plasticity might promote recovery. Soluble Nogo-Receptor-Fc decoy (AXER-204) blocks inhibitors of axon growth and promotes recovery of motor function after SCI in animals. This first-in-human and randomised trial sought to determine primarily the safety and pharmacokinetics of AXER-204 in individuals with chronic SCI, and secondarily its effect on recovery. We conducted a two-part study in adults (aged 18–65 years) with chronic (>1 year) cervical traumatic SCI at six rehabilitation centres in the USA. In part 1, AXER-204 was delivered open label as single intrathecal doses of 3 mg, 30 mg, 90 mg, or 200 mg, with primary outcomes of safety and pharmacokinetics. Part 2 was a randomised, parallel, double-blind comparison of six intrathecal doses of 200 mg AXER-204 over 104 days versus placebo. Participants were randomly allocated (1:1) by investigators using a central electronic system, stratified in blocks of four by American Spinal Injury Association Impairment Scale grade and receipt of AXER-204 in part 1. All investigators and patients were masked to treatment allocation until at least day 169. The part 2 primary objectives were safety and pharmacokinetics, with a key secondary objective to assess change in International Standards for Neurological Classification of SCI (ISNCSCI) Upper Extremity Motor Score (UEMS) at day 169 for all enrolled participants. This trial is registered with ClinicalTrials.gov, NCT03989440, and is completed. We treated 24 participants in part 1 (six per dose; 18 men, six women), and 27 participants in part 2 (13 placebo, 14 AXER-204; 23 men, four women), between June 20, 2019, and June 21, 2022. There were no deaths and no discontinuations from the study due to an adverse event in part 1 and 2. In part 2, treatment-related adverse events were of similar incidence in AXER-204 and placebo groups (ten [71%] vs nine [69%]). Headache was the most common treatment-related adverse event (five [21%] in part 1, 11 [41%] in part 2). In part 1, AXER-204 reached mean maximal CSF concentration 1 day after dosing with 200 mg of 412 000 ng/mL (SD 129 000), exceeding those concentrations that were efficacious in animal studies. In part 2, mean changes from baseline to day 169 in ISNCSCI UEMS were 1·5 (SD 3·3) for AXER-204 and 0·9 (2·3) for placebo (mean difference 0·54, 95% CI –1·48 to 2·55; p=0·59). This study delivers the first, to our knowledge, clinical trial of a rationally designed pharmacological treatment intended to promote neural repair in chronic SCI. AXER-204 appeared safe and reached target CSF concentrations; exploratory biomarker results were consistent with target engagement and synaptic stabilisation. Post-hoc subgroup analyses suggest that future trials could investigate efficacy in patients with moderately severe SCI without prior AXER-204 exposure. Wings for Life Foundation, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, National Institute on Drug Abuse, and ReNetX Bio.

Medial ganglionic eminence (MGE)-like interneuron precursors derived from human induced pluripotent stem cells (hiPSCs) are ideal for developing patient-specific cell therapy in temporal lobe epilepsy (TLE). However, their efficacy for alleviating spontaneous recurrent seizures (SRS) or cognitive, memory, and mood impairments has never been tested in models of TLE. Through comprehensive video- electroencephalographic recordings and a battery of behavioral tests in a rat model, we demonstrate that grafting of hiPSC-derived MGE-like interneuron precursors into the hippocampus after status epilepticus (SE) greatly restrained SRS and alleviated cognitive, memory, and mood dysfunction in the chronic phase of TLE. Graft-derived cells survived well, extensively migrated into different subfields of the hippocampus, and differentiated into distinct subclasses of inhibitory interneurons expressing various calcium-binding proteins and neuropeptides. Moreover, grafting of hiPSC-MGE cells after SE mediated several neuroprotective and antiepileptogenic effects in the host hippocampus, as evidenced by reductions in host interneuron loss, abnormal neurogenesis, and aberrant mossy fiber sprouting in the dentate gyrus (DG). Furthermore, axons from graft-derived interneurons made synapses on the dendrites of host excitatory neurons in the DG and the CA1 subfield of the hippocampus, implying an excellent graft–host synaptic integration. Remarkably, seizure-suppressing effects of grafts were significantly reduced when the activity of graft-derived interneurons was silenced by a designer drug while using donor hiPSC-MGE cells expressing designer receptors exclusively activated by designer drugs (DREADDs). These results implied the direct involvement of graft-derived interneurons in seizure control likely through enhanced inhibitory synaptic transmission. Collectively, the results support a patient-specific MGE cell grafting approach for treating TLE.

Ischemic stroke is common in the elderly, and it is one of the main causes of long-term disability worldwide. After ischemic stroke, spontaneous recovery and functional reconstruction take place. These processes are possible thanks to neuroplasticity, which involves neurogenesis, synaptogenesis, and angiogenesis. However, the repair of ischemic damage is not incomplete, and neurological deficits develop eventually. The WHO recommends acupuncture as an alternative and complementary method for the treatment of stroke. Moreover, clinical and experimental evidence has documented the potential of acupuncture to ameliorate ischemic stroke-induced neurological deficits, particularly sequelaes such as dyskinesia, spasticity, cognitive impairment, and dysphagia. These effects is related to the ability of acupuncture to promote spontaneous neuroplasticity after ischemic stroke. Specifically, acupuncture can stimulate neurogenesis, activate axon regeneration and sprouting, and improve the structure and function of synapses. These processes modify the neural network and function of the damaged brain area, producing the improvement of various skills and adaptability. Astrocytes and microglia may be involved in the regulation of acupuncture on neuroplasticity, such as the production and release of a variety of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), etc. Moreover, the presented evidence confirms that the functional reconstruction of the whole brain after ischemia plays an important role in the process of acupuncture regulating neuroplasticity. Therefore, neuroplasticity is expected to become a new target for acupuncture in the treatment of neurological deficits after ischemic stroke, and it is of great clinical value to conduct in-depth research and excavation on it.

Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades inhibitory chondroitin sulfate proteoglycans and improves axonal sprouting and functional recovery after spinal cord injury in rodents. We evaluated the effects of Chase in rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, we administered multiple intraparenchymal Chase injections below the lesion, targeting spinal cord circuits that control hand function. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in spinal cord injury.

The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.

Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological preparations. Here, we employ three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in a murine model of pancreatic ductal adenocarcinoma (PDAC). Our results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing sympathetic nerves within tumors plus an active, localized sprouting of axon terminals into non-neoplastic lesions and tumor periphery. Ablation of the innervating sympathetic nerves increases tumor growth and spread. This effect is explained by the observation that sympathectomy increases intratumoral CD163 + macrophage numbers, which contribute to the worse outcome. Altogether, our findings provide insights into the mechanisms by which the sympathetic nervous system exerts cancer-protective properties in a mouse model of PDAC. The autonomic nervous systems densely innervate the pancreas, but its contribution to pancreatic ductal adenocarcinoma (PDAC) progression is not fully understood. Here, the authors characterize the pattern of sympathetic innervation by 3D imaging in a murine model of PDAC and show that sympathectomy aggravates cancer progression.

Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-know n inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution.

Extracellular matrix (ECM) hydrogels, produced by tissue decellularization are natural injectable materials suitable for neural tissue repair. However, the rapid biodegradation of these materials may disrupt neural tissue reconstruction in vivo . The aim of this study was to improve the stability of the previously described ECM hydrogel derived from human umbilical cord using genipin and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), crosslinking at concentration of 0.5–10 mM. The hydrogels, crosslinked by genipin (ECM/G) or EDC (ECM/D), were evaluated in vitro in terms of their mechanical properties, degradation stability and biocompatibility. ECM/G, unlike ECM/D, crosslinked hydrogels revealed improved rheological properties when compared to uncrosslinked ECM. Both ECM/G and ECM/D slowed down the gelation time and increased the resistance against in vitro enzymatic degradation, while genipin crosslinking was more effective than EDC. Crosslinkers concentration of 1 mM enhanced the in vitro bio-stability of both ECM/G and ECM/D without affecting mesenchymal stem cell proliferation, axonal sprouting or neural stem cell growth and differentiation. Moreover, when injected into cortical photochemical lesion, genipin allowed in situ gelation and improved the retention of ECM for up to 2 weeks without any adverse tissue response or enhanced inflammatory reaction. In summary, we demonstrated that genipin, rather than EDC, improved the bio-stability of injectable ECM hydrogel in biocompatible concentration, and that ECM/G has potential as a scaffold for neural tissue application.