The ability of the adult brain to form new connections in areas denervated by a lesion (axonal sprouting) is more widespread than previously thought, but mechanisms remain unknown. We have previously demonstrated an unexpected, robust axonal sprouting of contralateral corticostriatal neurons into the denervated striatum after ischemic cortical lesions. We now take advantage of marked differences in the degree of axonal sprouting from contralateral homotypic cortex after two types of cortical lesions to define the role of neuronal activity in this response. Thermal-ischemic lesions (TCL) of sensorimotor cortex, which induce axonal sprouting, produced two sequential patterns of low-frequency, synchronized neuronal activity that are not seen after similarly sized aspiration lesions, which do not induce axonal sprouting. An early rhythm of synchronous neuronal activity occurred in perilesion cortex on day 1 after lesion, with a frequency range of 0.2-2 Hz. A later pattern of activity occurred on days 2 and 3 after lesion, with a frequency range of 0.1-0.4 Hz. This second rhythm synchronized neuronal activity across widespread areas, including the cortical areas that contain the cell bodies of the sprouting axons. TTX was used to block this patterned neuronal activity and determine whether axonal sprouting was prevented. Chronic TTX infusion into the lesion site blocked the synchronous neuronal activity after TCL as well as axonal sprouting. Thus, both after different types of lesions and in the blockade experiments axonal sprouting was strongly correlated with synchronous neuronal activity, suggesting a role for this activity in anatomical reorganization after brain lesion in the adult.

Highlights d CCR5 is differentially upregulated in neurons after stroke d Knockdown of CCR5 induces motor recovery after stroke and improves cognition after TBI d Treatment with an FDA-approved drug, maraviroc induces recovery after stroke and TBI d Human carriers for CCR5delta32 have better outcomes after stroke

Objectives N‐acetylcysteine (NAC) is a clinically approved thiol‐containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an “antioxidant,” poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke. Methods Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons. Striatal infusion of collagenase was used to model intracerebral hemorrhage (ICH) in mice and rats. Chemical biology, targeted lipidomics, arachidonate 5‐lipoxygenase (ALOX5) knockout mice, and viral‐gene transfer were used to gain insight into the pharmacological targets and mechanism of action of NAC. Results NAC prevented hemin‐induced ferroptosis by neutralizing toxic lipids generated by arachidonate‐dependent ALOX5 activity. NAC efficacy required increases in glutathione and is correlated with suppression of reactive lipids by glutathione‐dependent enzymes such as glutathione S ‐transferase. Accordingly, its protective effects were mimicked by chemical or molecular lipid peroxidation inhibitors. NAC delivered postinjury reduced neuronal death and improved functional recovery at least 7 days following ICH in mice and can synergize with clinically approved prostaglandin E 2 (PGE 2 ). Interpretation NAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE 2 in vitro and in vivo. The findings provide novel insight into a target for NAC, beyond the generic characterization as an antioxidant, resulting in neuroprotection and offer a feasible combinatorial strategy to optimize efficacy and safety in dosing of NAC for treatment of neurological disorders involving ferroptosis such as ICH. Ann Neurol 2018;84:854–872

Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature.

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