Region-specific and activity-dependent regulation of SVZ neurogenesis and recovery after stroke.

Stroke is the leading cause of adult disability. Neurogenesis after stroke is associated with repair; however, the mechanisms regulating poststroke neurogenesis and its functional effect remain unclear. Here, we investigate multiple mechanistic routes of induced neurogenesis in the poststroke brain, using both a forelimb overuse manipulation that models a clinical neurorehabilitation paradigm, as well as local manipulation of cellular activity in the peri-infarct cortex. Increased activity in the forelimb peri-infarct cortex via either modulation drives increased subventricular zone (SVZ) progenitor proliferation, migration, and neuronal maturation in peri-infarct cortex. This effect is sensitive to competition from neighboring brain regions. By using orthogonal tract tracing and rabies virus approaches in transgenic SVZ-lineage-tracing mice, SVZ-derived neurons synaptically integrate into the peri-infarct cortex; these effects are enhanced with forelimb overuse. Synaptic transmission from these newborn SVZ-derived neurons is critical for spontaneous recovery after stroke, as tetanus neurotoxin silencing specifically of the SVZ-derived neurons disrupts the formation of these synaptic connections and hinders functional recovery after stroke. SVZ-derived neurogenesis after stroke is activity-dependent, region-specific, and sensitive to modulation, and the synaptic connections formed by these newborn cells are functionally critical for poststroke recovery

Global and Local Processing in Adult Humans (Homo Sapiens), 5-year Old Children (Homo Sapiens), and Adult Cotton Top Tamarins (Saguinus Oedipus)

This study compared adults (Homo sapiens), young children (Homo sapiens), and adult tamarins (Saguinus oedipus) while they discriminated global and local properties of stimuli. Subjects were trained to discriminate a circle made of circle elements from a square made of square elements and were tested with circles made of squares and squares made of circles. Adult humans showed a global bias in testing that was unaffected by the density of the elements in the stimuli. Children showed a global bias with dense displays but discriminated by both local and global properties with sparse displays. Adult tamarins’ biases matched those of the children. The striking similarity between the perceptual processing of adult monkeys and humans diagnosed with autism and the difference between this and normatively developing human perception is discussed

Glutamate receptor autoimmune diseases: Understanding the mechanisms, determining the epitopes, and developing better tests

Anti-NMDA receptor and anti-AMPA receptor encephalitis are two recently discovered autoimmune disorders in which patients develop antibodies to ionotropic glutamate receptors. These antibodies cause varied and severe neurologic and psychiatric symptoms. Both disorders are treatable with immunosuppression. Little is know about the mechanisms by which these antibodies cause the disorders or the sites to which antibodies bind on their target receptors. Here, we use a variety of molecular biological, biochemical, and electrophysiological techniques to study the binding site of patients\u27 antibodies and the effects of antibody binding, with the dual goals of determining how antibodies cause disease and developing better methods to test antibodies. Anti-NMDAR encephalitis antibodies bind to the bottom lobe of the amino terminal domain (ATD) of the GluN1 subunit of the NMDA receptor and show specific dependence on amino acid identity of a small region within the bottom lobe. Antibody binding is dependent on ATD conformation, and stabilizes the open conformation of the receptor. Within three hours of binding and continuing in severity over twenty-four hours, antibody causes a titer-dependent decrease in surface receptor expression. This decrease is mediated by proteasomal activity and partially mitigated by increased protein synthesis, and causes an increase in basal calcium concentration within neurons. Similarly, anti-AMPAR encephalitis cerebrospinal fluid (CSF) antibodies bind to the bottom lobe of the ATD of the GluA1 or GluA2 subunits. These antibodies appear to be less conformation sensitive, as denatured fusion proteins expressing AMPAR domains can be recognized by patient antibody on western blot. Fusion proteins also reveal significant variability between the antibody response of serum and CSF, and the serum antibody population appears to change over disease progression. The consequences of this serum variability are unknown; fusion proteins may represent an ideal tool to explore this question. Together, these results significantly increase our understanding of anti-NMDAR and anti-AMPAR encephalitis, although considerable work remains to fully understand these complex and evolving disorders

Glutamate receptor autoimmune diseases: Understanding the mechanisms, determining the epitopes, and developing better tests

Anti-NMDA receptor and anti-AMPA receptor encephalitis are two recently discovered autoimmune disorders in which patients develop antibodies to ionotropic glutamate receptors. These antibodies cause varied and severe neurologic and psychiatric symptoms. Both disorders are treatable with immunosuppression. Little is know about the mechanisms by which these antibodies cause the disorders or the sites to which antibodies bind on their target receptors. Here, we use a variety of molecular biological, biochemical, and electrophysiological techniques to study the binding site of patients\u27 antibodies and the effects of antibody binding, with the dual goals of determining how antibodies cause disease and developing better methods to test antibodies. Anti-NMDAR encephalitis antibodies bind to the bottom lobe of the amino terminal domain (ATD) of the GluN1 subunit of the NMDA receptor and show specific dependence on amino acid identity of a small region within the bottom lobe. Antibody binding is dependent on ATD conformation, and stabilizes the open conformation of the receptor. Within three hours of binding and continuing in severity over twenty-four hours, antibody causes a titer-dependent decrease in surface receptor expression. This decrease is mediated by proteasomal activity and partially mitigated by increased protein synthesis, and causes an increase in basal calcium concentration within neurons. Similarly, anti-AMPAR encephalitis cerebrospinal fluid (CSF) antibodies bind to the bottom lobe of the ATD of the GluA1 or GluA2 subunits. These antibodies appear to be less conformation sensitive, as denatured fusion proteins expressing AMPAR domains can be recognized by patient antibody on western blot. Fusion proteins also reveal significant variability between the antibody response of serum and CSF, and the serum antibody population appears to change over disease progression. The consequences of this serum variability are unknown; fusion proteins may represent an ideal tool to explore this question. Together, these results significantly increase our understanding of anti-NMDAR and anti-AMPAR encephalitis, although considerable work remains to fully understand these complex and evolving disorders

Astrocytic therapies for neuronal repair in stroke

Stroke is a leading cause of disability and death worldwide. Much of the work on improving stroke recovery has focused on preventing neuronal loss; however, these approaches have repeatedly failed in clinical trials. Conversely, relatively little is known about the mechanisms of repair and recovery after stroke. Stroke causes an initial process of local scar formation that confines the damage, and a later and limited process of tissue repair that involves the formation of new connections and new blood vessels. Astrocytes are central to both scar formation and to tissue repair after stroke. Astrocytes regulate the synapses and blood vessels within their cellular projections, or domain, and both respond to and release neuroimmune molecules in response to damage. Despite this central role in brain function, astrocytes have been largely neglected in the pursuit of effective stroke therapeutics. Here, we will review the changes astrocytes undergo in response to stroke, both beneficial and detrimental, and discuss possible points of intervention to promote recovery

Glia in neurodegeneration: Drivers of disease or along for the ride?

While much of the research on neurodegenerative diseases has focused on neurons, non-neuronal cells are also affected. The extent to which glia and other non-neuronal cells are causally involved in disease pathogenesis versus more passively responding to disease is an area of active research. This is complicated by the fact that there is rarely one known cause of neurodegenerative diseases; rather, these disorders likely involve feedback loops that perpetuate dysfunction. Here, we will review genetic as well as experimental evidence that suggest that non-neuronal cells are at least partially driving disease pathogenesis in numerous neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and Parkinson's disease

A toolbox of astrocyte-specific, serotype-independent adeno-associated viral vectors using microRNA targeting sequences.

Astrocytes, one of the most prevalent cell types in the central nervous system (CNS), are critically involved in neural function. Genetically manipulating astrocytes is an essential tool in understanding and affecting their roles. Adeno-associated viruses (AAVs) enable rapid genetic manipulation; however, astrocyte specificity of AAVs can be limited, with high off-target expression in neurons and sparsely in endothelial cells. Here, we report the development of a cassette of four copies of six miRNA targeting sequences (4x6T) which triggers transgene degradation specifically in neurons and endothelial cells. In combination with the GfaABC1D promoter, 4x6T increases astrocytic specificity of Cre with a viral reporter from <50% to >99% in multiple serotypes in mice, and confers astrocyte specificity in multiple recombinases and reporters. We also present empty vectors to add 4x6T to other cargo, independently and in Cre/Dre-dependent forms. This toolbox of AAVs allows rapid manipulation of astrocytes throughout the CNS, is compatible with different AAV serotypes, and demonstrates the efficacy of using multiplexed miRNA targeting sequences to decrease expression in multiple off-target cell populations simultaneously

Motor Activity-Induced White Matter Repair in White Matter Stroke.

Subcortical white matter stroke (WMS) is a progressive disorder which is demarcated by the formation of small ischemic lesions along white matter tracts in the CNS. As lesions accumulate, patients begin to experience severe motor and cognitive decline. Despite its high rate of incidence in the human population, our understanding of the cause and outcome of WMS is extremely limited. As such, viable therapies for WMS remain to be seen. This study characterizes myelin recovery following stroke and motor learning-based rehabilitation in a mouse model of subcortical WMS. Following WMS, a transient increase in differentiating oligodendrocytes occurs within the peri-infarct in young male adult mice, which is completely abolished in male aged mice. Compound action potential recording demonstrates a decrease in conduction velocity of myelinated axons at the peri-infarct. Animals were then tested on one of three distinct motor learning-based rehabilitation strategies (skilled reach, restricted access to a complex running wheel, and unrestricted access to a complex running wheel) for their capacity to induce repair. These studies determined that unrestricted access to a complex running wheel alone increases the density of differentiating oligodendrocytes in infarcted white matter in young adult male mice, which is abolished in aged male mice. Unrestricted access to a complex running wheel was also able to enhance conduction velocity of myelinated axons at the peri-infarct to a speed comparable to naive controls suggesting functional recovery. However, there was no evidence of motor rehabilitation-induced remyelination or myelin protection.SIGNIFICANCE STATEMENT White matter stroke is a common disease with no medical therapy. A form of motor rehabilitation improves some aspects of white matter repair and recovery