Molecular and cellular evolution of the primate dorsolateral prefrontal cortex.

The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that is centrally involved in cognition. We assessed more than 600,000 single-nucleus transcriptomes from adult human, chimpanzee, macaque, and marmoset dlPFC. Although most cell subtypes defined transcriptomically are conserved, we detected several that exist only in a subset of species as well as substantial species-specific molecular differences across homologous neuronal, glial, and non-neural subtypes. The latter are exemplified by human-specific switching between expression of the neuropeptide somatostatin and tyrosine hydroxylase, the rate-limiting enzyme in dopamine production in certain interneurons. The above molecular differences are also illustrated by expression of the neuropsychiatric risk gene FOXP2, which is human-specific in microglia and primate-specific in layer 4 granular neurons. We generated a comprehensive survey of the dlPFC cellular repertoire and its shared and divergent features in anthropoid primates.

NogoA-expressing astrocytes limit peripheral macrophage infiltration after ischemic brain injury in primates.

Astrocytes play critical roles after brain injury, but their precise function is poorly defined. Utilizing single-nuclei transcriptomics to characterize astrocytes after ischemic stroke in the visual cortex of the marmoset monkey, we observed nearly complete segregation between stroke and control astrocyte clusters. Screening for the top 30 differentially expressed genes that might limit stroke recovery, we discovered that a majority of astrocytes expressed RTN4A/ NogoA, a neurite-outgrowth inhibitory protein previously only associated with oligodendrocytes. NogoA upregulation on reactive astrocytes post-stroke was significant in both the marmoset and human brain, whereas only a marginal change was observed in mice. We determined that NogoA mediated an anti-inflammatory response which likely contributes to limiting the infiltration of peripheral macrophages into the surviving parenchyma.

Replicating infant-specific reactive astrocyte functions in the injured adult brain.

Infants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adults after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was only expressed on infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged focal ischemic injury significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries.

The Involvement of the Myelin-Associated Inhibitors and Their Receptors in CNS Plasticity and Injury.

The limited capacity for the central nervous system (CNS) to repair itself was first described over 100 years ago by Spanish neuroscientist Ramon Y. Cajal. However, the exact mechanisms underlying this failure in neuronal regeneration remain unclear and, as such, no effective therapeutics yet exist. Numerous studies have attempted to elucidate the biochemical and molecular mechanisms that inhibit neuronal repair with increasing evidence suggesting that several inhibitory factors and repulsive guidance cues active during development actually persist into adulthood and may be contributing to the inhibition of repair. For example, in the injured adult CNS, there are various inhibitory factors that impede the outgrowth of neurites from damaged neurons. One of the most potent of these neurite outgrowth inhibitors is the group of proteins known as the myelin-associated inhibitors (MAIs), present mainly on the membranes of oligodendroglia. Several studies have shown that interfering with these proteins can have positive outcomes in CNS injury models by promoting neurite outgrowth and improving functional recovery. As such, the MAIs, their receptors, and downstream effectors are valid drug targets for the treatment of CNS injury. This review will discuss the current literature on MAIs in the context of CNS development, plasticity, and injury. Molecules that interfere with the MAIs and their receptors as potential candidates for the treatment of CNS injury will additionally be introduced in the context of preclinical and clinical trials.

Reduced post-stroke glial scarring in the infant primate brain reflects age-related differences in the regulation of astrogliosis.

Ischemic stroke remains a leading cause of disability worldwide. Surviving patients often suffer permanent neurological impairments, and spontaneous recovery rarely occurs. However, observations that early-life brain injuries, including strokes, elicit less severe long-term functional impairments, compared to adults, continue to intrigue. While much research has focussed on neuronal changes and plasticity, less is known regarding the regulation of astrogliosis and glial scar formation after a stroke at different stages of life. Therefore, we investigated the cellular, molecular and temporal differences in chronic scar development in the infant and adult nonhuman primate (NHP) post-stroke as it bears greater clinical relevance in the close temporal and pathophysiological homology with humans. This project utilized the endothelin-1 model of focal ischemic stroke in the infant and adult primary visual cortex and investigated differences in the subacute and chronic period. We report here that the post-stroke infant neocortex generates a smaller, more discrete chronic scar, correlating to greater neuronal sparing. Reactive astrocytes that comprise the chronic scar are generated earlier in infants compared to adults, and the expression of critical markers of astrocyte reactivity differs in the subacute period between post-stroke infants and adults. Most importantly, we report that unlike adults, infant astrocyte reactivity is not dependent on several crucial regulators: signal transducer and activator of transcription 3, lipocalin2 and collagen I. Our results demonstrate that infant reactive astrocytes are not regulated by the same intrinsic and extrinsic factors that control these processes in adults, resulting in a more discrete chronic glial scar that is more permissible to neuronal sparing.