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.

Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke.

BACKGROUND AND PURPOSE: Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke. METHODS: We tested the efficacy of acute (1.5 hours) or delayed (1-3 days) poststroke intravenous injection of hAECs in 4 established animal models of cerebral ischemia. Animals included young (7-14 weeks) and aged mice (20-22 months) of both sexes, as well as adult marmosets of either sex. RESULTS: We found that hAECs administered 1.5 hours after stroke in mice migrated to the ischemic brain via a CXC chemokine receptor type 4-dependent mechanism and reduced brain inflammation, infarct development, and functional deficits. Furthermore, if hAECs administration was delayed until 1 or 3 days poststroke, long-term functional recovery was still augmented in young and aged mice of both sexes. We also showed proof-of-principle evidence in marmosets that acute intravenous injection of hAECs prevented infarct development from day 1 to day 10 after stroke. CONCLUSIONS: Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery.

MRI-guided stereotaxic brain surgery in the infant and adult common marmoset.

In the past decade, the New World common marmoset (Callithrix jacchus) has taken a seminal position in neurobiological research, fueled in part by its smooth cortical sheet, which allows cortical areas to be easily accessed by current technologies on the dorsal surface of the brain. In this protocol, we describe a method for the precision placement of agents (e.g., tracers or neurotoxins) into small brain regions of the infant and adult marmoset, using an MRI-guided approach. This strategy uses a protocol for prolonged anesthesia without the need for intubation that we have recently developed, alongside appropriate analgesia and monitoring. The protocol can be readily adapted to be used together with advanced research techniques, such as two-photon microscopy and optical imaging. Including a 5-d postoperative care plan, this protocol takes 7 d to complete. The protocol requires a team of personnel experienced in marmoset care and handling, and small-animal neurosurgery; an assistant for monitoring the animal and assisting with anesthesia; and an MRI technician.

Physiological responses of New World monkey V1 neurons to stimuli defined by coherent motion.

We studied the responses of neurons in area V1 of marmosets to visual stimuli that moved against dynamic textured backgrounds. The stimuli were defined either by a first-order cue ('solid' bars, which were either darker or lighter than the background) or by a second-order cue ('camouflaged' bars, defined only by coherent motion). Forty-two per cent of the neurons demonstrated a similar selectivity for the direction of motion of the solid and camouflaged bars, thereby characterizing a population of cue-invariant (CI) cells. The other cells either showed different selectivity to the movement of solid and camouflaged bars (non-cue-invariant, or NCI cells), or responded equally well to movement in all directions. CI neurons, which were rare in layer 4, tended to have larger receptive fields and to be more strongly direction selective than NCI cells. Although V1 neurons tended to show maximal responses to camouflaged bars that were longer than the 'optimal' solid bars, many CI neurons preferred first- and second-order stimuli of similar lengths. Finally, the activity evoked by the camouflaged bars was delayed in relation to that evoked by solid bars. These results demonstrate that motion CI responses are relatively common in primate V1, especially among a population of strongly direction-selective neurons. They also indicate that this response property may depend on feedback from extrastriate areas, or on complex intrinsic interactions within V1.