Degeneration and regeneration of the nervous system

Macrophages dominate sites of CNS injury in which they promote both injury and repair. These divergent effects may be caused by distinct macrophage subsets, i.e., "classically activated" proinflammatory (M1) or "alternatively activated" anti-inflammatory (M2) cells. Here, we show that an M1 macrophage response is rapidly induced and then maintained at sites of traumatic spinal cord injury and that this response overwhelms a comparatively smaller and transient M2 macrophage response. The high M1/M2 macrophage ratio has significant implications for CNS repair. Indeed, we present novel data showing that only M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth response in adult sensory axons, even in the context of inhibitory substrates that dominate sites of CNS injury (e.g., proteoglycans and myelin). Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or "alternatively" activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.

https://www.jneurosci.org/content/jneuro/29/43/13435.full.pdf

Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord.

Redox signaling: nitrosylation and related target interactions of nitric oxide.

Reaching and grasping in primates depend on the coordination of neural activity in large frontoparietal ensembles. Here we demonstrate that primates can learn to reach and grasp virtual objects by controlling a robot arm through a closed-loop brain–machine interface (BMIc) that uses multiple mathematical models to extract several motor parameters (i.e., hand position, velocity, gripping force, and the EMGs of multiple arm muscles) from the electrical activity of frontoparietal neuronal ensembles. As single neurons typically contribute to the encoding of several motor parameters, we observed that high BMIc accuracy required recording from large neuronal ensembles. Continuous BMIc operation by monkeys led to significant improvements in both model predictions and behavioral performance. Using visual feedback, monkeys succeeded in producing robot reach-and-grasp movements even when their arms did not move. Learning to operate the BMIc was paralleled by functional reorganization in multiple cortical areas, suggesting that the dynamic properties of the BMIc were incorporated into motor and sensory cortical representations.

https://www.ai.rug.nl/~lambert/projects/BCI/literature/serious/invasive/neural-implants-plbi-01-02-carmena.pdf

Learning to Control a Brain–Machine Interface for Reaching and Grasping by Primates

https://www.cell.com/cell/pdf/0092-8674(94)90267-4.pdf

NO at work

Although maturing neurons undergo a precipitous decline in the expression of genes associated with developmental axon growth, structural changes in axon arbors occur in the adult nervous system under both normal and pathological conditions. Furthermore, some neurons support extensive regrowth of long axons after nerve injury. Analysis of adult dorsal root ganglion (DRG) neurons in culture now shows that competence for distinct types of axon growth depends on different patterns of gene expression. In the absence of ongoing transcription, newly isolated neurons can extend compact, highly branched arbors during the first day in culture. Neurons subjected to peripheral axon injury 2–7 d before plating support a distinct mode of growth characterized by rapid extension of long, sparsely branched axons. A transition from “arborizing” to “elongating” growth occurs in naive adult neurons after ∼24 hr in culture but requires a discrete period of new transcription after removal of the ganglia from the intact animal. Thus, peripheral axotomy—by nerve crush or during removal of DRGs—induces a transcription-dependent change that alters the type of axon growth that can be executed by these adult neurons. This transition appears to be triggered, in large part, by interruption of retrogradely transported signals, because blocking axonal transportin vivo can elicit competence for elongating growth in many DRG neurons. In contrast to peripheral axotomy, interruption of the centrally projecting axons of DRG neurons in vivoleads to subsequent growth in vitro that is intermediate between “arborizing” and “elongating” growth. This suggests that the transition between these two modes of growth is a multistep process and that individual steps may be regulated separately. These observations together suggest that structural remodeling in the adult nervous system need not involve the same molecular apparatus as long axon growth during development and regeneration.

https://www.jneurosci.org/content/jneuro/17/2/646.full.pdf

A Transcription-Dependent Switch Controls Competence of Adult Neurons for Distinct Modes of Axon Growth

Outgrowth of distinct axonal and dendritic processes is essential for the development of the functional polarity of nerve cells. In cultures of neurons from the hippocampus, where the differential outgrowth of axons and dendrites is readily discernible, we have sought molecules that might underlie the distinct modes of elongation of these two types of processes. One particularly interesting protein is GAP-43 (also termed B-50, F1 or P-57), a neuron-specific, membrane-associated phosphoprotein whose expression is dramatically elevated during neuronal development and regeneration. GAP-43 is among the most abundant proteins in neuronal growth cones, the motile structures that form the tips of advancing neurites, but its function in neuronal growth remains unknown. Using immunofluorescence staining, we show that GAP-43 is present in axons and concentrated in axonal growth cones of hippocampal neurons in culture. Surprisingly, we could not detect GAP-43 in growing dendrites and dendritic growth cones. These results show that GAP-43 is compartmentalized in developing nerve cells and provide the first direct evidence of important molecular differences between axonal and dendritic growth cones. The sorting and selective transport of GAP-43 may give axons and axonal growth cones certain of their distinctive properties, such as the ability to grow rapidly over long distances or the manner in which they recognize and respond to cues in their environment.

Development of neuronal polarity: GAP-43 distinguishes axonal from dendritic growth cones

https://www.cell.com/cell/pdf/0092-8674(87)90616-7.pdf

Primary structure and transcriptional regulation of GAP-43, a protein associated with nerve growth

In contrast to peripheral nerves, damaged axons in the mammalian brain and spinal cord rarely regenerate. Peripheral nerve injury stimulates neuronal expression of many genes that are not generally induced by CNS lesions, but it is not known which of these genes are required for regeneration. Here we show that co-expressing two major growth cone proteins, GAP-43 and CAP-23, can elicit long axon extension by adult dorsal root ganglion (DRG) neurons in vitro. Moreover, this expression triggers a 60-fold increase in regeneration of DRG axons in adult mice after spinal cord injury in vivo. Replacing key growth cone components, therefore, could be an effective way to stimulate regeneration of CNS axons.

Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons.

Nitric oxide, a free-radical gas produced endogenously by several mammalian cell types, has been implicated as a diffusible intercellular messenger subserving use-dependent modification of synaptic efficacy in the mature central nervous system. It has been suggested on theoretical grounds that nitric oxide might play an analogous role during the establishment of ordered connections by developing neurons. We report here that nitric oxide rapidly and reversibly inhibits growth of neurites of rat dorsal root ganglion neurons in vitro. In addition, we show that exposure to nitric oxide inhibits thioester-linked long-chain fatty acylation of neuronal proteins, possibly through a direct modification of substrate cysteine thiols. Our results demonstrate a potential role for nitric oxide in the regulation of process outgrowth and remodelling during neuronal development, which may be effected at least in part through modulation of dynamic protein fatty acylation in neuronal growth cones.

J. H. Pate Skene

Papers

A Transcription-Dependent Switch Controls Competence of Adult Neurons for Distinct Modes of Axon Growth

Development of neuronal polarity: GAP-43 distinguishes axonal from dendritic growth cones

Primary structure and transcriptional regulation of GAP-43, a protein associated with nerve growth

Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons.

Neuronal growth cone collapse and inhibition of protein fatty acylation by nitric oxide