The response to injury of the cerebrum of the mature rat was studied chronologically in stereotactically placed knife wounds by using both light and electron microscopical, and immunohistochemical, techniques. Immediately after injury haematogenous cells fill the lesion and ischaemic necrosis occurs along the margins and a zone of cell swelling occupies the surrounding area. This phase is transformed by the appearance of large numbers of macrophages and fibroblasts, and some reactive astrocytes in the zone of cell swelling at 4 days. Blood vessels grow into the lesion at this time. Collagen deposition begins in the subpial region of the wound and, with time, scarring progresses into the deeper parts of the wound. By 8 days, the lesion contains a matrix of collagen fibrils, capillaries, fibroblasts, macrophages and astrocytes. The wound margins are better defined as astrocytes become aligned and secrete the basement membrane of the glia limitans, initially in the subpial regions of the scar. By 16 days, a glia limitans is complete along the margins of the entire lesion and the scar tissue between is reduced in area and contain fibroblasts, scattered macrophages, collagen fibrils and a few extra- parenchymatous astrocytes. Subsequently the scar condenses to a thin layer and becomes less vascularized; few cells remain. The persistence of astrocytes within mesenchymatous scar tissue excluded from the cerebral neuropile is a new finding. No further changes are seen in the scar after 30 days. The progressive development and maturation of scar tissue from the pial surface of the wound into the deeper regions of the cerebrum suggests that the major source of fibroblasts is from the meninges. The appearance of macrophages before fibroblasts in the wound may indicate that macrophages secrete a substance that is a trophic stimulus for fibroblasts. The organization of a glia limitans by astrocytes also proceeds inwards from the pial surface. Within the neuropile, degeneration of damaged neural elements is the prominent feature in the first 8 days after injury. Macrophages and reactive astrocytes also appear among the debris and are numerous by 4 days at the junctions of viable and necrotic neuropile. Signs of a regenerative response of neural processes is first seen at 4 days as growth cones appear in the viable neuropile at the edges of the necrotic zone. Growth cones are most numerous at 8 days. Evidence for new synapse formation is seen over the surface of dendritic swellings from 16 days onwards. Synapses of varying maturity are present, the most mature are adjacent to the dendritic shaft. This observation may suggest-that these swellings are true growth cones, in which case, this new synaptogenesis is similar to that over dendritic growth cones during development. It is not possible to judge the relative importance of either collateral sprouting or true regeneration in the reorganization of connections after injury, but neurite growth and the associated synaptogenesis described here could contribute to the recovery process. If the swellings on dendritic processes are true growth cones, then this is evidence for the regeneration of dendritic processes.
