18 involving different cell types might thus stimulate reactive astrocytes to produce potentially cytotoxic levels of mole- cules or might lead to chronic inﬂammation or neuropathic pain. A greater understanding of such combinatorial signaling could facilitate targeted therapeutic strategies that preserve the beneﬁcial and attenuate the potentially detri- mental aspects of reactive astrogliosis. In this regard, it will also be interesting in future studies to look for genetic polymorphisms that may alter reactive astrocyte functions in certain individuals and thereby predispose them to certain disease processes. Molecular dissection of reactive astrogliosis using transgenic technologies Many experimental investigations of mechanisms and functions of reactive astrogliosis and glial scar formation make use of transgenic technologies combined with experimental animal models, which has revolutionized the study of neural injury and disease by allowing in vivo dissection of molecular and cellular mechanisms [226]. Nevertheless, in interpreting results derived from studies using transgenic mice it is important to understand asso- ciated caveats [226]. For example, different promoters (human or mouse GFAP, GLAST, etc.) may have different targeting properties/efﬁciencies as regards astrocytes and related cells. Although not all astrocytes express GFAP or GFAP-regulated transgenes in healthy tissue, most if not all appear to do so after CNS injury or other insults [33, 95, 251]. It is essential that authors deﬁne transgene expression levels individually and speciﬁcally in every tissue region and experimental model being studied, as well as control for any possible confounding effects that may result from transgene expression in other cells both within and outside of the CNS [33, 95, 226, 251]. Astrocyte appearance and roles in CNS disorders and pathology CNS trauma Traumatic brain and spinal cord injury are major causes of premature death, permanent physical disability, or long- lasting neuropsychiatric impairment [138]. Reactive as- trogliosis and glial scar formation are prominent features of CNS trauma and are increasingly implicated as playing important roles in determining long-term clinical outcome [41, 226]. The appearance of reactive astrogliosis after CNS trauma (whether in the brain or spinal cord) varies with the (1) type of the trauma, i.e., whether it is pene- trating, contusional, or diffuse (as in the case of diffuse axonal injury), (2) severity of the trauma, (3) length of time 123 Acta Neuropathol (2010) 119:7–35 that has elapsed between injury and biopsy or autopsy, and (4) distance of the tissue examined from the site of injury/ trauma. The same specimen may exhibit different severi- ties of reactive astrogliosis in different locations, such as a distinct glial scar along areas of damaged tissue after penetrating or severe contusive trauma (Fig. 4d), which may be surrounded by areas of decreasing severity of reactive astrogliosis (Fig. 4c) as distance away from the lesion center increases (Fig. 4b). Tissue at a considerable distance from the site of direct injury may show sequelae of transient edema and/or downstream effects such as Wal- lerian or trans-synaptic degeneration, or a combination of the two, signiﬁcantly contributing to neurologic disability. Severe reactive astrogliosis and glial scar formation at sites of CNS trauma are well documented to inhibit axonal regeneration [219] and are widely regarded as detrimental to clinical outcome. Nevertheless, recent studies using transgenic mouse models indicate that scar-forming reac- tive astrocytes exert essential neuroprotective functions after both brain and spinal cord trauma [33, 68, 95, 144, 175, 226] as discussed earlier. Diffuse traumatic brain injury can lead to mild or moderate diffuse astrogliosis without obvious scar forma- tion, in which reactive astrocytes hypertrophy and up regulate gene expression, including GFAP, but in which there is little or no loss of individual astrocyte domains (Figs. 3b, 4b). In animal experiments, mild to moderate reactive astrogliosis of this type exhibits the potential for resolution [226], but the functional consequences of these changes are not well understood. A cerebral concussion almost certainly impacts on astrocyte structure and func- tion, but such injury is not life threatening, results in minimal if any abnormalities on neuroimaging, and is thus (by deﬁnition) not usually the subject of neuropathological review or investigation. Stroke and cerebrovascular disease Brain parenchyma and the blood vessels that supply it are not, as they once were, viewed as separate ‘compartments’ within the CNS. Rather, the concept of the ‘neurovascular unit’ takes an integrated view of a given brain parenchymal blood vessel and the glial elements that surround it [38, 139, 206]. Cellular elements in the vessel wall inﬂuence surrounding CNS parenchyma, just as the surrounding parenchymal elements affect vascular morphology and function. The ‘neurovascular unit’ idea becomes especially important when considering functional recovery after an ischemic infarct or ‘stroke’. From a practical diagnostic perspective, the appearance of astrocytes around a region of cystic encephalomalacia within brain that has resulted from an ischemic infarct or hemorrhage can be used to ‘date’ such a lesion (i.e.,