Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

/pdf/astrocytes-biology-and-pathology-2hq13zf0bo.pdf

Astrocytes: biology and pathology

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

Drug addiction, dysregulation of reward, and allostasis.

Adolescence is a developmental period characterized by suboptimal decisions and actions that are associated with an increased incidence of unintentional injuries, violence, substance abuse, unintended pregnancy, and sexually transmitted diseases. Traditional neurobiological and cognitive explanations for adolescent behavior have failed to account for the nonlinear changes in behavior observed during adolescence, relative to both childhood and adulthood. This review provides a biologically plausible model of the neural mechanisms underlying these nonlinear changes in behavior. We provide evidence from recent human brain imaging and animal studies that there is a heightened responsiveness to incentives and socioemotional contexts during this time, when impulse control is still relatively immature. These findings suggest differential development of bottom-up limbic systems, implicated in incentive and emotional processing, to top-down control systems during adolescence as compared to childhood and adulthood. This developmental pattern may be exacerbated in those adolescents prone to emotional reactivity, increasing the likelihood of poor outcomes.

The Adolescent Brain

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

https://pharmrev.aspetjournals.org/content/pharmrev/52/3/415.full.pdf

International Union of Pharmacology. XXIII. The Angiotensin II Receptors

Regulation of inositol transport by glucose and protein kinase C in mesangial cells

Background: Acute and chronic ethanol exposure has been found to decrease hippocampal neurogenesis, reduce dendritic differentiation of new neurons, and increase cell death Interestingly, abstinence from such treatment increases hippocampal neurogenesis and microglial genesis across several brain regions The goal of the current investigation was to study cellular alterations on neuro- and cell-genesis during abstinence following alcohol self-administration using alcoholpreferring rats (P rats) Methods: Male and female P rats were given the choice of drinking 10% alcohol in water or pure water for 7 weeks Social interaction behavioral assessments were conducted at 5 hours upon removal of alcohol, followed by bromo-deoxyuridine (BrdU, 150 mg ⁄ kg · 1 ⁄ d · 14 d) injections to label proliferating cells Animals were then killed 4 weeks later to conduct immunohistochemical and confocal analyses using antibodies against BrdU and other phenotypic markers (NeuN for mature neurons; Iba-1 for microglia; GFAP for astrocytes; and NG2 for oligodendrocyte progenitors) Results: Mild alcohol withdrawal anxiety was detected by reduction in social interactions The number of hippocampal BrdU + cells was increased approximately 50% during alcohol abstinence (26 ± 28 in controls vs 39 ± 4 in alcohol group) BrdU + cells were also increased in the substantia nigra (SN) approximately 65% in the alcohol abstinent group (12 ± 1 in controls vs 19 ± 15 in alcohol group) No gender differences were found Confocal analyses indicated that approximately 75% of co-localization of BrdU + cells with NeuN in the hippocampal dentate gyrus (DG) resulting a net increase in neurogenesis in the alcohol abstinent group compared to controls In cingulum, greater proportion of BrdU + cells were co-localized with NG2 in the alcohol abstinent group indicating increased differentiation toward oligodendrocyte progenitors in both genders However, the phenotype of the BrdU + cells in SN and other brain regions were not identified by NeuN, Iba-1, GFAP, or NG2 suggesting that these BrdU + cells probably remain in a nondifferentiated stage Conclusions: These data indicate that abstinence from moderate alcohol drinking increases hippocampal neurogenesis, cingulate NG2 differentiation, and SN undifferentiated cell proliferation in both males and females Such cellular alteration during abstinence could contribute to the spontaneous partial restoration of cognitive deficits upon sobriety

Abstinence from moderate alcohol self-administration alters progenitor cell proliferation and differentiation in multiple brain regions of male and female P rats.

Neurogenesis in hippocampal dentate gyrus (DG) and subventricular zone (SVZ) matures during adolescence to adult levels. Binge drinking is prevalent in adolescent humans, and could alter brain neurogenesis and maturation in a manner that persists into adulthood. To determine the impact of adolescent binge drinking on adult neurogenesis, Wistar rats received adolescent intermittent ethanol (AIE) exposure (5.0 g/kg/day, i.g., 2 days on/2 days off from postnatal day, P25-P54) and sacrificed on P57 or P95. Neural progenitor cell proliferation, differentiation, survival and maturation using immunohistochemistry was determined in the DG and SVZ. We found that AIE exposure decreased neurogenesis in both brain regions in adulthood (P95). In the DG at P57, AIE exposure resulted in a significant reduction of SOX2+, Tbr2+, Prox1+ and parvalbumin+IR expression, and at P95 decreased DCX+ and parvalbumin+IR expression. AIE exposure also reduced the expression of two cell proliferation markers (Ki67+ and BrdU+IR with 300 mg/kg, 2 hours) at P95. The immune signaling molecule -2 microglobulin+ and the cell death marker activated caspase-3+IR were significantly increased in the DG by AIE exposure. In the SVZ, AIE exposure decreased SOX2+, Mash1+, DCX+ and Dlx2+IR expression at P95, but not at P57. Thus, in adulthood both brain regions have reduced neurogenesis following AIE exposure. To assess progenitor cell survival and maturation, rats were treated with BrdU (150 mg/kg/day, 14 days) to label proliferating cells and were sacrificed weeks later on P95. In the hippocampus DG, AIE exposure increased survival BrdU+ cells which differentiated into Iba1+ microglia. In contrast, SVZ had decreased BrdU+ cells similar to decreased DCX+ neurogenesis. These data indicate that AIE exposure causes a lasting decrease in both adult hippocampal DG and forebrain SVZ neurogenesis with brain regional differences in the AIE response that persist into adulthood.

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Fulton T. Crews

Papers

Regulation of inositol transport by glucose and protein kinase C in mesangial cells

Abstinence from moderate alcohol self-administration alters progenitor cell proliferation and differentiation in multiple brain regions of male and female P rats.

Persistent Decreases in Adult Subventricular and Hippocampal Neurogenesis Following Adolescent Intermittent Ethanol Exposure.

Age dependent changes in the methylation of rat brain phospholipids.

Neuroimmune and epigenetic mechanisms underlying persistent loss of hippocampal neurogenesis following adolescent intermittent ethanol exposure.