Loss of Basal Forebrain Cholinergic Neurons Following Adolescent Binge Ethanol Exposure: Recovery With the Cholinesterase Inhibitor Galantamine.
Loss of Basal Forebrain Cholinergic Neurons Following Adolescent Binge Ethanol Exposure: Recovery With the Cholinesterase Inhibitor Galantamine.
复制标题
青少年酗酒暴露后基底前脑胆碱能神经元的丢失：用胆碱酯酶抑制剂加兰他敏恢复。
DOI：
10.3389/fnbeh.2021.652494
复制
发表时间：
2021
影响因子：
3
通讯作者：
Vetreno RP
中科院分区：
文献类型：
--
作者：
Crews FT;Fisher R;Deason C;Vetreno RP
酗酒和酗酒在青少年时期很常见，在成人基底前脑引起认知缺陷和持久的胆碱能病理。乙酰胆碱具有抗炎作用，使用临床前青少年间歇乙醇（AIE; 5.0 g/kg, ig，产后2天开/休息2天[P]25 ~ P54）人类青少年狂饮模型的研究报告显示，乙酰胆碱减少了基底前脑胆碱能神经元（BFCNs），并诱导了持续到成年的促炎基因。最近的研究将aie诱导的神经免疫激活与胆碱能病理联系起来，但导致BFCNs持续丢失的潜在机制尚不清楚。我们报告说，在AIE期间（即P25-P54）或AIE结束后（即P57-P72）给予胆碱酯酶抑制剂加兰他明（4.0 mg/kg, i.p）治疗恢复了胆碱能神经元表型标记物（即ChAT， TrkA和p75NTR）的持续丢失，以及已知在AIE暴露的成年人中持续存在的残余ChAT +神经元的染色体萎缩。加兰他明治疗也恢复了aie -促炎受体TLR4和RAGE，内源性TLR4/RAGE激动剂HMGB1和转录激活标记物pNF-κB p65的表达增加。有趣的是，我们发现BFCNs表达TLR4和RAGE， AIE治疗增加了成人ChAT + IR神经元中pNF-κB p65的表达，这与BFCNs内细胞内HMGB1-TLR4/RAGE信号传导一致。AIE增加了成人基底前脑的表观遗传转录沉默标记（即H3K9me2和H3K9me3）和H3K9me2在胆碱能表型基因启动子（即ChAT和TrkA）上的占用。加兰他明逆转AIE诱导的ChAT +神经元丢失、TLR4/RAGE-pNF-κB p65信号和表观遗传转录沉默标记物，AIE未引起基底前脑NeuN +神经元总数的变化，提示AIE不会导致细胞死亡，而是胆碱能表型的丧失。综上所述，这些数据表明AIE通过表观遗传组蛋白转录沉默诱导HMGB1-TLR4/RAGE-pNF-κB p65信号，导致胆碱能表型（即ChAT、TrkA和p75NTR）的丧失，从而导致可通过加兰他明预防和恢复的BFCN表型的丧失。
Binge drinking and alcohol abuse are common during adolescence and cause both cognitive deficits and lasting cholinergic pathology in the adult basal forebrain. Acetylcholine is anti-inflammatory and studies using the preclinical adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2 day on/2 day off from postnatal day [P]25 to P54) model of human adolescent binge drinking report decreased basal forebrain cholinergic neurons (BFCNs) and induction of proinflammatory genes that persist long into adulthood. Recent studies link AIE-induced neuroimmune activation to cholinergic pathology, but the underlying mechanisms contributing to the persistent loss of BFCNs are unknown. We report that treatment with the cholinesterase inhibitor galantamine (4.0 mg/kg, i.p.) administered during AIE (i.e., P25–P54) or following the conclusion of AIE (i.e., P57–P72) recovered the persistent loss of cholinergic neuron phenotype markers (i.e., ChAT, TrkA, and p75NTR) and somal shrinkage of residual ChAT + neurons known to persist in AIE-exposed adults. Galantamine treatment also recovered the AIE-increased expression of the proinflammatory receptors TLR4 and RAGE, the endogenous TLR4/RAGE agonist HMGB1, and the transcription activation marker pNF-κB p65. Interestingly, we find BFCNs express TLR4 and RAGE, and that AIE treatment increased pNF-κB p65 expression in adult ChAT + IR neurons, consistent with intracellular HMGB1-TLR4/RAGE signaling within BFCNs. AIE increased epigenetic transcription silencing markers (i.e., H3K9me2 and H3K9me3) in the adult basal forebrain and H3K9me2 occupancy at cholinergic phenotype gene promoters (i.e., ChAT and TrkA). The finding of no AIE-induced changes in total basal forebrain NeuN + neurons with galantamine reversal of AIE-induced ChAT + neuron loss, TLR4/RAGE-pNF-κB p65 signals, and epigenetic transcription silencing markers suggests that AIE does not cause cell death, but rather the loss of the cholinergic phenotype. Together, these data suggest that AIE induces HMGB1-TLR4/RAGE-pNF-κB p65 signals, causing the loss of cholinergic phenotype (i.e., ChAT, TrkA, and p75NTR) through epigenetic histone transcription silencing that result in the loss of the BFCN phenotype that can be prevented and restored by galantamine.
登录
查看更多内容
影响因子：
4.6
作者：
Fujita K;Motoki K;Tagawa K;Chen X;Hama H;Nakajima K;Homma H;Tamura T;Watanabe H;Katsuno M;Matsumi C;Kajikawa M;Saito T;Saido T;Sobue G;Miyawaki A;Okazawa H
通讯作者：
Okazawa H
青少年暴饮暴食改变了小鼠的成人脑神经递质的表达，行为，大脑区域体积和神经化学。
DOI：
10.1111/j.1530-0277.2010.01385.x
发表时间：
2011-04
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Coleman LG Jr;He J;Lee J;Styner M;Crews FT
通讯作者：
Crews FT
影响因子：
10.6
作者：
Crews, Fulton T.;Qin, Liya;Sheedy, Donna;Vetreno, Ryan P.;Zou, Jian
通讯作者：
Zou, Jian
影响因子：
10.5
作者：
Berger, Shelley L.;Kouzarides, Tony;Shilatifard, Ali
通讯作者：
Shilatifard, Ali
DOI：
10.1007/7854_2016_467
发表时间：
2018-01-01
期刊：
BEHAVIORAL NEUROSCIENCE OF LEARNING AND MEMORY
影响因子：
--
作者：
Blake, M. G.;Boccia, M. M.
通讯作者：
Boccia, M. M.