Advances in the Mechanism of Enriched Environment Improving Chronic Cerebral Hypoperfusion-induced Cognitive Impairment

doi:10.12114/j.issn.1007-9572.2022.0122

Abstract

Abstract:

Chronic cerebral hypoperfusion-induced cognitive impairment (CCHCI) is a cognitive deficit caused by cerebral cortex or subcortical infarction, white matter degeneration, blood-cerebrospinal fluid barrier, and hippocampal injury due to long-term hypoperfusion of the brain. Clinical evidence shows that there is still no effective pharmacological treatment for CCHCI. But numerous animal studies have demonstrated that enriched environment can alleviate brain tissue damage caused by chronic hypoperfusion and promote nerve growth and functional recovery in ischemic brain areas. We reviewed the latest advances in the use of enriched environment as a non-drug intervention for CCHCI in animal models via regulating autophagy and epigenetic mechanisms to inhibit oxidative stress, protect the blood-cerebrospinal fluid barrier, promote neurovascular reconstruction and stimulate synaptic plasticity. We hope the review could provide new ideas for the treatment and clinical research of CCHCI to reverse CCHCI-induced neurological impairment and improve cognitive impairment.

Key words: Cognition disorders, Brain ischemia, Chronic hypoperfusion, Environmental enrichment, Epigenomics, Trauma, nervous system, Review

摘要：

慢性低灌注性认知障碍是因大脑长期处于低灌注状态，导致脑皮质或皮质下梗死、脑白质变性、血-脑脊液屏障及海马等损伤而出现的一种认知缺陷。目前，慢性低灌注性认知障碍在临床治疗中尚未发现有效的治疗药物。大量动物研究表明丰富环境干预能减轻慢性低灌注造成的脑组织损伤，促进缺血脑区的神经生长和功能恢复。为此，本文总结了丰富环境作为非药物干预方式通过调控细胞自噬及表观遗传机制、抑制氧化应激、保护血-脑脊液屏障、促进神经血管重建和突触可塑性的研究进展，为慢性低灌注性认知障碍的治疗及临床研究提供新的思路，逆转慢性低灌注造成的神经功能损伤，改善认知障碍。

关键词: 认知障碍, 脑缺血, 慢性低灌注, 丰富环境, 表观基因组学, 创伤，神经系统, 综述

Huanhuan LIU,Jing GAO,Kaiqi SU, et al. Advances in the Mechanism of Enriched Environment Improving Chronic Cerebral Hypoperfusion-induced Cognitive Impairment[J]. Chinese General Practice, 2022, 25(23): 2903-2909. DOI: 10.12114/j.issn.1007-9572.2022.0122.
刘环环,高静,苏凯奇等. 丰富环境对慢性低灌注性认知障碍保护作用的机制研究进展[J]. 中国全科医学, 2022, 25(23): 2903-2909. DOI: 10.12114/j.issn.1007-9572.2022.0122.

References 53

[1]	YU T W，LANE H Y，LIN C H. Novel therapeutic approaches for Alzheimer's disease：an updated review[J]. Int J Mol Sci，2021，22（15）：8208. DOI：10.3390/ijms22158208.
[2]	BHAGYA V R，SRIKUMAR B N，VEENA J，et al. Short-term exposure to enriched environment rescues chronic stress-induced impaired hippocampal synaptic plasticity，anxiety，and memory deficits[J]. J Neurosci Res，2017，95（8）：1602-1610. DOI：10.1002/jnr.23992.
[3]	ZHANG Y J，XU D，QI H，et al. Enriched environment promotes post-stroke neurogenesis through NF-κB-mediated secretion of IL-17A from astrocytes[J]. Brain Res，2018，1687：20-31. DOI：10.1016/j.brainres.2018.02.030.
[4]	ZHI X Y，FENG W Z，RONG Y G，et al. Anatomy of autophagy：from the beginning to the end[J]. Cell Mol Life Sci，2018，75（5）：815-831. DOI：10.1007/s00018-017-2657-z.
[5]	LEVINE B，KROEMER G. Biological functions of autophagy genes：a disease perspective[J]. Cell，2019，176（1/2）：11-42. DOI：10.1016/j.cell.2018.09.048.
[6]	XIA D J，SUI R B，MIN L Q，et al. Fastigial nucleus stimulation ameliorates cognitive impairment via modulating autophagy and inflammasomes activation in a rat model of vascular dementia[J]. J Cell Biochem，2019，120（4）：5108-5117. DOI：10.1002/jcb.27787.
[7]	DENG Y H，DONG L L，ZHANG Y J，et al. Enriched environment boosts the post-stroke recovery of neurological function by promoting autophagy[J]. Neural Regen Res，2021，16（5）：813-819. DOI：10.4103/1673-5374.297084.
[8]	CUI D，XU X R. DNA methyltransferases，DNA methylation，and age-associated cognitive function[J]. Int J Mol Sci，2018，19（5）：1315. DOI：10.3390/ijms19051315.
[9]	ZIMMER-BENSCH G，ZEMPEL H. DNA methylation in genetic and sporadic forms of neurodegeneration：lessons from Alzheimer's，related tauopathies and genetic tauopathies[J]. Cells，2021，10（11）：3064. DOI：10.3390/cells10113064.
[10]	REDOLAT R，MESA-GRESA P，SAMPEDRO-PIQUERO P，et al. Editorial：environmental enrichment as a treatment? epigenetic mechanisms，challenges and limitations[J]. Front Pharmacol，2021，12：658970. DOI：10.3389/fphar.2021.658970.
[11]	WANG X，CHEN A G，WU H H，et al. Enriched environment improves post-stroke cognitive impairment in mice by potential regulation of acetylation homeostasis in cholinergic circuits[J]. Brain Res，2016，1650：232-242. DOI：10.1016/j.brainres.2016.09.018.
[12]	NEIDL R，SCHNEIDER A，BOUSIGES O，et al. Late-life environmental enrichment induces acetylation events and nuclear factor κB-dependent regulations in the Hippocampus of aged rats showing improved plasticity and learning[J]. J Neurosci，2016，36（15）：4351-4361. DOI：10.1523/JNEUROSCI.3239-15.2016.
[13]	WANG X，MENG Z X，CHEN Y Z，et al. Enriched environment enhances histone acetylation of NMDA receptor in the Hippocampus and improves cognitive dysfunction in aged mice[J]. Neural Regen Res，2020，15（12）：2327-2334. DOI：10.4103/1673-5374.285005.
[14]	SHEN J，LI Y Q，QU C J，et al. The enriched environment ameliorates chronic unpredictable mild stress-induced depressive-like behaviors and cognitive impairment by activating the SIRT1/miR-134 signaling pathway in Hippocampus[J]. J Affect Disord，2019，248：81-90. DOI：10.1016/j.jad.2019.01.031.
[15]	QIAN Y，SONG J L，OUYANG Y M，et al. Advances in roles of miR-132 in the nervous system[J]. Front Pharmacol，2017，8：770. DOI：10.3389/fphar.2017.00770.
[16]	HANSEN K F，SAKAMOTO K，ATEN S，et al. Targeted deletion of miR-132 /-212 impairs memory and alters the hippocampal transcriptome[J]. Learn Mem，2016，23（2）：61-71. DOI：10.1101/lm.039578.115.
[17]	WEI Z Y，MENG X J，EL FATIMY R，et al. Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways[J]. Neurobiol Dis，2020，134：104617. DOI：10.1016/j.nbd.2019.104617.
[18]	KUBOTA K，NAKANO M，KOBAYASHI E，et al. An enriched environment prevents diabetes-induced cognitive impairment in rats by enhancing exosomal miR-146a secretion from endogenous bone marrow-derived mesenchymal stem cells[J]. PLoS One，2018，13（9）：e0204252. DOI：10.1371/journal.pone.0204252.
[19]	ERGEN F B，COSAN D T，KANDEMIR T，et al. An enriched environment leads to increased synaptic plasticity-associated miRNA levels after experimental subarachnoid hemorrhage[J]. J Stroke Cerebrovasc Dis，2021，30（6）：105766. DOI：10.1016/j.jstrokecerebrovasdis.2021.105766.
[20]	SIES H，JONES D P. Reactive oxygen species （ROS） as pleiotropic physiological signalling agents[J]. Nat Rev Mol Cell Biol，2020，21（7）：363-383. DOI：10.1038/s41580-020-0230-3.
[21]	NORMANN M C，MCNEAL N，DAGNER A，et al. The influence of environmental enrichment on cardiovascular and behavioral responses to social stress[J]. Psychosom Med，2018，80（3）：271-277. DOI：10.1097/PSY.0000000000000558.
[22]	ZHANG X X，YUAN M，YANG S B，et al. Enriched environment improves post-stroke cognitive impairment and inhibits neuroinflammation and oxidative stress by activating Nrf2-ARE pathway[J]. Int J Neurosci，2021，131（7）：641-649. DOI：10.1080/00207454.2020.1797722.
[23]	牛磊，罗诗诗，李威，等. 丰富环境通过抑制NOD样受体蛋白3炎性小体活化缓解脂多糖小鼠的认知障碍[J]. 解剖学报，2020，51（2）：172-177. DOI：10.16098/j.issn.0529-1356.2020.02.004.
[24]	LIEBNER S，DIJKHUIZEN R M，REISS Y，et al. Functional morphology of the blood-brain barrier in health and disease[J]. Acta Neuropathol，2018，135（3）：311-336. DOI：10.1007/s00401-018-1815-1.
[25]	NATION D A，SWEENEY M D，MONTAGNE A，et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction[J]. Nat Med，2019，25（2）：270-276. DOI：10.1038/s41591-018-0297-y.
[26]	QU C H，XU L L，SHEN J，et al. Protection of blood-brain barrier as a potential mechanism for enriched environments to improve cognitive impairment caused by chronic cerebral hypoperfusion[J]. Behav Brain Res，2020，379：112385. DOI：10.1016/j.bbr.2019.112385.
[27]	QU C H，SONG H，SHEN J，et al. Mfsd2a reverses spatial learning and memory impairment caused by chronic cerebral hypoperfusion via protection of the blood-brain barrier[J]. Front Neurosci，2020，14：461. DOI：10.3389/fnins.2020.00461.
[28]	ZHAN Y，LI M Z，YANG L，et al. The three-phase enriched environment paradigm promotes neurovascular restorative and prevents learning impairment after ischemic stroke in rats[J]. Neurobiol Dis，2020，146：105091. DOI：10.1016/j.nbd.2020.105091.
[29]	MA Q，REITER R J，CHEN Y D. Role of melatonin in controlling angiogenesis under physiological and pathological conditions[J]. Angiogenesis，2020，23（2）：91-104. DOI：10.1007/s10456-019-09689-7.
[30]	GUO D X，ZHU Z B，ZHONG C K，et al. Increased serum netrin-1 is associated with improved prognosis of ischemic stroke[J]. Stroke，2019，50（4）：845-852. DOI：10.1161/STROKEAHA.118.024631.
[31]	RUST R，GRÖNNERT L，WEBER R Z，et al. Refueling the ischemic CNS：guidance molecules for vascular repair[J]. Trends Neurosci，2019，42（9）：644-656. DOI：10.1016/j.tins.2019.05.006.
[32]	XIE Q F，CHENG J Y，PAN G Y，et al. Treadmill exercise ameliorates focal cerebral ischemia/reperfusion-induced neurological deficit by promoting dendritic modification and synaptic plasticity via upregulating caveolin-1/VEGF signaling pathways[J]. Exp Neurol，2019，313：60-78. DOI：10.1016/j.expneurol.2018.12.005.
[33]	HAYASHI Y，JINNOU H，SAWAMOTO K，et al. Adult neurogenesis and its role in brain injury and psychiatric diseases[J]. J Neurochem，2018，147（5）：584-594. DOI：10.1111/jnc.14557.
[34]	LU J，XU S W，HUO Y Q，et al. Sorting nexin 3 induces heart failure via promoting retromer-dependent nuclear trafficking of STAT3[J]. Cell Death Differ，2021，28（10）：2871-2887. DOI：10.1038/s41418-021-00789-w.
[35]	WU X Y，LIU S Q，HU Z H，et al. Enriched housing promotes post-stroke neurogenesis through calpain 1-STAT3/HIF-1α/VEGF signaling[J]. Brain Res Bull，2018，139：133-143. DOI：10.1016/j.brainresbull.2018.02.018.
[36]	OLDE ENGBERINK A，HERNANDEZ R，DE GRAAN P，et al. Rapamycin-sensitive late-LTP is enhanced in the Hippocampus of IL-6 transgenic mice[J]. Neuroscience，2017，367：200-210. DOI：10.1016/j.neuroscience.2017.10.040.
[37]	OHLINE S M，ABRAHAM W C. Environmental enrichment effects on synaptic and cellular physiology of hippocampal neurons[J]. Neuropharmacology，2019，145（Pt A）：3-12. DOI：10.1016/j.neuropharm.2018.04.007.
[38]	DANDI Ε，KALAMARI A，TOULOUMI O，et al. Beneficial effects of environmental enrichment on behavior，stress reactivity and synaptophysin/BDNF expression in Hippocampus following early life stress[J]. Int J Dev Neurosci，2018，67：19-32. DOI：10.1016/j.ijdevneu.2018.03.003.
[39]	CORDIER J M，AGUGGIA J P，DANELON V，et al. Postweaning enriched environment enhances cognitive function and brain-derived neurotrophic factor signaling in the Hippocampus in maternally separated rats[J]. Neuroscience，2021，453：138-147. DOI：10.1016/j.neuroscience.2020.09.058.
[40]	SKOWRONSKA K，OBARA-MICHLEWSKA M，CZARNECKA A，et al. Persistent overexposure to N-methyl-D-aspartate （NMDA） calcium-dependently downregulates glutamine synthetase，aquaporin 4，and Kir4.1 channel in mouse cortical astrocytes[J]. Neurotox Res，2019，35（1）：271-280. DOI：10.1007/s12640-018-9958-3.
[41]	HANADA T. Ionotropic glutamate receptors in epilepsy：a review focusing on AMPA and NMDA receptors[J]. Biomolecules，2020，10（3）：E464. DOI：10.3390/biom10030464.
[42]	ZHANG X，SHI X H，WANG J Q，et al. Enriched environment remedies cognitive dysfunctions and synaptic plasticity through NMDAR-Ca²⁺-Activin A circuit in chronic cerebral hypoperfusion rats[J]. Aging （Albany NY），2021，13（16）：20748-20761. DOI：10.18632/aging.203462.
[43]	HOSSAIN M F，WANG N，CHEN R J，et al. Exploring the multifunctional role of melatonin in regulating autophagy and sleep to mitigate Alzheimer's disease neuropathology[J]. Ageing Res Rev，2021，67：101304. DOI：10.1016/j.arr.2021.101304.
[44]	ADAMS J N，LOCKHART S N，LI L X，et al. Relationships between tau and glucose metabolism reflect Alzheimer's disease pathology in cognitively normal older adults[J]. Cereb Cortex，2018，29（5）：1997-2009. DOI：10.1093/cercor/bhy078.
[45]	GRIÑáN-FERRé C，IZQUIERDO V，OTERO E，et al. Environmental enrichment improves cognitive deficits，AD hallmarks and epigenetic alterations presented in 5xFAD mouse model[J]. Front Cell Neurosci，2018，12：224. DOI：10.3389/fncel.2018.00224.
[46]	NAKANO M，KUBOTA K，HASHIZUME S，et al. An enriched environment prevents cognitive impairment in an Alzheimer's disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus[J]. Brain Behav Immun Health，2020，9：100149. DOI：10.1016/j.bbih.2020.100149.
[47]	JANKOWSKY J L，XU G L，FROMHOLT D，et al. Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease[J]. J Neuropathol Exp Neurol，2003，62（12）：1220-1227. DOI：10.1093/jnen/62.12.1220.
[48]	SALMIN V V，KOMLEVA Y K，KUVACHEVA N V，et al. Differential roles of environmental enrichment in Alzheimer's type of neurodegeneration and physiological aging[J]. Front Aging Neurosci，2017，9：245. DOI：10.3389/fnagi.2017.00245.
[49]	BEN-ARI H，LIFSCHYTZ T，WOLF G，et al. White matter lesions，cerebral inflammation and cognitive function in a mouse model of cerebral hypoperfusion[J]. Brain Res，2019，1711：193-201. DOI：10.1016/j.brainres.2019.01.017.
[50]	ZHOU T T，LIN L，HAO C Z，et al. Environmental enrichment rescues cognitive impairment with suppression of TLR4-p38MAPK signaling pathway in vascular dementia rats[J]. Neurosci Lett，2020，737：135318. DOI：10.1016/j.neulet.2020.135318.
[51]	SONG M K，KIM Y J，LEE J M，et al. Neurovascular integrative effects of long-term environmental enrichment on chronic cerebral hypoperfusion rat model[J]. Brain Res Bull，2020，163：160-169. DOI：10.1016/j.brainresbull.2020.07.020.
[52]	SIMON R，MELLER R，YANG T，et al. Enhancing base excision repair of mitochondrial DNA to reduce ischemic injury following reperfusion[J]. Transl Stroke Res，2019，10（6）：664-671. DOI：10.1007/s12975-018-0680-5.
[53]	YUAN M，ZHANG X X，FU X C，et al. Enriched environment alleviates post-stroke cognitive impairment through enhancing α7-nAChR expression in rats[J]. Arq Neuropsiquiatr，2020，78（10）：603-610. DOI：10.1590/0004-282X20200081.