内侧隔核注射淀粉样β蛋白损害大鼠的长时程增强和认知行为（英文）
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摘要
胆碱能神经元的逐渐丢失和进行性认知功能障碍是阿尔茨海默病(Alzheimer’s disease,AD)的主要特征。脑内胆碱能神经元集中分布的区域之一是基底前脑的内侧隔核(medial septum,MS),其发出投射纤维至海马。尽管AD患者和动物模型脑内淀粉样β蛋白(amyloidβprotein,Aβ)的神经毒性包括特异性损伤胆碱能神经系统的作用已被广泛报道,但仍不清楚聚集在MS的Aβ是否会影响海马突触可塑性,进而影响学习记忆行为。本研究采用Morris水迷宫、Y型迷宫和在体海马长时程增强(long-term potentiation,LTP)记录,观察了MS注射Aβ对大鼠海马LTP及认知行为的影响,同时还以能特异性损伤γ氨基丁酸(γ-aminobutyric acid,GABA)能神经元的海人藻酸(kainic acid,KA)作为对照,进行了效应比较。结果显示:(1)MS注射Aβ_(25–35),而非KA,明显损伤了大鼠在经典Morris水迷宫和对位水迷宫中的空间学习记忆能力;(2)MS注射Aβ_(25–35)和KA均损害了大鼠在Y迷宫中的新异环境探索能力;(3)MS注射Aβ_(25–35),而非KA,明显抑制了大鼠海马CA1区在体LTP;(4)Aβ_(25–35)和KA均未影响大鼠在行为学测试中的运动能力和电生理记录中的海马CA1区双脉冲易化(paired-pulse facilitation,PPF)。以上结果表明,MS注射Aβ能够损伤大鼠空间学习记忆能力、学习记忆灵活性和探索行为,并压抑海马LTP。结合以往研究,本研究提示:MS的胆碱能神经元及其海马投射可能是AD病程中受Aβ神经毒性作用损害的主要细胞和组织,选择性损伤MS中的胆碱能神经元会导致AD病程中的海马突触可塑性损伤和认知功能伤害。
The specific loss of cholinergic neurons and the progressive deficits of cognitive function are the most primary characteristics of Alzheimer's disease(AD). Although the neurotoxicity of amyloid β protein(Aβ) in AD has been investigated extensively, it is still unclear whether the Aβ aggregated in the medial septum(MS), a major cholinergic nucleus projecting to the hippocampus, could affect hippocampal synaptic plasticity and further impair the memory behaviors. The present study investigated the effects of Aβ injection into the MS on hippocampal long-term potentiation(LTP) and cognitive behaviors of rats by using Morris water maze(MWM), Y maze and in vivo hippocampal LTP recording. The effects of kainic acid(KA), an agent with specific neurotoxicity to GABAergic neurons, were also observed. The results showed that:(1) Intra-MS injection of Aβ_(25–35), not KA, impaired spatial learning and memory of rats in classical and reversal MWM tests;(2) Both Aβ_(25–35) and KA impaired novelty-seeking behavior of rats in Y maze;(3) Intra-MS injection of Aβ_(25–35), not KA, suppressed in vivo hippocampal LTP in the CA1 region of rats;(4) Both Aβ_(25–35) and KA did not affect the motor ability in behavioral tests and the hippocampal paired-pulse facilitation(PPF) in electrophysiological recording. These results indicate that intra-MS injection of Aβ could impair spatial memory, cognitive flexibility and exploratory motivation, as well as hippocampal LTP in rats, suggesting that the cholinergic neurons in the MS and the septo-hippocampal projection could be important targets of neurotoxic Aβ, and the specific damage of cholinergic neurons in the MS is likely responsible for the impairments of hippocampal synaptic plasticity and cognitive function in AD.
The specific loss of cholinergic neurons and the progressive deficits of cognitive function are the most primary characteristics of Alzheimer's disease(AD). Although the neurotoxicity of amyloid β protein(Aβ) in AD has been investigated extensively, it is still unclear whether the Aβ aggregated in the medial septum(MS), a major cholinergic nucleus projecting to the hippocampus, could affect hippocampal synaptic plasticity and further impair the memory behaviors. The present study investigated the effects of Aβ injection into the MS on hippocampal long-term potentiation(LTP) and cognitive behaviors of rats by using Morris water maze(MWM), Y maze and in vivo hippocampal LTP recording. The effects of kainic acid(KA), an agent with specific neurotoxicity to GABAergic neurons, were also observed. The results showed that:(1) Intra-MS injection of Aβ_(25–35), not KA, impaired spatial learning and memory of rats in classical and reversal MWM tests;(2) Both Aβ_(25–35) and KA impaired novelty-seeking behavior of rats in Y maze;(3) Intra-MS injection of Aβ_(25–35), not KA, suppressed in vivo hippocampal LTP in the CA1 region of rats;(4) Both Aβ_(25–35) and KA did not affect the motor ability in behavioral tests and the hippocampal paired-pulse facilitation(PPF) in electrophysiological recording. These results indicate that intra-MS injection of Aβ could impair spatial memory, cognitive flexibility and exploratory motivation, as well as hippocampal LTP in rats, suggesting that the cholinergic neurons in the MS and the septo-hippocampal projection could be important targets of neurotoxic Aβ, and the specific damage of cholinergic neurons in the MS is likely responsible for the impairments of hippocampal synaptic plasticity and cognitive function in AD.
引文
1 Prince M,Comas-Herrera A,Knapp M,Guerchet M,Karagiannidou M.World Alzheimer Report 2016:Improving healthcare for people living with dementia:coverage,quality and costs now and in the future.London:Alzheimer’s Disease International(ADI),2016.
2 Selkoe DJ,Hardy J.The amyloid hypothesis of Alzheimer’s disease at 25 years.EMBO Mol Med 2016;8(6):595-608.
3 Baker-Nigh A,Vahedi S,Davis EG,Weintraub S,Bigio EH,Klein WL,Geula C.Neuronal amyloid-beta accumulation within cholinergic basal forebrain in ageing and Alzheimer’s disease.Brain 2015;138(Pt 6):1722-1737.
4 Yamin G,Ono K,Inayathullah M,Teplow DB.Amyloid beta-protein assembly as a therapeutic target of Alzheimer’s disease.Curr Pharm Des 2008;14(30):3231-3246.
5 Sala Frigerio C,De Strooper B.Alzheimer’s disease mechanisms and emerging roads to novel therapeutics.Annu Rev Neurosci 2016;39:57-79.
6 Wu MN,Zhou LW,Wang ZJ,Han WN,Zhang J,Liu XJ,Tong JQ,Qi JS.Colivelin ameliorates amyloid beta peptide-induced impairments in spatial memory,synaptic plasticity,and calcium homeostasis in rats.Hippocampus 2015;25(3):363-372.
7 Wu MN,He YX,Guo F,Qi JS.Alpha4beta2 nicotinic acetylcholine receptors are required for the amyloid beta protein-induced suppression of long-term potentiation in rat hippocampal CA1 region in vivo.Brain Res Bull 2008;77(2-3):84-90.
8 Davies P,Maloney AJ.Selective loss of central cholinergic neurons in Alzheimer’s disease.Lancet 1976;2(8000):1403.
9 Muller C,Remy S.Septo-hippocampal interaction.Cell Tissue Res 2017;doi:10.1007/s00441-017-2745-2.
10 Baxter MG,Bucci DJ,Gorman LK,Wiley RG,Gallagher M.Selective immunotoxic lesions of basal forebrain cholinergic cells:effects on learning and memory in rats.Behav Neurosci2013;127(5):619-627.
11 Gu Z,Yakel JL.Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity.Neuron2011;71(1):155-165.
12 Kwakowsky A,Potapov K,Kim S,Peppercorn K,Tate WP,Abraham IM.Treatment of beta amyloid 1-42(Aβ1-42)-induced basal forebrain cholinergic damage by a non-classical estrogen signaling activator in vivo.Sci Rep 2016;6:21101.
13 Colom LV,Castaneda MT,Hernandez S,Perry G,Jaime S,Touhami A.Intrahippocampal amyloid-beta(1-40)injections injure medial septal neurons in rats.Curr Alzheimer Res2011;8(8):832-840.
14 Pepeu G,Grazia Giovannini M.The fate of the brain cholinergic neurons in neurodegenerative diseases.Brain Res2017;1670:173-184.
15 Villette V,Dutar P.GABAergic microcircuits in Alzheimer’s disease models.Curr Alzheimer Res 2017;14(1):30-39.
16 Abbas G,Mahmood W,Kabir N.Recent progress on the role of GABAergic neurotransmission in the pathogenesis of Alzheimer’s disease.Rev Neurosci 2016;27(4):449-455.
17 Andrews-Zwilling Y,Gille spie AK,Kravitz AV,Nelson AB,Devidze N,Lo I,Yoon SY,Bien-Ly N,Ring K,Zwilling D,Potter GB,Rubenstein JL,Kreitzer AC,Huang Y.Hilar GABAergic interneuron activity controls spatial learning and memory retrieval.PLo S One 2012;7(7):e40555.
18 Tiwari V,Patel AB.Impaired glutamatergic and GABAergic function at early age in Abeta PPswe-PS1d E9 mice:implications for Alzheimer’s disease.J Alzheimers Dis 2012;28(4):765-769.
19 Parent MB,Baxter MG.Septohippocampal acetylcholine:involved in but not necessary for learning and memory?Learn Mem 2004;11(1):9-20.
20 Pang KC,Nocera R,Secor AJ,Yoder RM.GABAergic septohippocampal neurons are not necessary for spatial memory.Hippocampus 2001;11(6):814-827.
21 Castaneda MT,Lopez ED,Touhami A,Tovar R,Ortega MR,Rodriguez JM.Neuroprotection of medial septal cholinergic neurons by memantine after intralateral septal injection of Abeta1-40.Neuroreport 2015;26(8):450-454.
22 Colom LV,Castaneda MT,Banuelos C,Puras G,Garcia-Hernandez A,Hernandez S,Mounsey S,Benavidez J,Lehker C.Medial septal beta-amyloid 1-40 injections alter septo-hippocampal anatomy and function.Neurobiol Aging 2010;31(1):46-57.
23 Dwyer TA,Servatius RJ,Pang KC.Noncholinergic lesions of the medial septum impair sequential learning of different spatial locations.J Neurosci 2007;27(2):299-303.
24 Paxinos G,Watson C.The Rat Brain in Stereotaxic Coordinates.6th ed.Academic Press,2007.
25 Kim D,Chung S,Lee SH,Choi SY,Kim SM,Koo J,Lee JH,Jahng JW.Decreased hippocampal brain-derived neurotrophic factor and impaired cognitive function by hypoglossal nerve transection in rats.J Cell Mol Med 2017;21(12):3752-3760.
26 Labrousse VF,Nadjar A,Joffre C,Costes L,Aubert A,Gregoire S,Bretillon L,Laye S.Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice.PLo S One 2012;7(5):e36861.
27 Doherty GH,Beccano-Kelly D,Yan SD,Gunn-Moore FJ,Harvey J.Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid beta.Neurobiol Aging 2013;34(1):226-237.
28 Wei Z,Song MS,Mac Tavish D,Jhamandas JH,Kar S.Role of calpain and caspase in beta-amyloid-induced cell death in rat primary septal cultured neurons.Neuropharmacology2008;54(4):721-733.
29 Han WN,Holscher C,Yuan L,Yang W,Wang XH,Wu MN,Qi JS.Liraglutide protects against amyloid-beta proteininduced impairment of spatial learning and memory in rats.Neurobiol Aging 2013;34(2):576-588.
30 Li Y,Xu J,Xu P,Song S,Liu P,Chi T,Ji X,Jin G,Qiu S,Hou Y,Zheng C,Wang L,Meng D,Zou L.Xanthoceras sorbifolia extracts ameliorate dendritic spine deficiency and cognitive decline via upregulation of BDNF expression in a rat model of Alzheimer’s disease.Neurosci Lett 2016;629:208-214.
31 Bliss TV,Collingridge GL.A synaptic model of memory:long-term potentiation in the hippocampus.Nature 1993;361(6407):31-39.
32 Martin SJ,Grimwood PD,Morris RG.Synaptic plasticity and memory:an evaluation of the hypothesis.Annu Rev Neurosci 2000;23:649-711.
33 Melonakos ED,White JA,Fernandez FR.Gain modulation of cholinergic neurons in the medial septum-diagonal band of broca through hyperpolarization.Hippocampus 2016;26(12):1525-1541.
34 Stewart M,Fox SE.Do septal neurons pace the hippocampal theta rhythm?Trends Neurosci 1990;13(5):163-168.
35 Yang D(杨东),Shen Y,Wang X,Li S,Zhang J,Qi J.Medial septal Aβ25-35 injection suppressed the theta power in the hippocampal CA1 region of rats in vivo.Chin J Neuroanat(神经解剖学杂志)2011;27(4):389-394.
36 Damborsky JC,Smith KG,Jensen P,Yakel JL.Local cholinergic-GABAergic circuitry within the basal forebrain is modulated by galanin.Brain Struct Funct 2017;222(3):1385-1400.
37 Maurer SV,Williams CL.The cholinergic system modulates memory and hippocampal plasticity via its interactions with non-neuronal cells.Front Immunol 2017;8:1489.
38 Cutuli D,Foti F,Mandolesi L,De Bartolo P,Gelfo F,Federico F,Petrosini L.Cognitive performances of cholinergically depleted rats following chronic donepezil administration.JAlzheimers Dis 2009;17(1):161-176.
39 Dickson DW,Murray ME.Intraneuronal amyloid-beta accumulation in basal forebrain cholinergic neurons:a marker of vulnerability,yet inversely related to neurodegeneration.Brain 2015;138(Pt 6):1444-1445.
40 Harkany T,De Jong GI,Soos K,Penke B,Luiten PG,Gulya K.Beta-amyloid(1-42)affects cholinergic but not parvalbumin-containing neurons in the septal complex of the rat.Brain Res 1995;698(1-2):270-274.
41 Zeng X,Wang T,Jiang L,Ma G,Tan S,Li J,Gao J,Liu K,Zhang Y.Diazoxide and cyclosporin A protect primary cholinergic neurons against beta-amyloid(1-42)-induced cytotoxicity.Neurol Res 2013;35(5):529-536.
42 Ke HC,Huang HJ,Liang KC,Hsieh-Li HM.Selective improvement of cognitive function in adult and aged APP/PS1 transgenic mice by continuous non-shock treadmill exercise.Brain Res 2011;1403:1-11.
43 Nell HJ,Whitehead SN,Cechetto DF.Age-dependent effect of beta-amyloid toxicity on basal forebrain cholinergic neurons and inflammation in the rat brain.Brain Pathol 2015;25(5):531-542.
44 Nava-Mesa MO,Jimenez-Diaz L,Yajeya J,Navarro-Lopez JD.GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer’s disease.Front Cell Neurosci 2014;8:167.
45 Dashiani MG,Kruashvili LB,Rusadze Kh Z,Matatradze SB,Beselia GV.Effects of immunotoxic and electrolytic lesions of medial septal area on spatial short-term memory in rats.Georgian Med News 2015(239):98-103.
46 Burjanadze M,Mataradze S,Rusadze K,Chkhikvishvili N,Dashniani M.Selective lesion of GABA-ergic neurons in the medial septum by GAT1-saporin impairs spatial learning in a water-maze.Georgian Med News 2015(240):59-64.
47 Pang KC,Jiao X,Sinha S,Beck KD,Servatius RJ.Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance:effects on proactive interference.Hippocampus 2011;21(8):835-846.
2 Selkoe DJ,Hardy J.The amyloid hypothesis of Alzheimer’s disease at 25 years.EMBO Mol Med 2016;8(6):595-608.
3 Baker-Nigh A,Vahedi S,Davis EG,Weintraub S,Bigio EH,Klein WL,Geula C.Neuronal amyloid-beta accumulation within cholinergic basal forebrain in ageing and Alzheimer’s disease.Brain 2015;138(Pt 6):1722-1737.
4 Yamin G,Ono K,Inayathullah M,Teplow DB.Amyloid beta-protein assembly as a therapeutic target of Alzheimer’s disease.Curr Pharm Des 2008;14(30):3231-3246.
5 Sala Frigerio C,De Strooper B.Alzheimer’s disease mechanisms and emerging roads to novel therapeutics.Annu Rev Neurosci 2016;39:57-79.
6 Wu MN,Zhou LW,Wang ZJ,Han WN,Zhang J,Liu XJ,Tong JQ,Qi JS.Colivelin ameliorates amyloid beta peptide-induced impairments in spatial memory,synaptic plasticity,and calcium homeostasis in rats.Hippocampus 2015;25(3):363-372.
7 Wu MN,He YX,Guo F,Qi JS.Alpha4beta2 nicotinic acetylcholine receptors are required for the amyloid beta protein-induced suppression of long-term potentiation in rat hippocampal CA1 region in vivo.Brain Res Bull 2008;77(2-3):84-90.
8 Davies P,Maloney AJ.Selective loss of central cholinergic neurons in Alzheimer’s disease.Lancet 1976;2(8000):1403.
9 Muller C,Remy S.Septo-hippocampal interaction.Cell Tissue Res 2017;doi:10.1007/s00441-017-2745-2.
10 Baxter MG,Bucci DJ,Gorman LK,Wiley RG,Gallagher M.Selective immunotoxic lesions of basal forebrain cholinergic cells:effects on learning and memory in rats.Behav Neurosci2013;127(5):619-627.
11 Gu Z,Yakel JL.Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity.Neuron2011;71(1):155-165.
12 Kwakowsky A,Potapov K,Kim S,Peppercorn K,Tate WP,Abraham IM.Treatment of beta amyloid 1-42(Aβ1-42)-induced basal forebrain cholinergic damage by a non-classical estrogen signaling activator in vivo.Sci Rep 2016;6:21101.
13 Colom LV,Castaneda MT,Hernandez S,Perry G,Jaime S,Touhami A.Intrahippocampal amyloid-beta(1-40)injections injure medial septal neurons in rats.Curr Alzheimer Res2011;8(8):832-840.
14 Pepeu G,Grazia Giovannini M.The fate of the brain cholinergic neurons in neurodegenerative diseases.Brain Res2017;1670:173-184.
15 Villette V,Dutar P.GABAergic microcircuits in Alzheimer’s disease models.Curr Alzheimer Res 2017;14(1):30-39.
16 Abbas G,Mahmood W,Kabir N.Recent progress on the role of GABAergic neurotransmission in the pathogenesis of Alzheimer’s disease.Rev Neurosci 2016;27(4):449-455.
17 Andrews-Zwilling Y,Gille spie AK,Kravitz AV,Nelson AB,Devidze N,Lo I,Yoon SY,Bien-Ly N,Ring K,Zwilling D,Potter GB,Rubenstein JL,Kreitzer AC,Huang Y.Hilar GABAergic interneuron activity controls spatial learning and memory retrieval.PLo S One 2012;7(7):e40555.
18 Tiwari V,Patel AB.Impaired glutamatergic and GABAergic function at early age in Abeta PPswe-PS1d E9 mice:implications for Alzheimer’s disease.J Alzheimers Dis 2012;28(4):765-769.
19 Parent MB,Baxter MG.Septohippocampal acetylcholine:involved in but not necessary for learning and memory?Learn Mem 2004;11(1):9-20.
20 Pang KC,Nocera R,Secor AJ,Yoder RM.GABAergic septohippocampal neurons are not necessary for spatial memory.Hippocampus 2001;11(6):814-827.
21 Castaneda MT,Lopez ED,Touhami A,Tovar R,Ortega MR,Rodriguez JM.Neuroprotection of medial septal cholinergic neurons by memantine after intralateral septal injection of Abeta1-40.Neuroreport 2015;26(8):450-454.
22 Colom LV,Castaneda MT,Banuelos C,Puras G,Garcia-Hernandez A,Hernandez S,Mounsey S,Benavidez J,Lehker C.Medial septal beta-amyloid 1-40 injections alter septo-hippocampal anatomy and function.Neurobiol Aging 2010;31(1):46-57.
23 Dwyer TA,Servatius RJ,Pang KC.Noncholinergic lesions of the medial septum impair sequential learning of different spatial locations.J Neurosci 2007;27(2):299-303.
24 Paxinos G,Watson C.The Rat Brain in Stereotaxic Coordinates.6th ed.Academic Press,2007.
25 Kim D,Chung S,Lee SH,Choi SY,Kim SM,Koo J,Lee JH,Jahng JW.Decreased hippocampal brain-derived neurotrophic factor and impaired cognitive function by hypoglossal nerve transection in rats.J Cell Mol Med 2017;21(12):3752-3760.
26 Labrousse VF,Nadjar A,Joffre C,Costes L,Aubert A,Gregoire S,Bretillon L,Laye S.Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice.PLo S One 2012;7(5):e36861.
27 Doherty GH,Beccano-Kelly D,Yan SD,Gunn-Moore FJ,Harvey J.Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid beta.Neurobiol Aging 2013;34(1):226-237.
28 Wei Z,Song MS,Mac Tavish D,Jhamandas JH,Kar S.Role of calpain and caspase in beta-amyloid-induced cell death in rat primary septal cultured neurons.Neuropharmacology2008;54(4):721-733.
29 Han WN,Holscher C,Yuan L,Yang W,Wang XH,Wu MN,Qi JS.Liraglutide protects against amyloid-beta proteininduced impairment of spatial learning and memory in rats.Neurobiol Aging 2013;34(2):576-588.
30 Li Y,Xu J,Xu P,Song S,Liu P,Chi T,Ji X,Jin G,Qiu S,Hou Y,Zheng C,Wang L,Meng D,Zou L.Xanthoceras sorbifolia extracts ameliorate dendritic spine deficiency and cognitive decline via upregulation of BDNF expression in a rat model of Alzheimer’s disease.Neurosci Lett 2016;629:208-214.
31 Bliss TV,Collingridge GL.A synaptic model of memory:long-term potentiation in the hippocampus.Nature 1993;361(6407):31-39.
32 Martin SJ,Grimwood PD,Morris RG.Synaptic plasticity and memory:an evaluation of the hypothesis.Annu Rev Neurosci 2000;23:649-711.
33 Melonakos ED,White JA,Fernandez FR.Gain modulation of cholinergic neurons in the medial septum-diagonal band of broca through hyperpolarization.Hippocampus 2016;26(12):1525-1541.
34 Stewart M,Fox SE.Do septal neurons pace the hippocampal theta rhythm?Trends Neurosci 1990;13(5):163-168.
35 Yang D(杨东),Shen Y,Wang X,Li S,Zhang J,Qi J.Medial septal Aβ25-35 injection suppressed the theta power in the hippocampal CA1 region of rats in vivo.Chin J Neuroanat(神经解剖学杂志)2011;27(4):389-394.
36 Damborsky JC,Smith KG,Jensen P,Yakel JL.Local cholinergic-GABAergic circuitry within the basal forebrain is modulated by galanin.Brain Struct Funct 2017;222(3):1385-1400.
37 Maurer SV,Williams CL.The cholinergic system modulates memory and hippocampal plasticity via its interactions with non-neuronal cells.Front Immunol 2017;8:1489.
38 Cutuli D,Foti F,Mandolesi L,De Bartolo P,Gelfo F,Federico F,Petrosini L.Cognitive performances of cholinergically depleted rats following chronic donepezil administration.JAlzheimers Dis 2009;17(1):161-176.
39 Dickson DW,Murray ME.Intraneuronal amyloid-beta accumulation in basal forebrain cholinergic neurons:a marker of vulnerability,yet inversely related to neurodegeneration.Brain 2015;138(Pt 6):1444-1445.
40 Harkany T,De Jong GI,Soos K,Penke B,Luiten PG,Gulya K.Beta-amyloid(1-42)affects cholinergic but not parvalbumin-containing neurons in the septal complex of the rat.Brain Res 1995;698(1-2):270-274.
41 Zeng X,Wang T,Jiang L,Ma G,Tan S,Li J,Gao J,Liu K,Zhang Y.Diazoxide and cyclosporin A protect primary cholinergic neurons against beta-amyloid(1-42)-induced cytotoxicity.Neurol Res 2013;35(5):529-536.
42 Ke HC,Huang HJ,Liang KC,Hsieh-Li HM.Selective improvement of cognitive function in adult and aged APP/PS1 transgenic mice by continuous non-shock treadmill exercise.Brain Res 2011;1403:1-11.
43 Nell HJ,Whitehead SN,Cechetto DF.Age-dependent effect of beta-amyloid toxicity on basal forebrain cholinergic neurons and inflammation in the rat brain.Brain Pathol 2015;25(5):531-542.
44 Nava-Mesa MO,Jimenez-Diaz L,Yajeya J,Navarro-Lopez JD.GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer’s disease.Front Cell Neurosci 2014;8:167.
45 Dashiani MG,Kruashvili LB,Rusadze Kh Z,Matatradze SB,Beselia GV.Effects of immunotoxic and electrolytic lesions of medial septal area on spatial short-term memory in rats.Georgian Med News 2015(239):98-103.
46 Burjanadze M,Mataradze S,Rusadze K,Chkhikvishvili N,Dashniani M.Selective lesion of GABA-ergic neurons in the medial septum by GAT1-saporin impairs spatial learning in a water-maze.Georgian Med News 2015(240):59-64.
47 Pang KC,Jiao X,Sinha S,Beck KD,Servatius RJ.Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance:effects on proactive interference.Hippocampus 2011;21(8):835-846.