学习记忆能力下降大鼠神经细胞增殖的研究

目的　观察学习记忆能力减退老年大鼠海马齿状回神经细胞的增殖。方法　Morris水迷宫筛选出学习记忆能力减退大鼠 (痴呆组 )与正常大鼠 (对照组 )。BrdU标记海马齿状回增殖细胞。TUNEL法标记DNA片段原位检测凋亡细胞。计数海马颗粒细胞层与海马门的BrdU阳性细胞与凋亡细胞数。结果　痴呆组与对照组大鼠相比 ,海马颗粒细胞层BrdU阳性细胞显著增加 (P <0 0 1) ,而凋亡细胞数无显著差异 (P >0 0 5 )。海马门BrdU阳性细胞数及凋亡细胞数均无显著差异 (P >0 0 5 )。结论　学习记忆能力减退的老年大鼠海马齿状回神经细胞增殖能力减低。     

Effects of cholinergic drugs on learning impairment in ventral globus pallidus-lesioned rats

The excitotoxin kainic acid (10 nmol/microliter) was used to produce bilateral lesions in the nucleus basalis magnocellularis (NBM) of rats which provides extensive cholinergic innervation to the cerebral cortex. The behavioral effects of physostigmine, THA (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrate hydrochloride) were investigated by observing locomotor activity, shock sensitivity and passive avoidance response in the NBM-lesioned rats. Evaluation of locomotor activity and shock sensitivity in the experimental animals did not reveal any sensorimotor disturbances caused by the lesions. Oral administration of 1 and 2 mg/kg physostigmine reduced the locomotor activity in the NBM-lesioned rats, while physostigmine (0.5 mg/kg), THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) had no effect on locomotor activity. Compared with the sham-operated controls, the NBM-lesioned rats exhibited a significantly lesser deficit in the retention of the passive avoidance response. THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) elicited good retention of the passive avoidance response. Rats with NBM lesions showed impaired acquisition of a passive avoidance response when trained repeatedly at 24-h intervals. Also, when post-training NBM lesions were induced, there was rapid extinction of the acquired passive avoidance response. THA or NIK-247 administered at doses of 3 mg/kg significantly increased response latencies of post-trained NBM-lesioned rats. THA or NIK-247 administered once a day in doses of 1 or 3 mg/kg p.o. produced a very significant increase of acetylcholine in the cerebral cortex of NBM-lesioned rats after the 21st administration. These finding suggest that THA and NIK-247 exert an ameliorating effect on memory disturbance induced by NBM lesions in rats.     

Relationship between cholinergic dysfunction and discrimination learning disabilities in Wistar rats following chronic cerebral hypoperfusion

The effects of chronic hypoperfusion of cerebral blood flow (CBF) on central cholinergic indices and intellectual functions were investigated in rats. Male Wistar rats, aged 9 weeks, were anesthetized with pentobarbital, and the bilateral common carotid arteries were permanently ligated. Cortical CBF in the hypoperfused rats was markedly decreased at 6 weeks after the operation. In the hypoperfused group, cholinergic indices were changed to consist two phases after the operation, before (acute) and after (chronic) 6 weeks after the operation. At 6 weeks, choline acetyltransferase activity was restored to the sham-operated level compared with the changes in the frontal cortex and thalamus + midbrain at 3 weeks. On the other hand, the maximum number of muscarinic acetylcholine receptors was reduced in the frontal cortex, hippocampus and striatum at 6 weeks and thereafter remained at this low level. In discrimination learning task, the percentage of correct responses in the hypoperfused rats was generally reduced in contrast with that of the sham-operated rats, although the number of total responses were not changed. As a consequence, cholinergic dysfunctions correlate with discrimination learning disabilities in the hypoperfused rats. These findings suggest that the hypoperfused rat may be useful for the cerebrovascular type dementia model to clarify pathophysiology.     

Effects of cholinergic depletion on evoked activity inthe cortex of young and aged rats

Degeneration of cholinergic neurons in the basal forebrain is a neural marker ofAlzheimers disease and is associated with perceptual and cognitive deficits. An idea that hasattracted scientific scutiny is that aging makes the brain more susceptible to neurodegenerativediseases such as Alzheimers. The purpose of this study was to compare the effects of the loss ofcholinergic input from nucleus basalis of Meynert on evoked activity in the posteromedial barrelsubfield of the somatosensory cortex in young (2–2.5 months) and aged (28–30 months) maleFisher hybrid rats. The mean firing rate and receptive fields of single neurons in the posteromedialbarrel subfield of the somatosensory cortex were examined after selective lesions of cholinergicneurons in the nucleus basalis of Meynert with an immunotoxin, IgG 192-saporin.

Functional properties of single neurons in young animals were affected much moresignificantly by cholinergic depletion than those in aged animals. In cholinergic-depleted younganimals, the mean firing rate of evoked activity and receptive field of posteromedial barrel subfieldneurons were significantly decreased. Cholinergic depletion caused a 14% decrease in evokedactivity and a 33% increase in receptive field size in young animals. The mean firing rate andreceptive field of single neurons were not affected by cholinergic depletion in aged animals. It isconcluded that functional properties of cortical sensory neurons in young animals are morevulnerable to cholinergic depletion than are those of aged animals and that cholinergic depletiondoes not further impact the properties of neurons exposed to the processes of aging.     

Effects of Gossypium herbaceam extract administration on the learning and memory function in the naturally aged rats: neuronal niche improvement

Aging-associated cognitive impairment is an important health care issue since individuals with mild cognitive impairment are more likely to develop Alzheimer's disease. In the present study, the protective effect of Gossypium herbaceam extracts (GHE) on learning and memory impairment associated with aging were examined in vivo using Morris water maze and step through task. Furthermore, the antioxidant activity and neuroprotective effect of GHE was investigated with methods of histochemistry and biochemistry. These data showed that oral administration with GHE at the doses of 35, 70, and 140 mg/kg exerted an improved effect on the learning and memory impairment in aged rats. Subsequently, GHE afforded a beneficial action on eradication of free radicals without influence on the activity of glutathione peroxidase and superoxide dismutase. GHE treatment enhanced the expression levels of nerve growth factor. Meanwhile, proliferation of neural progenitor cells was elevated in hippocampus after treatment with GHE. Taken together, neurogenic niche improvement could be involved in the mechanism underlying neuroprotection of GHE against aging-associated cognitive impairment. These findings suggested that GHE might be a potential agent as cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer's disease or treatment of aging-associated cognitive impairment.     

Interactions between histaminergic and cholinergic systems in learning and memory.

The aim of this review is to survey biochemical, electrophysiological and behavioral evidence of the interactions between the cholinergic and histaminergic systems and evaluate their possible involvement in cognitive processes. The cholinergic system has long been implicated in cognition, and there is a plethora of data showing that cholinergic deficits parallel cognitive impairments in animal models and those accompanying neurodegenerative diseases or normal aging in humans. Several other neurotransmitters, though, are clearly implicated in cognitive processes and interact with the cholinergic system. The neuromodulatory effect that histamine exerts on acetylcholine release is complex and multifarious. There is clear evidence indicating that histamine controls the release of central acetylcholine (ACh) locally in the cortex and amygdala, and activating cholinergic neurones in the nucleus basalis magnocellularis (NBM) and the medial septal area-diagonal band that project to the cortex and to the hippocampus, respectively. Extensive experimental evidence supports the involvement of histamine in learning and memory and the procognitive effects of H(3) receptor antagonists. However, any attempt to strictly correlate cholinergic/histaminergic interactions with behavioral outcomes without taking into account the contribution of other neurotransmitter systems is illegitimate. Our understanding of the role of histamine in learning and memory is still at its dawn, but progresses are being made to the point of suggesting potential treatment strategies that may produce beneficial effects on neurodegenerative disorders associated with impaired cholinergic function.     

孕烯醇酮对老年大鼠胆碱能系统的影响

目的 通过试剂盒检测ChAT、AchE和PREG的表达,探讨PREG与老年大鼠胆碱能系统的关系及其机制.方法 24月龄雄性SD大鼠40只随机分为4组,空白对照组,溶剂对照组(隔日腹腔注射等体积DMSO),小剂量组(按照0.5 mg/kg隔日腹腔注射PREG).大剂量组(按照2.0 mg/kg隔日腹腔注射PREG).采用试剂盒检测大鼠额叶、颞叶、海马组织ChAT、AchE活性以及血象PREG含量,然后运用Stata软件处理检测结果.结果 大剂量PREG明显增加老年大鼠ChAT、PREG表达,降低AchE的表达(P＜0.05),而小剂量PREG仅仅提高了血浆PREG含量.结论 大剂量PREG能提高胆碱能系统的表达,可能提高记忆功能.     

去松果树对大鼠学习记忆及大脑皮质胆碱能纤维的影响

目的　探讨松果体功能减退致褪黑素 (MT)分泌减少对大鼠学习记忆及大脑皮质胆碱能纤维分布的影响。方法　将大鼠进行Y型迷宫测试 ,淘汰学习障碍的大鼠 ,将学习正常的大鼠随机分 2组 ,实验组手术摘除松果体 ,对照组给予假手术 ,饲养 40d后再行Y型迷宫测试 ,乙酰胆碱酯酶 (AChE)组织化学法测AChE。结果　实验组大鼠学习成绩由术前 (14.7± 5 .0 )次增加到术后(2 8.7± 2 .4)次 ,学习记忆能力明显低于术前自身及对照组 (13.8± 8.3)次 (P <0 .0 1) ,运动皮质、体感皮质第Ⅱ～Ⅳ层 ,海马CA1、CA2、CA3区辐状层、腔隙层、分子层和齿状回多形细胞层AChE阳性纤维密度明显低于对照组 (P <0 .0 1)。结论　大鼠松果体摘除可以引起大鼠学习记忆障碍及大脑皮质胆碱能纤维密度降低     

Prenatal exposure to methadone affects central cholinergic neuronal activity in the weanling rat.

The effect of prenatal exposure to methadone via maternal osmotic minipumps was studied on brain regional acetylcholine (ACh) turnover and dopamine (DA), norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT) and their metabolites in 21-day-old female and male rats. ACh content was not affected in any region studied. However, the turnover rate of ACh (TRAch) was increased significantly in the striata and parietal cortices of both sexes. Two gender-specific changes were observed: a profound decrease in hypothalamic TRACh in the females and an increase in hippocampal TRACh in the males. No changes were observed in TRACh in the medulla-pons or the frontal cortex of either sex. The reduction in TRACh was accompanied by a threefold increase in DA content in the hypothalamus of the methadone-exposed females. No other changes were observed in DA, NE, or 5-HT, save for increased 5-HT content in the medulla-pons of the male methadone-exposed rats. Thus, prenatal methadone exposure produces several lingering changes in cholinergic function, many of which were not apparent in the immediate postnatal period. Although striatal ACh content was no longer reduced in methadone-exposed rats, striatal cholinergic function remains disrupted. It remains to be proven whether these differences are a direct effect of methadone exposure or are a consequence of neonatal withdrawal.     

Effects of test experience and neocortical microgyria on spatial and non-spatial learning in rats

Neocortical neuronal migration anomalies such as microgyria and heterotopia have been associated with developmental language learning impairments in humans, and rapid auditory processing deficits in rodent models. Similar processing impairments have been suggested to play a causal role in human language impairment. Recent data from our group has shown spatial working memory deficits associated with neocortical microgyria in rats. Similar deficits have also been identified in humans with language learning impairments. To further explore the extent of learning deficits associated with cortical neuronal migration anomalies, we evaluated the effects of neocortical microgyria and test order experience using spatial (Morris water maze) and non-spatial water maze learning paradigms. Two independent groups were employed (G1 or G2) incorporating both microgyria and sham conditions. G1 received spatial testing for five days followed by non-spatial testing, while the reverse order was followed for G2. Initial analysis, including both test groups and both maze conditions, revealed a main effect of treatment, with microgyric rats performing significantly worse than shams. Overall analysis also revealed a task by order interaction, indicating that each group performed better on the second task as compared to the first, regardless of which task was presented first. Independent analyses of each task revealed a significant effect of treatment (microgyria worse than sham) only for the spatial water maze condition. Results indicate that prior maze experience (regardless of task type) leads to better subsequent performance. Results suggest that behavioral abnormalities associated with microgyria extend beyond auditory and working memory deficits seen in previous studies, to include spatial but not non-spatial learning impairments and that non-specific test experience may improve behavioral performance.     

知母皂苷Ⅱ对老龄大鼠学习记忆行为及海马区神经元的影响

目的本实验研究知母皂苷BⅡ(Timosaponin B-Ⅱ,TB-Ⅱ)对自然衰老大鼠学习记忆能力的改善及海马区神经元的保护作用。方法 SD大鼠老年对照组(15只)、青年大鼠对照组(15只)、TB-II 1 mg/kg组(15只)、TB-II2 mg/kg组(15只)和TB-II 4 mg/kg组(15只)。Morris水迷宫实验测量动物逃避潜伏时间; Elisa法测定脑脊液IL-6和TNF-α含量; TUNEL法检测海马区凋亡神经元; HPLC法检测多巴胺、去甲肾上腺素和5-羟色胺含量。结果水迷宫实验显示老龄对照组逃避潜伏时间比青年对照组增加,差异有统计学意义(P 0. 05);给药组与老年对照组相比逃避潜伏时间明显缩短,差异有统计学意义(P 0. 05);给药组脑脊液IL-6和TNF-α浓度下降(P 0. 05);给药组海马区神经元凋亡减少(P 0. 05);给药组DA、NE和5-HT含量增加(P 0. 05)。结论知母皂苷BⅡ通过抑制大脑炎症介质生成和抑制海马区神经元凋亡,提高神经递质含量,明显改善自然衰老大鼠的学习和记忆能力。     

Effects of nimodipine on psychological-stress situation in aged rats.

Female aged rats treated with nimodipine, a calcium-blocker dihydropyridine derivative, were submitted to a psychological-stress situation. Nimodipine at the doses of 3 and 6 mg/Kg antagonized the stress-related body-weight decrease and lethality. These findings seem to validate the role of Ca-mediated mechanisms in the physiopathology of stress and the protective effects of the Ca-blockers in the stress-related illnesses.     

Effects of cholinergic blockers on auditory brain-stem evoked potentials in rats.

The pharmacology of auditory brain-stem evoked potentials (ABEP) pathways is poorly understood. There are anecdotal reports on the involvement of various neurotransmitters but they were not investigated systematically. The aim of this study was to investigate the effects on ABEP of muscarinic and nicotinic blockers, administered into the cerebral ventricles. Atropine sulfate, d-Tubocurarine and saline were injected stereotactically into the lateral cerebral ventricle of anesthetized male rats. Auditory clicks were given at a rate of 20 s(-1). ABEP recording was performed before and 30 min after injection. Pre- and post-injection peak latencies and peak-to-peak amplitudes of positive waves were compared for each animal. Atropine reduced the amplitudes of waves P1, P3 and P4 and increased mildly the brain stem transmission time. d-Tubocurarine reduced the amplitudes of P1 and P4 with no significant effect on the peak latencies. Saline injection had no effect on any of the parameters. These results show that both cholinergic systems are involved in ABEP generation or transmission. Mechanism of action could be either direct inhibition of afferent pathways or indirect effect, via modulating efferent pathways.     

Action of a chronic disulfiram administration on memory decay and on central cholinergic and adrenergic systems.

The chronic administration (15 days) of disulfiram reduced the levels of noradrenaline (NA) in the olfactory system and in the subcortex at all the tested doses (50, 200 and 400 mg/kg/day). No modification of the density (Bmax) and of the dissociation constant (Kd) for alpha 1-adrenergic receptors was observed (radioligand [3H]prazosin). Only in the hippocampus the acetylcholine (ACh) levels and the Bmax for muscarinic receptors (radioligand [3H]QNB) were increased at all doses tested. Modifications of the cholinergic system were observed in the subcortex and in the cortex only at the higher doses of disulfiram. After 20 days interruption of the daily training in the staircase maze, 50, 100 and 200 mg/kg/day of disulfiram accelerated spontaneous decay of memory. It is hypothesized that the modifications of the hippocampal cholinergic system (increase of the ACh levels and of the density of the muscarinic receptors) may be the condition determining the acceleration of the decay of memory caused by disulfiram.     

Effects of the lateral septum and latent inhibition on successive discrimination learning.

Damage to the lateral nucleus of the septum in the rat resulted in atypical learning to a previously meaningless stimulus. Nonreinforced preexposure to a stimulus normally makes more difficult subsequent use of that stimulus for learning. The effect of this preexposure on learning is termed latent inhibition and was demonstrated in sham operated animals. Rats in which the lateral septum was damaged demonstrated a paradoxically smaller learning deficit in the presence of a conditioned stimulus that was previously presented without reinforcement, when compared to the performance of both septal lesioned rats no receiving nonreinforced preexposure and sham operates receiving preexposure. The interaction of nonreinforced preexposure and lateral septal lesions can be explained using a proposed sensitization hypothesis.     

Effects of chronic intraventricular infusion of heparin glycosaminoglycan on learning and brain acetylcholine parameters in aged rats

We reported previously that the glycosaminoglycan heparin (HP) has the facility to improve learning in adult rodents when administered into the nucleus basalis of the ventral pallidum. Here we gauged the effects of chronic intraventricular infusion of HP (20 ng per day over 28 days) in 26-month-old rats in terms of Morris water maze performance, habituation to a novel open field, retention of a step-through inhibitory avoidance task and changes in forebrain acetylcholine (ACh) levels. Control groups included vehicle-infused old and adult (3-month-old) rats. The chronic infusion of HP did not significantly influence the performance of the old animals in any of the learning and memory tasks employed. HP only slightly facilitated the retention of the inhibitory avoidance task and the rate of habituation in the open-field paradigm. In the water maze, the glycosaminoglycan did not counteract the navigation deficits observed for aged controls and even impaired performance during the initial place-learning trials. After behavioural testing, tissue levels of ACh were determined in frontal cortex, ventral striatum, neostriatum and hippocampus without detecting any obvious neurochemical differences between groups. The current results, together with our previous work, indicate that HP differentially affects learning and memory parameters in adult and aged rats. Thus, whereas the glycosaminoglycan proved effective in facilitating mnemonic functions in normal adult animals, no such a clear-cut beneficial effect was observed in behaviourally impaired old rats.     

慢性应激对大鼠学习记忆功能和海马神经细胞粘附分子表达的影响

目的观察慢性应激对大鼠学习记忆功能和海马神经细胞粘附分子（NCAM）表达的影响,探讨海马NCAM表达在慢性应激影响学习记忆机制的作用。方法20只SD大鼠随机被分为对照组（10只）和慢性应激组（10只）,后者以束缚浸水应激方式连续应激21天,三周后行水迷宫实验,并用免疫组化法测定大鼠的脑海马区NCAM的表达。结果应激组在水迷宫测试中寻找水中隐藏平台的潜伏期为（7．1±8．9）秒,对照组为（12．3±4．2）秒,差异有统计学意义;穿越平台次数：应激组为（8．4±1．1）次,对照组为（12．5±1．9）次,差异有统计学意义。应激组海马CA3区NCAM的表达：25．2％±3．6％,对照组为37．9％±5．1％,差异有统计学意义。结论慢性应激对大鼠的学习记忆功能有抑制作用。其机制可能与应激抑制海马CA3区NCAM表达有关。     

The interaction between central cholinergic and peripheral β-adrenergic systems on radial maze performance in rats

The interaction between cholinergic and β-adrenergic systems on radial arm maze performance was investigated. Scopolamine significantly disrupted radial maze performance. Although neither propranolol (a centrally and peripherally acting β-antagonist), nor atenolol (a peripherally acting β1-antagonist) affected the maze performance, both antagonists significantly augmented the scopolamine disruption. These results suggest the importance of the interaction between central cholinergic and peripheral β-adrenergic systems on radial maze performance.