Water maze performance,exploratory activity,inhibitory avoidance and hippocampal plasticity in aged superior and inferior learners

In 28- to 30-month-old rats, in vitro short-term and long-term potentiation (STP and LTP) were measured in area CA1 of the hippocampus in seven superior and seven inferior learners, that were selected from a pool of 40 rats based on water maze escape performance over a period of 9 days. The aim was to examine whether levels of STP and LTP could account for group differences in learning of water maze escape, spatial preference and wall (thigmotaxis)-avoidance and in short-term retention of an inhibitory avoidance task. There was no significant group difference in open-field exploration, i.e. the number of rearings. In contrast to expectation, the superior and inferior learners did not differ significantly from each other in levels of STP and LTP. However, variability in escape and spatial learning, but not thigmotaxis-avoidance learning, was significantly predicted by variability in STP and LTP in the superior group. Also, open-field exploratory rearings were significantly correlated with STP and LTP as well as with maze escape learning in the superior group. The results show that, in the aged superior group, levels of CA1 STP and LTP coincided with residual water maze escape and spatial preference learning as well as open-field exploration, i.e. behavioural expressions known to be related to hippocampal functioning, but not with learning to avoid thigmotaxis in the maze. The lack of such correlations in the inferior group may be due to the severe impairment in escape and spatial preference learning and/or the influence of yet unknown third variables on these relationships.     

Effects of naloxone on the long-term potentiation of EPSPs from the pathway of Schaffer collateral to CA1 region of hippocampus in aged rats with declined memory

Morris water maze (MWM) was employed to distinguish the aged rats with declined memory to investigate the effect of naloxone on the synaptic plasticity of hippocampus in declined memory aged rats. After administration with naloxone for 7 days, LTP of excitatory post-synaptic potentials (EPSPs) from Schaffer collateral to CA1 region was recorded. The results showed that the maintenance of LTP of EPSPs from Schaffer collateral to CA1 subfield in isolate hippocampal brain slice was prolonged by naloxone with improved Morris water maze performance and reduced threshold of EPSPs. It is suggested that naloxone can improve learning and memory through enhancement of the synaptic plasticity of hippocampus in aged rats with declined memory.     

Reduced density of NMDA receptors and increased sensitivity to dizocilpine-induced learning impairment in aged rats

About 20 min prior to training in a shock-motivated 14-unit T-maze, young (3-4 months) and aged (24-25 months) male Fischer-344 rats were given s.c. injections of either saline or dizocilpine (MK-801, 0.02 or 0.04 mg/kg), a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. The aged rats showed a dose-dependent impairment in maze performance. Deficiencies were manifested as increases in errors, in runtime from start to goal, and in the number and duration of shocks received. In contrast, young rats exhibited no detrimental effects of dizocilpine on maze performance. Analysis of [3H]glutamate binding in these rats revealed a marked age-related decline in NMDA receptor binding in hippocampus. A significant correlation was observed between errors in the maze and hippocampal [3H]-glutamate binding, but the correlation was positive, i.e., rats that made the most errors had the highest level of NMDA receptor binding. Thus, compared to young rats, aged rats were more sensitive to the behavioral effects of NMDA receptor antagonism and they showed a hippocampal loss of [3H]glutamate in binding, which may be related to the increased sensitivity to dizocilpine. The positive correlation between poor maze performance and NMDA receptor binding suggests that the behaviors assessed involve complex interactions between NMDA receptors and other neuronal systems in the hippocampus.     

Regional and selective effects of oestradiol and progesterone on NMDA and AMPA receptors in the rat brain

We investigated the effect of 10 months ovariectomy and a correction therapy, 2 weeks before the rats were killed, of oestradiol, progesterone or their combination on NMDA and AMPA receptor binding in the hippocampus, dentate gyrus, striatum, nucleus accumbens and frontal cortex of the rat brain as well as on amino acid levels in frontal cortex. NMDA and AMPA binding densities were assayed by autoradiography using, respectively, L-[3H]glutamate and [3H]AMPA; amino acid concentrations were measured by high performance liquid chromatograhy (HPLC) coupled with UV detection. Ovariectomy was without effect on NMDA and AMPA binding density in all brain regions assayed except in the hippocampal CA1 region and dentate gyrus where it decreased NMDA binding density compared to intact rats values. Oestradiol restored and increased NMDA binding density in the CA1 subfield and the dentate gyrus of ovariectomized rats but, by contrast, it decreased binding density in the striatum and in the frontal cortex while having no effect in the CA2/3 subfield of the hippocampus and in the nucleus accumbens. Oestradiol was without effect on AMPA binding density in the hippocampus and the dentate gyrus but it reduced AMPA binding density in the striatum, the frontal cortex and the nucleus accumbens. Progesterone, and oestradiol combined with progesterone, decreased NMDA but not AMPA binding density in the frontal cortex of ovariectomized rats, and they were without effect on these receptors in the other brain regions assayed. Amino acid concentrations in the frontal cortex were unchanged after ovariectomy or steroid treatments. The effect of oestradiol in the hippocampus confirmed in the present study and our novel findings in the frontal cortex, striatum and nucleus accumbens may have functional significance for schizophrenia and neurodegenerative diseases.     

Water maze and radial maze learning and the density of binding sites of glutamate, GABA, and serotonin receptors in the hippocampus of inbred mouse strains

Correlations between the densities of ionotropic glutamate, GABA(A), and serotonin binding sites in the hippocampus of seven inbred mouse strains and strain-specific learning capacities in two types of maze were studied. Binding site densities were measured with quantitative receptor autoradiography. Learning capacities were determined in a water maze task as well as in spatial and nonspatial versions of an eight-arm radial maze. The densities of most binding sites differed significantly between the strains in the subfields of Ammon's horn (CA1 and CA3) and the dentate gyrus, except for serotonin binding sites in CA1. By comparing the different strains, significant receptor-behavioral correlations between the densities of the GABA(A) receptors and the activity-dependent behavior in the water maze as well as the spatial learning in the radial maze were found. The densities of D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionate (AMPA) and kainate receptors correlated positively with learning capacity in the spatial eight-arm radial maze. We conclude that hereditary variations mainly in AMPA, kainate, and GABA(A) receptor densities are involved in behavioral variations in spatial and nonspatial learning tasks.     

γ-氨基丁酸对慢性脑缺血致血管性痴呆大鼠学习记忆能力的影响

目的观察γ-氨基丁酸（GABA）对慢性脑缺血致血管性痴呆（VD）大鼠学习记忆能力及海马CA1区神经元形态学的影响。方法将SD大鼠随机分为假手术组、模型组、GABA组,采用双侧颈总动脉永久性结扎法建立VD模型。GABA组术后腹腔注射GABA0.5g.kg-1.d-1,连续注射60d;用Morris水迷宫实验检测大鼠空间学习记忆能力;Nissl染色观察大鼠海马CA1区神经元形态学变化。结果 GABA能明显改善VD大鼠学习记忆能力,也能减轻海马CA1区神经元损伤。结论 GABA能改善慢性脑缺血致VD大鼠的学习记忆能力,减轻海马神经元损伤可能是其机制之一。     

Regulation of high-affinity GABAA receptors in the dorsal hippocampus by estradiol and progesterone

The effects of estradiol benzoate (EB) and of progesterone (P) treatment on high-affinity [3H]muscimol binding in the dorsal hippocampal formation were examined in ovariectomized and adrenalectomized female rats by in vitro autoradiography. EB injected subcutaneously increased [3H]muscimol binding in specific subregions of the Ammon's horn (CA1 and stratum radiatum of CA4) and of the dentate gyrus (dorsal molecular layer). In these particular regions, estrogen receptors have been shown to be present. P did not significantly affect [3H]muscimol binding in any region of the hippocampus when administered alone or in combination with EB. Results suggest that estrogens may regulate the activity of specific hippocampal neurons by modulating their sensitivity to GABA.     

AMPA,kainate, and NMDA receptor densities in the hippocampus of untreated male rats and females in estrus and diestrus

Steroid hormones systematically affect numerous neuronal targets, thus influencing, in a permanent or a transitory manner, the way the brain reacts to external and internal stimuli. The hippocampus is an important brain region for learning and memory and the glutamatergic intrahippocampal pathway plays a major role in performing such functions. We applied quantitative in vitro receptor autoradiography to examine how the in vivo hormone milieu affects the densities of AMPA, kainate, and NMDA receptors in the hippocampus of adult male rats and females in estrus and diestrus. All three examined receptor types presented significant gender-specific differences in their densities. The hippocampus of male rats contains significantly more AMPA, kainate, and NMDA receptors than that of female rats. Female rats in diestrus have significantly higher AMPA receptor densities than female rats in estrus. AMPA changes occurred to the same extent in CA1-3 and in the dentate gyrus. Significant differences in the densities of NMDA receptors were observed in the CA1-3 regions, whereas kainate receptor differences were restricted to the CA1 region. These results further support that steroid hormones, through their modulation of AMPA and NMDA receptors, may be involved in the control of synaptic efficacy and, therefore, influence learning and memory.     

吗啡戒断性焦虑大鼠海马突触界面结构及突触素表达变化

目的 探讨吗啡依赖戒断焦虑行为与海马CA1、CA3区突触界面结构和突触素表达变化之间的相关性.方法 剂量递增法建立大鼠吗啡依赖模型,高架十字迷宫检测焦虑行为,透射电镜技术结合图像分析系统、免疫组织化学比较对照组、模型组和治疗组(各6只)大鼠海马CA1、CA3区突触界面结构和突触素(P38)的表达.结果 (1)行为学:模型组开放臂的次数和时间均少于对照组和治疗组[最小有意义差异t检验(下同),P＜0.01或P＜0.05).(2)突触界面结构:模型组CA1区突触后致密物厚度[(10.7±0.9)nm]、突触活性区长度[(45±4)am]、突触间隙宽度[(3.80±0.30)nm]和突触界面曲率(1.37±0.12)均高于对照组和治疗组(P＜0.01或P＜0.05);模型组CA3区突触后致密物厚度[(12.7±1.1)nm]、突触活性区长度[(53±8)nm]、突触间隙宽度[(3.81 ±0.59)nm]、突触界面曲率(1.39±0.30)亦均高于对照组和治疗组(P＜0.01或P＜0.05).(3)突触素表达:模型组CA1、CA3区突触素吸光度(A)值分别为(0.42±0.06)和(0.43±0.05),显著高于对照组(0.2±0.02,0.25±0.03)和治疗组(0.27±0.04,0.26±0.03).结论吗啡戒断焦虑行为与海马CA1、CA3区突触形态结构可塑性及突触素表达水平有一定的相关性.     

Infusions of allopregnanolone into the hippocampus and amygdala,but not into the nucleus accumbens and medial prefrontal cortex,produce antidepressant effects on the learned helplessness rats

Patients with depression showed a decrease in plasma and cerebrospinal fluid allopregnanolone (ALLO). But antidepressants increased the contents of ALLO in the rat brain. We examined the antidepressant‐like effects of infusion of ALLO into the cerebral ventricle, hippocampus, amygdala, nucleus accumbens, or prefrontal cortex of learned helplessness (LH) rats (an animal model of depression). Of these regions, infusions of ALLO into the cerebral ventricle, the CA3 region of hippocampus, or the central region of amygdala exerted antidepressant‐like effects. Infusion of ALLO into the hippocampal CA3 region or the central amygdala did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. It is well documented that ALLO exerts its effects through GABA receptors. Therefore, we examined the antagonistic effects of flumazenil (a GABA receptor antagonist) on the antidepressant‐like effects of ALLO. Coinfusion of flumazenil with ALLO into the hippocampal CA3 region, but not into the central amygdala, blocked the antidepressant‐like effects of ALLO. However, coinfusion of (+)MK801 (an NMDA receptor antagonist), but not cycloheximide (a protein synthesis inhibitor), blocked the antidepressant‐like effects of ALLO in the central amygdala. These results suggest that ALLO exerts antidepressant‐like effects in the CA3 region of hippocampus through the GABA system and in the central region of amygdala, dependently on the activation of the glutamatergic mechanisms. © 2010 Wiley‐Liss, Inc.