Beneficial effects of docosahexaenoic acid on active avoidance performance in 1K-1C hypertensive rats

The present study evaluated the role of chronic docosahexaenoic acid (DHA) supplementation on active avoidance learning task performance in experimental hypertension. Male Wistar rats were randomly divided into five experimental groups as follows: control, sham, DHA treated, 1K-1C hypertensive, and 1K-1C hypertensive+DHA treated. Hypertension was induced in 1K-1C rats via placing a silver clip (0.20-mm ID) around the left renal artery following a right uninephrectomy. DHA (36 mg/kg/day) was given to the treatment groups for 60 days by gastric gavage. Arterial blood pressure was measured by using the tail-cuff method. Active avoidance responses were determined by an automated shuttle-box. In brain (cerebrum) and hippocampus tissues, thiobarbituric acid reactive substances (TBARS) and nitrite levels were measured by fluorometric methods. DHA supplementation decreased blood pressure in hypertensive rats. Data from active avoidance training indicated that performance of active avoidance learning tasks were significantly impaired in 1K-1C hypertensive rats, but was completely restored by DHA supplementation. Increased cerebrum TBARS levels in 1K-1C rats were abolished by DHA administration. Cerebrum nitrite levels were lower in the DHA, 1K-1C and 1K-1C+DHA treated groups compared to controls. Hippocampus nitrite levels were lower in DHA treated and 1K-1C hypertensive rats compared to controls and higher in 1K-1C+DHA treated rats compared to the 1K-1C group. Our data indicates that DHA supplementation improves the performance of active avoidance learning tasks which is impaired in experimental hypertension. These affirmative changes might be due to a DHA-induced decrease in lipid peroxidation which may in turn limit the consumption of nitric oxide (NO) which promotes active avoidance learning.     

Intrahippocampal insulin improves memory in a passive-avoidance task in male wistar rats

The main impacts of insulin favor the peripheral organs. Although it functions as a neuropeptide, insulin possesses also some central effects. The aim of this study was to determine the effect of intrahippocampal infusion of insulin on passive avoidance learning in healthy male rats. Thirty male wistar rats were divided into three groups (n=10 each). The experimental group had posttraining insulin infusion into the CA1 region of dorsal hippocampus, after which they were compared with sham (saline) and control (intact) groups. Insulin treated animals had greater latency to enter the dark compartment in compare with saline treated (p=0.023) or control groups (p=0.017). Upon our results, we concluded that intrahippocampal injections of insulin may enhance memory for a simple learning task which supports the concept that insulin possibly plays an endogenous role in memory formation.     

Limbic networks and associative learning: II. Entorhinal contributions to spontaneous alternation,passive avoidance,and taste aversion learning

The hippocampus plays an important role in learning and memory, but the precise nature of that involvement remains uncertain. Transection of the perforant path, a primary input pathway to the hippocampus, has been shown to produce changes in reaction to novelty and acquisition of active avoidance; the nature and magnitude of these changes vary with lateral or medial perforant path damage. In a series of experiments on adult rats, the role of these pathways in spontaneous alternation, exploration, acquisition and extinction of conditioned responses, passive avoidance, and conditioned taste aversion was investigated. Lateral transection reduced exploration while medial transection facilitated acquisition of an active avoidance response; no effects were observed on any other measure. Results are discussed in terms of what perforant path damage might reveal regarding the interactions of the hippocampus with other brain regions.     

Limbic networks and associative learning: II. Entorhinal contributions to spontaneous alternation, passive avoidance, and taste aversion learning

The hippocampus plays an important role in learning and memory, but the precise nature of that involvement remains uncertain. Transection of the perforant path, a primary input pathway to the hippocampus, has been shown to produce changes in reaction to novelty and acquisition of active avoidance; the nature and magnitude of these changes vary with lateral or medial perforant path damage. In a series of experiments on adult rats, the role of these pathways in spontaneous alternation, exploration, acquisition and extinction of conditioned responses, passive avoidance, and conditioned taste aversion was investigated. Lateral transection reduced exploration while medial transection facilitated acquisition of an active avoidance response; no effects were observed on any other measure. Results are discussed in terms of what perforant path damage might reveal regarding the interactions of the hippocampus with other brain regions.     

Locomotor, avoidance,and maze behavior in rats with selective disruption of hippocampal output.

Behavioral correlates of selective disruption of hippocampal output were investigated in a series of five experiments. In two experiments an attempt was made through behavioral investigation to determine whether the CA1 neurons project to the fimbria or to the subiculum. The results supported recent views that the subiculum is the recipient of CA1 axons. Disruption of the CA1 output in the dorsal hippocampus of rats produced increased open-field activity, whereas passive avoidance and spontaneous alternation behaviors remained unchanged. No differentiation was obtained between CA1 damage and neocortical lesions in maze learning. Blocking of the fimbrial CA3 output from the dorsal hippocampus improved passive avoidance performance and impaired active avoidance performance, whereas open-field and spontaneous alternation behaviors were unaffected. Interruption of the CA3 output from the ventral hippocampus improved active avoidance performance and reduced spontaneous alternation behavior. Open-field behavior and passive avoidance performance remained unchanged. Total fimbrial sections increased open-field activity, improved passive and active avoidance, and reduced spontaneous alternation. The results are discussed in terms of functional differentiation between the CA1 and CA3 of the dorsal hippocampus and in terms of functional differences in the fimbrial CA3 output from the dorsal and ventral hippocampus.     

Effects of intrahippocampal injections of the cholinergic neurotoxin AF64A on open-field activity and avoidance learning in the rat

The effects of direct intrahippocampal administration of the cholinergic neurotoxin, AF64A, were investigated in male rats. Bilateral injections of AF64A (5 nmole/2 microliters) produced a significant decrease in choline acetyltransferase (CAT) activity in the dorsal hippocampus (25%) and overlying frontoparietal cortex (30%) but no changes in the striatum. Rats lesioned with AF64A exhibited increased levels of open-field activity, which was most marked at 1 week after the lesion; however, the rates of intrasession habituation were similar in lesioned and control rats. Lesioned rats also displayed deficits in acquisition and retention of a passive avoidance task and less dramatic deficits in acquisition of two-way shuttle box avoidance. These findings indicate that lesioning of cholinergic terminals in the hippocampus and/or cerebral cortex with AF64A leads to long-term deficits in learning and memory as well as increases in open-field activity.     

Long-term consequences of early experience on adult avoidance learning in female rats: role of the dopaminergic system

Following our hypothesis that juvenile emotional and/or cognitive experience should affect learning performance at preweaning age as well as adulthood, the present study in female Wistar rats aimed to examine the impact of (i) avoidance training at preweaning age, (ii) exposure to repeated maternal separation, (iii) the combination of both, and (iv) the blockade of dopaminergic neurotransmission on adult two-way active avoidance learning in rats. We found that preweaning, i.e. three week old, rats were less capable of avoidance learning compared to adults. Our main findings revealed that preweaning avoidance training alone improved avoidance learning in adulthood. Furthermore, maternal separation alone also improved avoidance learning in preweaning and in adult rats, but this effect of maternal separation did not add up to the beneficial effect of preweaning avoidance training on adult learning. In addition, the pharmacological blockade of dopamine receptors during preweaning avoidance training via systemic application of haloperidol impaired preweaning avoidance performance in a dose-dependent manner. Testing the haloperidol-treated preweaning presumed "non-learners" as adults revealed that they still showed improved learning as adults. Taken together, our results strongly support the hypothesis that emotional as well as cognitive experience at preweaning age leaves an enduring "memory trace," which can facilitate learning in adulthood. Our pharmaco-behavioral studies suggest that unlike the adult brain, preweaning learning and memory formation is less dependent on dopaminergic mechanisms, which raises the intriguing question of possible alternative pathways.     

Vitamins E and C pretreatment prevents ovariectomy-induced memory deficits in water maze

We investigated whether the pretreatment with vitamins E (alpha-tocopherol) and C (ascorbic acid) would act on ovariectomy-induced memory deficits in Morris water maze tasks. Adult female Wistar rats were divided into three groups: (1) naive (control), (2) sham (submitted to surgery without removal of ovaries) and (3) ovariectomized. Thirty days after surgery, they were trained in the Morris water maze in order to verify ovariectomy effects both on reference and working memory tasks. Results show that ovariectomized rats presented impairment in spatial navigation in the acquisition phase, as well as in the time spent in target quadrant and in the latency to cross over the location of the platform in test session, when compared to naive and sham groups (controls), in the reference memory task. Ovariectomy did not affect performance in the working memory task. Confirming our hypothesis, ovariectomized rats pretreated for 30 days with vitamins E and C had those impairments prevented. We conclude that ovariectomy significantly impairs spatial reference learning/memory and that pretreatment with vitamins E and C prevents such effect. Assuming this experimental memory impairment might mimic, at least in part, the cognitive deficit sometimes present in the human condition of lack of reproductive hormones, our findings lend support to a novel therapeutic strategy, based on vitamins E and C, to cognitive impairments in post-menopausal women.     

The relationship of structural ischemic brain damage to neurobehavioural deficit: the effect of postischemic MK-801

Global cerebral ischemia is well known to cause neuronal necrosis in selectively vulnerable sectors of the hippocampus. Since the hippocampus of the rat is involved in spatial navigation, learning, and memory, selective deficits in these abilities may arise from ischemic brain damage. Previous studies have shown (a) a detectable neurobehavioural deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus and (b) a reduction of ischemic neuronal necrosis with the noncompetitive N-methyl-D-Aspartate (NMDA) antagonist MK-801. This study was designed to determine the relationship between the improvement in structural brain damage in postischemically treated rats and any improvement in neurobehavioural performance, using a learning-set water task. Seventeen male Wistar rats received 10.5 min of forebrain ischemia induced by carotid clamping and hypotension. Brain temperature was estimated with probes in the temporalis muscle. Ten of these animals received no therapy (controls), and seven animals received 5 mg/kg MK-801 iv, 20 min postischemia. Six additional rats underwent a sham operation. Postischemic hypothermia was prevented with heating lamps. Four controls and one MK-801 treated animal died. The survivors were then tested on a place learning-set task in a swimming pool paradigm, and quantitative histopathologic analysis of their entire brains was done. The learning-set task revealed defects in spatial navigation, reflected as increased errors and latency in the performance of the untreated control rats. The performance of the MK-801 treated group progressively approached that of sham-operated rats over the course of testing and was significantly better than controls. Importantly, no long-term detrimental effect of MK-801 on the learning-set task performance was seen. Quantitative neuropathology revealed significantly less damage in the MK-801 treated group in all major brain regions. In the hippocampus, MK-801 treated animals showed hippocampal damage limited to the vulnerable portion of the pyramidal cell band comprising 48.8% of the CA1 pyramidal cells, as opposed to 72.4% in untreated controls. Extra-hippocampal damage was evident only in untreated control animals. MK-801 totally prevented neuronal necrosis in both the cerebral cortex and striatum and also prevented infarction in the neocortex and thalamus. Three conclusions emerge from the study. First, postischemic MK-801 mitigates structural brain damage in several brain regions in the absence of concomitant hypothermia. Second, neurobehavioural performance appears to be improved by MK-801 when performance trends are examined, but is somewhat less sensitive than quantitated histopathology due to compounding interanimal variation in performance abilities.(ABSTRACT TRUNCATED AT 400 WORDS)     

Involvement of hippocampal nitric oxide in spatial learning in the rat

Nitric oxide (NO) is thought to be involved in synaptic plasticity contributing to learning and memory in several brain areas including the hippocampus. The hippocampus is believed to have a critical role in the processing of spatial information. But, data on the role of hippocampal NO in spatial learning are not consistent. So the effect of NO synthase (NOS) inhibition in the CA1 region of rat hippocampus on spatial localization was investigated in the Morris water maze (MWM). Male albino Wistar rats cannulated in their CA1 region received bilateral injections of vehicle (saline) or N(omega)-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor (50, 100 and 200 microg/0.5 microl) through the cannulae 30 min before training each day. Animals were subjected to 5 days of training in the MWM; 4 days with the invisible platform to test spatial learning and the 5th day with the visible platform to test motivation and sensorimotor coordination. The results showed dose-dependent increases (p<0.001) in escape latency, traveled distance, heading angle, and dose-dependent decreases (p<0.01) in target quadrant entries in L-NAME-received groups as compared to the control group. This impairment was reversed by co-administration of mole-equivalent doses of L-arginine (L-Arg), the NO precursor. L-Arg alone at the dose of 129.2 microg, increased heading angle (p<0.01) with no effect on other parameters. On the basis of the present data, it is concluded that processes mediated by NO synthesis in the hippocampus are essentially involved in spatial learning.     

Differential roles of hippocampal metabotropic glutamate receptors 1 and 5 in inhibitory avoidance learning

Group I metabotropic glutamate receptors (mGlu1 and 5) have been implicated in synaptic plasticity and learning and memory. However, much of our understanding of how these receptors in different brain regions contribute to distinct memory stages in different learning tasks remains incomplete. The present study investigated the effects of the mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and mGlu1 receptor antagonist, (S)-(+)-alpha-amino-4-carboxy-2-methylbenzene-acetic acid (LY 367385) in the dorsal hippocampus on the consolidation and extinction of memory for inhibitory avoidance learning. Male, Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance task. MPEP, LY 367385 or saline were infused bilaterally into the CA1 region immediately after training or immediately after the first retention test which was given 24h after training. Rats receiving MPEP (1.5 or 5.0 microg/side) or LY 367385 (0.7 or 2.0 microg/side) infusion exhibited a dose-dependent decrease in retention when tested 24h later. MPEP was ineffective while LY 367385 significantly attenuated extinction when injected after the first retention test using an extinction procedure. These findings indicate a selective participation of hippocampal group I mGlu receptors in memory processing in this task.     

Androgens' effects to enhance learning may be mediated in part through actions at estrogen receptor-beta in the hippocampus

Testosterone (T) may enhance cognitive performance. However, its mechanisms are not well understood. First, we hypothesized that if T's effects are mediated in part through actions of its 5alpha-reduced metabolites, dihydrotestosterone (DHT) and/or 3alpha-androstanediol (3alpha-diol) in the hippocampus, then T, DHT, and 3alpha-diol-administration directly to the hippocampus should enhance learning and memory in the inhibitory avoidance task. In order to test this hypothesis, gonadectomized (GDX) male rats were administered T, DHT, or 3alpha-diol via intrahippocampal inserts immediately following training in the inhibitory avoidance task. We found that T tended to increase, and DHT and 3alpha-diol significantly increased, performance in the inhibitory avoidance task compared to vehicle-administered GDX rats. Second, we hypothesized that, if androgens' effects are due in part to actions of 3alpha-diol in the hippocampus, then systemic or intrahippocampal administration of 3alpha-diol should significantly enhance cognitive performance of GDX male rats. Third, we hypothesized that, if androgen metabolites can have actions at estrogen receptors (ERs) in the hippocampus, then administration of ER antisense oligonucleotides (AS-ODNs) directly to the hippocampus of GDX, 3alpha-diol replaced, rats would decrease learning in the inhibitory avoidance task. We found that intrahippocampal administration of AS-ODNs for ERbeta, but not ERalpha, significantly decreased learning and memory of 3alpha-diol replaced rats. Together, these findings suggest that T's effects to enhance learning and memory may take place, in part, through actions of its metabolite, 3alpha-diol, at ERbeta in the dorsal hippocampus.     

Functional activity in the brain of socially deprivated rats produced by an active avoidance test after razobazam (Hoe 175) treatment: a 2-deoxyglucose study

The 2-deoxyglucose (2-DG) autoradiographic method was used to map metabolic activity in the brain of socially deprivated rats during an active avoidance test. The method investigated the effects of razobazam during this learning test. The animals were socially deprivated for 5 weeks. On the first experimental day the animals were trained to avoid a footshock by jumping onto a platform. During training and testing, the total number of avoidance responses was scored. On the second day during one 2-DG session of 40 min, razobazam increased the avoidance score by 18% as compared to controls. Autoradiographs were analyzed using a two-dimensional densitometric method. The analysis of the brain structures showed a 22% reduction of optical density in the nucleus habenularis lateralis, a 25% increase in the caudal part of the nucleus accumbens, and a 13% increase in the frontal cortex in rats treated with razobazam, but no change in the amygdala. These results provide a preliminary concept to explain how the new compound razobazam produced a better learning performance in socially deprivated rats.     

The "anxiety state" and its relation with rat models of memory and habituation.

Rats selected as "anxious", "nonanxious," or normal according to their behavior in an elevated plus maze were submitted to memory tasks and the densities of central benzodiazepine receptors in the amygdala and the hippocampus were studied. Anxious rats exibited better retention scores in the inhibitory avoidance task while nonanxious rats exibited worse retention scores in inhibitory and two-way active avoidance tasks compared to normal rats. No significant differences were detected in the retention scores for habituation to an open field. Nonanxious rats presented a lower benzodiazepine receptor density in the hippocampus but not in the amygdala compared to the other groups. These data suggest that the benzodiazepine receptors are involved in the effect of "anxiety" or emotional states on memory storage processes.     

Intracranial self-stimulation recovers learning and memory capacity in basolateral amygdala-damaged rats

We studied the capacity of post-training intracranial self-stimulation (SS) to reverse or ameliorate learning and memory impairments caused by amygdala damage in rats. A first experiment showed that lesions of the basolateral amygdala (BLA) slow down acquisition of two-way active avoidance conditioning (2wAA). In a second experiment we observed that a post-training SS treatment administered immediately after each 2wAA conditioning session is able to completely reverse the disruptive effects of the BLA lesions, and the facilitative effect lasts for 10 days. A third experiment allowed us to differentiate the strong recuperative effects of the SS treatment from the slight effect caused by overtraining the same conditioning response. We concluded that SS is able to counteract the behavioral deficit induced by BLA damage, probably by activating alternative undamaged brain structures related to learning and memory, such as the hippocampus.     

Chronic, severe hypertension does not impair spatial learning and memory in Sprague-Dawley rats

This study tested the hypothesis that long-term hypertension impairs spatial learning and memory in rats. In 6-wk-old Sprague-Dawley rats, chronic hypertension was induced by placing one of three sizes of stainless steel clips around the descending aorta (above the renal artery), resulting in a 20–80-mm Hg increase of arterial pressure in all arteries above the clip, that is, the upper trunk and head. Ten months later, the rats were tested for 5 d in a repeated-acquisition water maze task, and on the fifth day, they were tested in a probe trial; that is, there was no escape platform present. At the end of the testing period, the nonsurgical and sham control groups had similar final escape latencies (16±4 sec and 23±9 sec, respectively) that were not significantly different from those of the three hypertensive groups. Rats with mild hypertension (140–160 mm Hg) had a final escape latency of 25±6 sec, whereas severely hypertensive rats (170–199 mm Hg) had a final escape latency of 21±7 sec and extremely hypertensive rats (>200 Hg) had a final escape latency of 19±5 sec. All five groups also displayed a similar preference for the correct quadrant in the probe trial. Together, these data suggest that sustained, severe hypertension for over 10 mo is not sufficient to impair spatial learning and memory deficits in otherwise normal rats.     

Several types of learning increase open field activity in mice

Experimental and control groups of mice were initially matched on the basis of their open field activity. Experimental groups were trained in one of six types of learning tasks: (1) active avoidance conditioning with light and sound signals as conditioned stimuli and electric shocks as uncoditioned stimulus, (2) learning of a linear 5-point maze, (3) learning of a T-maze, (4) passive avoidance conditioning, (5) learning of non-aggressive behavior, and (6) learning of aggressive behavior. In all cases, learning was associated with a significant increase of the open field activity over that of the untrained but otherwise similarly treated control mice. This effect was most marked during the learning phase and disappeared when the acquired behavior had become firmly established. It is suggested that several types of learning are associated with an increase of arousal level, possibly mediated by the activation of central catecholamine neurons.     

急性情绪应激对大鼠行为和脑神经颗粒素磷酸化水平的影响

为探讨急性情绪应激对大鼠旷场行为的影响,以及脑神经颗粒素（Neuroganin,NG）变化与应激性行为效应之间的相互关系。以急性不确定性空瓶刺激,建立情绪应激动物模型。将40只雄性SD大鼠随机分为情绪应激组1（ES1,接受情绪应激和旷场测试）、情绪应激组2（ES2,只接受情绪应激）、正常对照组1（C1,无情绪应激,但接受旷场测试）和正常对照组（C2,无情绪应激,也无旷场测试）（n=10）。以旷场行为和高架十字迷宫任务来评定大鼠应激后的行为变化,Western印迹杂交法（Western blotting）测定海马和前脑皮层中的NG含量和磷酸化水平。结果表明：（1） 应激后ES1组的水平活动增加,与C1组比较,差异有显著性, p<0.01;（2）ES1组海马和前脑皮层的NG磷酸化水平高于C1和C2组,差异有显著性, 均为p<0.05; ES2组的前脑皮层NG的磷酸化水平高于C1组,差异有显著性,为p<0.05;（3） 海马的NG磷酸化水平与水平活动之间的相关达显著水平。提示急性情绪应激能导致动物明显的行为改变如焦虑,这种行为改变可能与脑内NG磷酸化水平的变化有关。水平活动可能是反映急性情绪应激的较敏感行为指标,海马NG磷酸化水平可能是预测急性情绪应激所致焦虑或抑郁行为的较敏感生物学指标     

Avoidance conditioning as a function of appetitive stimulus pretraining: Response and stimulus transfer effects

Pretrained appetitive discriminative stimuli were used as warning signals in subsequent avoidance learning. In Expt 1 identical responses were required in pretraining and in avoidance learning. An appetitive S+ facilitated avoidance learning in rats in comparison to S? or a stimulus previously uncorrelated with food. In Expt 2, the type of response in pretraining and in avoidance learning was varied. Groups with homogeneous responses in the two situations replicated Expt 1 results, whereas groups with different responses in pretraining and avoidance learning failed to show an advantage when S+ served as warning; in the heterogeneous response groups, S? was as effective as S+. Inhibitory factors in the heterogeneous groups were discussed as an explanation for these results.     

Transient hippocampal down-regulation of Kv1.1 subunit mRNA during associative learning in rats

Voltage-gated potassium channels (Kv) are critically involved in learning and memory processes. It is not known, however, whether the expression of the Kv1.1 subunit, constituting Kv1 channels, can be specifically regulated in brain areas important for learning and memory processing. Radioactive in situ hybridization was used to evaluate the content of Kv1.1 α-subunit mRNA in the olfactory bulb, ventral, and dorsal hippocampus at different stages of an odor-discrimination associative task in rats. Naive, conditioned, and pseudoconditioned animals were sacrificed at different times either prior to a two-odor significance learning or after odor discrimination was established. Important decreases of Kv1.1 mRNA levels were transiently observed in the ventral hippocampus before successful learning when compared with the pseudoconditioned group. Moreover, temporal group analysis showed significant labeling alterations in the hippocampus of conditioned and pseudoconditioned groups throughout the training. Finally, Kv1.1 mRNA levels in the hippocampus were positively correlated with odor-reward association learning in rats that were beginning to discriminate between odors. These findings indicate that the Kv1.1 subunit is transiently down-regulated in the early stages of learning and suggest that Kv1 channel expression regulation is critical for the modification of neuronal substrates underlying new information acquisition.