Effects of medial septal or unilateral hippocampal inactivations on reference and working spatial memory in rats

The memory performances of rats receiving a reversible inactivation of either the medial septum or one side of the ventral hippocampus were compared in a radial arm maze task allowing the assessment of both working and reference memory. After pre-surgery training, rats were chronically equipped with bilateral cannulae into the ventral hippocampus and a single cannula into the medial septum. Following post-surgery retraining, animals received a series of test trials during which they received saline or lidocaine injections in either the medial septum or one side of the ventral hippocampus. Lidocaine injections in either structure resulted in both reference and working memory deficits. However, animals were more impaired after septal injections than after unilateral hippocampal injections. This result suggests that the septo-hippocampal formation acts as a functionally homogeneous structure essential for spatial processing. © 1994 Wiley-Liss, Inc.     

Galanin in the medial septal area impairs working memory

Galanin, a peptide of 29 amino acids, is co-localized with acetylcholine in a subpopulation of neurons of the medial septal area (MSA) that project to the hippocampus. Galanin reverses the actions of acetylcholine in several biochemical and behavioral procedures, and may be involved in memory processes. To test the possibility that galanin acts on the cell bodies of MSA neurons, two measures of septohippocampal function were assessed following intra-septal microinfusion of galanin or two synthetic fragments of galanin (1–16 and 21–29). The behavioral measure was choice accuracy in a working memory task in a T-maze. The electrophysiological measure was hippocampal theta activity recorded from the dentate hilus. The galanin fragment, 1–16, and the complete peptide, 1–29, decreased choice accuracy and decreased hippocampal theta activity in a dose-dependent fashion. Saline and the 21–29 fragment had no effect on choice accuracy and hippocampal theta. Sensorimotor performance was unaffected. These findings demonstrate that galanin impairs working memory when administered directly into the MSA and suggest that galanin inhibits MSA neural activity.     

Effect of reversible inactivation of the supramammillary nucleus on spatial learning and memory in rats

Memory includes processes such as acquisition, consolidation and retrieval. Reference memory (RM) and working memory (WM) are two kinds of memory that can be assessed in rodents using spatial tasks, especially using the Morris water maze. The Morris water maze is particularly sensitive to hippocampal lesions. The supramammillary nucleus (SuM) has strong links with the hippocampus and septum. The role of the SuM on spatial learning is controversial. In the present study, involvement of SuM in the different steps of spatial RM and WM was investigated in the Morris water maze using reversible inactivation of SuM with lidocaine. Lidocaine (0.5 microl, 4%) was injected into the SuM through a guide cannula implanted above the SuM. The rats were trained on RM and WM versions of the Morris water maze. SuM was inactivated before training or immediately after training or before the probe trial of retrieval tests. Reversible inactivation of the SuM impaired consolidation of RM, and of consolidation and retrieval of WM. Therefore, it seems that activity of SuM neurons plays a role in spatial RM and WM learning and memory in the rat.     

Effects of combined medial septal area, fimbria–fornix and entorhinal cortex tetrodotoxin inactivations on passive avoidance response consolidation in the rat

On the basis of previous experimental evidence, it has been concluded that the entorhinal cortex (EC), the fimbria–fornix (FF) complex and medial septal area (MSA) do not take part in the consolidation phase of passive avoidance response (PAR) memorization. On the other hand, a mnemonic role during consolidation of at least two of these structures has been argued, based on several considerations. In order to ascertain whether the EC and FF are still involved in PAR memorization during consolidation, the coupled fully reversible functional tetrodotoxin (TTX) inactivation of MSA, FF and EC was performed in rats having undergone a PAR training. In Experiment 1 MSA, FF and EC were inactivated pair-wise (FF and EC always bilaterally). Permanently cannulated animals were injected stereotaxically with TTX (5 ng in 0.5 μl saline) or saline (0.5 μl) immediately following PAR acquisition. It was shown that combined FF–EC inactivation induced PAR retention impairment, whereas FF–MSA and EC–MSA inactivation was not followed by amnesic effects. Having obtained a positive result, in Experiment 2 the combined FF–EC inactivation was performed at different post-acquisition delays (0.25 h, 1.5 h, 6 h), so as to assess the duration of their involvement in PAR consolidation. It was shown that only the coupled inactivation performed at the shortest post-acquisition delay was followed by amnesic effects. Thus EC and FF play a definite role during early consolidation. The results are discussed in relation to EC, FF, MSA, and hippocampal involvement in PAR memorization, as reported in previous studies, and to their connectivity.     

Male mice exhibit better spatial working and reference memory than females in a water-escape radial arm maze task

The present study examined sex differences in spatial working and reference memory in C57BL/6 mice. Males and females were tested in a version of the spatial 8-arm radial arm maze in which the motivating stimulus was escape from water. To test spatial working memory, four arms were baited with submerged escape platforms, each of which was removed after it was found. Four arms that never contained platforms assessed spatial reference memory. In addition to determining the number of working memory and reference memory errors made in each session, working memory errors made in each trial were analyzed to examine performance as the number of arms to be remembered (i.e. the working memory load) increased. Males committed significantly fewer working memory and reference memory errors than females throughout testing. Within a session, males committed fewer working memory errors than females as the working memory load increased. These sex differences were particularly evident during task acquisition. The data indicate that male C57BL/6 mice learn both the working and reference memory components of a water-escape motivated radial arm maze task better than female mice.     

Lidocaine reversible inactivation of the median raphe nucleus has no effect on reference memory but enhances working memory versions of the Morris water maze task

Numerous studies in the past have dealt with the role of serotonergic system lesions in tasks aimed at measurement of cognitive behavior, but the literature concerning the role of serotonin in cognition remains controversial. Rats with electrolytic lesions of the median raphe nucleus (MRN) were found to display a profound impairment in both the acquisition and retention of spatial memory task. In this study, the lidocaine inactivation was employed to evaluate the involvement of the rat's median raphe nucleus in reference and working memory versions of the Morris water maze (MWM) task. Lidocaine (0.5 microl, 2%) was injected through a single cannula aimed at the MRN; control groups were treated in the same way with a 0.5 microl injection of saline. In Experiment 1, rats were trained in a reference memory version of the MWM with two blocks of four trials per day for three consecutive days, with intra-cerebral injection made 5 min before training. No significant difference was found. In Experiment 2, intra-cerebral injection was applied immediately after two blocks of four trials, and in Experiment 3, the drug was injected 5 min before retention test in rats that had received eight trials per day on three consecutive days. Again, no significant difference between control and treatment groups was found. These results indicate that MRN has no role in acquisition, consolidation and retrieval of spatial reference memory. In subsequent experiments, rats were trained in a working memory version of the MWM task to find a new target position in trial 1, and retrieval was tested 75 min later. MRN inactivation 5 min before (Experiment 4) and immediately after the acquisition trial (Experiment 5) enhanced spatial working memory. It is concluded that normal activity of the MRN has no role in formation and retrieval of reference memory, but it has an inhibitory role in working memory. Our results are confirmed with other studies suggesting that the serotonergic system has a different role in long-term and short-term memory. Interaction with other neurotransmitter systems like acetylcholine may be involved in this case.     

Auditory working and reference memory can be tested in a single situation of stimuli for the rat

The comparison of working and reference memory is one of the most valuable research angles for revealing the precise neural mechanisms of memory. The present study introduces a method to test both auditory working and reference memory during a short period in the rat. The apparatus and stimuli are identical for both memory tasks. High and low tones, between which lies a 5-s interval, are continuously presented. The task for working memory is a continuous nonmatching-to-sample. The rat makes go and no-go responses to indicate whether the current tone is the same as (match) or different from (nonmatch) the preceding tone. The task for reference memory is a continuous discrimination. The rat makes go responses on high-tone trials and no-go responses on low-tone trials. With alternate training in these tasks, the rat comes to perform well in both tasks. The rat can only know which task is employed in a given session from its own response-reward contingency during the early trials of each session.     

Material-specific lateralization of working memory in the medial temporal lobe

Mnemonic deficits in patients with medial temporal lobe (MTL) damage arising from temporal lobe epilepsy (TLE) are traditionally constrained to long-term episodic memory, sparing short-term and working memory (WM). This view of WM as being independent of MTL structures has recently been challenged by a small number of patient and neuroimaging studies, which have focused primarily on visual and visuospatial WM. In the present study we investigated material-specific lateralization of WM in 96 patients with unilateral damage to MTL stemming from TLE (56 left) and 30 control subjects using a pair of matched verbal and visuospatial supraspan tasks. Patients with unilateral TLE were impaired on both verbal and visuospatial WM tasks irrespective of the affected hemisphere. Patients with unilateral right TLE showed an additional deficit for visuospatial WM capacity when contrasted with patients with left TLE, whereas patients with unilateral left TLE showed increased intrusion errors on the verbal task when compared to patients with right TLE. These findings suggest a material-specific lateralization of WM in the MTL.     

Interaction between paraventricular nucleus and medial septal area on the renal effects induced by adrenaline

The aim of the present study was to analyze the role of alpha1, alpha2-adrenoceptors, and the effects of losartan and PD123319 (selective ligands of the AT1 and AT2 angiotensin receptors, respectively) injected into the paraventricular nucleus (PVN) on the diuresis, natriuresis, and kaliuresis induced by administration of adrenaline into the medial septal area (MSA). Male Holtzman rats with a stainless steel cannula implanted into the MSA and bilaterally into the PVN were used. The administration of adrenaline into the MSA increased in a dose-dependent manner the urine, sodium, and potassium excretions. The previous administration of prazosin (an alpha1-adrenoceptor antagonist) injected into the PVN abolished the above effects of adrenaline, whereas yohimbine (an alpha2-adrenoceptor antagonist) doesn't affect the diuresis, natriuresis, and kaliuresis induced by adrenaline. Pretreatment with losartan into the PVN decreased in a dose-dependent manner the urine, sodium, and potassium excretions induced by MSA administration of adrenaline (50 ng), while PVN PD123319 was without effect. These results indicate that urinary and electrolyte excretion effects induced by adrenaline into the MSA are mediated primarily by PVN AT1 receptors. However, the doses of losartan were more effective when combined with the doses of PD123319 than given alone, suggesting that the urinary, natriuretic, and kaliuretic effects of MSA adrenaline may involve activation of multiple angiotensin II receptors subtypes into the PVN.     

LP-BM5 infection impairs spatial working memory in C57BL/6 mice in the Morris water maze

Previous studies show that the LP-BM5 murine leukemia virus causes an acquired immunodeficiency syndrome in C57BL/6 mice (MAIDS) and impairs learning and memory without gross motor impairment. To assess spatial working memory impairment after LP-BM5 infection and the time course of this impairment, we tested mice in a modified working-memory version of the Morris water maze. Twenty mice were inoculated with LP-BM5; controls received medium (Minimum Essential Medium). In the test procedure, animals had two 1-min training sessions to learn the position of a randomly placed hidden platform. Thirty seconds after the second training session, animals were placed in the maze without the platform, and time and pathlength spent in each quadrant of the maze were measured. For 9 weeks after LP-BM5 infection, both groups showed preference for the target quadrant compared to the opposite quadrant. At 10 and 11 weeks after infection, the LP-BM5 virus infected mice lost this target quadrant preference. We conclude that LP-BM5 infection impaired spatial working memory in a modified working-memory version of the Morris water maze test in C57BL/6 mice at 10 and 11 weeks after virus infection.     

Unilateral reversible inactivations of the nucleus tractus solitarius and amygdala attenuate the effects of bombesin on memory storage

This study examined the role of the nucleus tractus solitarius (NTS) and amygdala in mediating the effects of bombesin (BBS) on retention of inhibitory avoidance training by reversibly inactivating these regions with lidocaine immediately following training. In Expt. 1, peripheral injection of different doses of BBS (1, 2.5, 5, 10 or 20 μg/kg) to unoperated rats immediately after training in one trial inhibitory avoidance task (1 mA, 1.5 s footshock) produced a dose-dependent response on retention test scores which was given two days after training. In Expts. 2 and 3, rats were surgically implanted unilaterally with cannula tip placed above the NTS or amygdala, were trained in task and then received unilateral injections of saline or lidocaine (2%, 0.5 μl) into the NTS or amygdala and peripheral injections of saline or BBS (5 μg/kg). The results showed that the memory enhancing effect of BBS was attenuated by unilateral inactivation of the NTS or amygdala. These findings indicate that the NTS and amygdala are involved in mediating the memory modulating effects of peripheral BBS on memory storage.     

Prenatal choline deficiency decreases the cross-sectional area of cholinergic neurons in the medial septal nucleus

Levels of dietary choline in utero influence postnatal cognitive performance. To better understand this phenomenon, forebrain cholinergic neurons were studied in the 8-9 month old offspring of dams fed a control or choline-deficient diet from EDs 11-17. Serial sections were immunostained with antibodies against p75, a cholinergic marker. Neuronal morphology was analyzed in the basal forebrain, a heterogeneous area composed of several structures including the medial septal nucleus (MSN), nucleus of the diagonal band (DB), and the nucleus basalis of Meynert (NB). Neuronal cross-sectional areas were selectively reduced in the MSN of choline-deficient animals, compared to controls, but cell counts were not altered. Our findings suggest that cholinergic medial septal neurons may be selectively vulnerable to in utero choline deficiency.     

Effects of medial septal lesions on operant delayed alternation in rats

The septohippocampal system regulates spatial behavior, memory and response flexibility. This experiment determined which of these functions is disrupted by medial septal lesions which impair operant delayed alternation in rats. Male hooded rats received either medial septal lesions or a control operation. Following recovery, they were reinforced for alternating left and right lever presses in an operant chamber. The effects of various delays (0, 10 and 20 s), and exteroceptive cues were assessed. Medial septal lesions did not impair alternation performance at the 0-s delay, but did produce severe impairments at the 10- and 20-s delays. An exteroceptive light cue which reduced the spatial requirements of the task did not ameliorate this impairment. However, an exteroceptive light cue which reduced the working-memory requirements of the task did ameliorate the lesion-induced deficit on delayed alternation. While the lesioned rats also made more perseverative errors than the controls, statistically removing this influence from the data did not modify the results. These data suggest that medial septal lesions in rats impair operant delayed alternation by disrupting the general process of working-memory rather than spatial behavior or response flexibility.     

Effects of emotionally valenced working memory taxation on negative memories

Background and objectives

Memories enter a labile state during recollection. Thus, memory changes that occur during recollection can affect future instances of its activation. Having subjects perform a secondary task that taxes working memory while they recall a negative emotional memory often reduces its vividness and emotional intensity during subsequent recollections. However, researchers have not manipulated the emotional valence of the secondary task itself.

Methods

Subjects viewed a video depicting the aftermath of three fatal road traffic accidents, establishing the same negative emotional memory for all subjects. We then tested their memory for the video after randomly assigning them to no secondary task or a delayed match-to-sample secondary task involving photographs of positive, negative, or neutral emotional valence.

Results

The positive secondary task reduced memory for details about the video, whereas negative and neutral tasks did not.

Limitations

We did not assess the vividness and emotionality of the subjects' memory of the video.

Conclusions

Having subjects recall a stressful experience while performing a positively valent secondary task can decrement details of the memory and perhaps its emotionality.     

Developmental D-methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory

In previous studies, we have shown that P11-20 treatment with D-methamphetamine (MA) (10 mg/kg x 4/day at 2-h intervals) induces impairments in spatial learning and memory in the Morris water maze after the offspring reach adulthood. Using a split-litter, multiple dose, design (0, 5, 10, and 15 mg/kg MA administered s.c. 4/day at 2-h intervals), the spatial learning effect was further explored with a multiple shifted platform (reversal), reference memory-based procedure and a working memory procedure. Prior to spatial learning, animals were first tested for swimming ability (in a straight swimming channel), sequential learning (in the Cincinnati multiple-T water maze), and proximal cue learning (in the Morris water maze). Rats were then assessed in the hidden platform, reference memory-based spatial version of the Morris maze for acquisition and on five subsequent phases in which the platform was moved to new locations. After the reference memory-based, fixed platform position learning phases, animals were tested in the trial-dependent, matching-to-sample, working memory version of the Morris maze. No group differences were found in straight channel, sequential maze, or cued Morris maze performance. By contrast, all MA groups were impaired in spatial learning during acquisition, multiple shift, and shifted with a reduced platform phases of reference memory-based learning. In addition, MA animals were impaired on memory (probe) trials during the acquisition and shifted with a reduced platform phases of learning. No effects on trial-dependent, matching-to-sample, working memory were found. The findings demonstrate that neonatal treatment with MA induces a selective impairment of reference memory-based spatial learning while sparing sequential, cued, and working memory-based learning.     

Effects of TDCS dosage on working memory in healthy participants

Background

Transcranial direct current stimulation (tDCS) has been found to improve working memory (WM) performance in healthy participants following a single session. However, results are mixed and the overall effect size is small. Interpretation of these results is confounded by heterogeneous study designs, including differences in tDCS dose (current intensity) and sham conditions used.

Limbic seizures, but not kindling, reversibly impair place learning in the Morris water maze

We investigated the effects of kindling and kindled seizures in different limbic structures on place and cue learning in the Morris water maze. The triggering of seizures by stimulation of the perforant path, septum, or amygdala prior to daily training impaired place learning, but had little effect on visible platform training or swim speed. Seizures triggered by stimulation of the medial perforant path after daily training also impaired place learning. Conversely, place learning proceeded normally in rats tested 24 h after kindling triggered by stimulation of the perforant path, septum, or amygdala, indicating that kindling per se does not affect place learning. Each group was able to learn the location of a reversed platform when pretraining seizures were discontinued; and perforant path and septal kindled rats, but not amygdaloid kindled rats, were impaired at learning the location of a reversed platform when seizures were triggered before training. The results confirm previous reports that limbic seizures produce amnesia, but they contradict the finding that hippocampal kindling impairs learning on tasks sensitive to hippocampal lesions.     

Applications of the Morris water maze in the study of learning and memory

The Morris water maze (MWM) was described 20 years ago as a device to investigate spatial learning and memory in laboratory rats. In the meanwhile, it has become one of the most frequently used laboratory tools in behavioral neuroscience. Many methodological variations of the MWM task have been and are being used by research groups in many different applications. However, researchers have become increasingly aware that MWM performance is influenced by factors such as apparatus or training procedure as well as by the characteristics of the experimental animals (sex, species/strain, age, nutritional state, exposure to stress or infection). Lesions in distinct brain regions like hippocampus, striatum, basal forebrain, cerebellum and cerebral cortex were shown to impair MWM performance, but disconnecting rather than destroying brain regions relevant for spatial learning may impair MWM performance as well. Spatial learning in general and MWM performance in particular appear to depend upon the coordinated action of different brain regions and neurotransmitter systems constituting a functionally integrated neural network. Finally, the MWM task has often been used in the validation of rodent models for neurocognitive disorders and the evaluation of possible neurocognitive treatments. Through its many applications, MWM testing gained a position at the very core of contemporary neuroscience research.     

The effects of working memory demands on the neural correlates of prospective memory

Event-related brain potentials (ERPs) were used to examine the reciprocal costs of working and prospective memory loads on the neural correlates of the realization of delayed intentions and the detection of target stimuli. The electrophysiological data revealed several interesting results: (1) distinct modulations of the ERPs were elicited by working memory targets and prospective memory cues, (2) working memory load modulated the amplitude of the N300 elicited by prospective memory cues, (3) prospective memory load was associated with a broadly distributed sustained modulation that began shortly after stimulus onset, and (4) brain-behavior correlations between the neural correlates of prospective memory and working memory varied with the working memory demands of the ongoing activity. These findings appear to indicate that attentional processes associated with the detection of prospective memory cues are sensitive to the working memory demands of the ongoing activity and that different processes may support prospective memory depending on the working memory demands of the ongoing activity.     

Medial septal modulation of entorhinal single unit activity in anesthetized and freely moving rats

Reversible inactivation of the medial septal area results in a spatial memory impairment and selective disruption of hilar/CA3, but not CA1, location-specific discharge. The present study examined the possibility that such septal deafferentation produces effects on hippocampal function by altering physiological properties of the primary input and output structures for hippocampus, the entorhinal cortex and the subiculum, respectively. Single unit activity of hippocampal, entorhinal, and subicular cells was recorded before, during, and after septal injection of lidocaine in anesthetized rats. When compared to hippocampal cells, relatively few subicular and entorhinal cells showed a change in mean firing rate following septal inactivation. Entorhinal unit responses to septal inactivation (via tetracaine injection) were also examined in freely moving rats performing a spatial maze task. About one-third of entorhinal cells showed enhanced or reduced firing rates of 40% or more. Also, the spatial distribution of cells found in the superficial, but not deep, entorhinal layers became less clear following septal inactivation. Together, these data are consistent with the hypothesis that manipulation of the medial septum affects hippocampal function via its septosubicular and septoentorhinal projections in addition to the more direct septohippocampal pathway. Since entorhinal cortical function was affected by tetracaine injection into the septum, it does not appear that direct entorhinal-CA1 afferents were primarily responsible for the maintenance of CA1 location-specific neural activity in previous septal inactivation experiments. Rather, these data are consistent with the hypothesis that the persistence of CA1 place fields was accomplished by intrahippocampal neural network operations.