Effect of reversible inactivation of reuniens nucleus on memory processing in passive avoidance task

The reuniens nucleus (RE) is the largest nucleus of the midline thalamic nuclei (MLN). RE has strongly connections with the amygdala and hippocampus, the structures that are involved in the learning and memory processes. In our previous report we have shown the role of RE in the spatial learning and memory using Morris water maze (MWM) task. Since RE is connected to multiple limbic structures, its involvement in the emotional learning and memory is a possibility. The present study was designed to elucidate the role of RE in acquisition, consolidation, and retrieval on the passive avoidance (PA) task which depends on a distributed network including the thalamus, amygdala, medial prefrontal cortex (mPFC) and hippocampus. For this purpose, rats were chronically implanted with a cannula aimed at the RE through which 0.5 μl tetracaine (2%) or saline were injected. Rats were trained in a PA task and their retention test was performed 24 h later. The injection of saline or tetracaine was applied 5 min before or 5, 90, and 360 min after the acquisition trial and 5 min before the retention tests. Our findings showed that inactivation of RE before training did not affect acquisition, but affected memory retention 24 h later in PA task. Moreover, inactivation of RE only 5 min after training impaired consolidation but not after 90 or 360 min. Also, inactivation of the RE, 5 min before the retrieval test impaired memory retrieval in PA task. In conclusion, it seems that RE is involved in memory processes in rats.     

Activation of hippocampal postsynaptic muscarinic receptors is involved in long-term spatial memory formation

Spatial memory has been strongly associated with hippocampal function. There are several reports of the participation of this structure in acquisition and consolidation of spatial tasks. In this study, we evaluated the effects of selective and non-selective muscarinic antagonists in the dorsal hippocampus of rats during acquisition and encoding of a spatial task. Rats were trained in a Morris water maze for 4 days with identical daily sessions, and tested for long-term memory (LTM) 1 week after training. The animals were injected bilaterally in the dorsal hippocampus 20 min before the start of every day of training. The results showed that the non-selective muscarinic antagonist, scopolamine, disrupted acquisition of water maze memory formation. Moreover, microinjections of a selective postsynaptic muscarinic antagonist, pirenzepine, disrupted LTM, whereas it did not affect acquisition. Conversely, a selective presynaptic muscarinic antagonist, AFDX-116, did not disrupt either water maze acquisition or LTM formation. Combination of AFDX-116 and pirenzepine had similar effects as scopolamine, partially blocking acquisition and impairing long-term spatial memory. These results support the view that muscarinic receptors are involved in spatial learning and that postsynaptic muscarinic receptors in the dorsal hippocampus are particularly involved in long-term spatial memory formation.     

Scopolamine blocks the effects of swim stress on memory retrieval in rats

Summary This study examined whether application of swim stress improved retrieval of a passive avoidance memory and if pretreatment with the anticho-linergic agent, scopolamine, blocked this effect on memory retrieval. Animals initially given a passive avoidance training session were subjected to either a two or four swim stress sessions (15 min each) with or without prior treatment of scopolamine (0.05 or 0.1 mg/kg). The retrieval performance in passive avoidance test and motor activity was assessed 24 hr after the last swim stress session. In an independent control experiment, the passive avoidance training and test were conducted respectively, 24 and 72 hr after the last of four swim stress sessions with or without prior injection of scopolamine (0.1 mg/kg). The results showed an enhanced performance for the passive avoidance task in rats subjected to four swim stress sessions in both experiments and scopolamine given 30 min prior to each stress session diminished this performance of animals in the passive avoidance test. Two swim stress sessions with or without scopolamine treatment caused no significant effects on the retrieval performance. Also, no significant difference was observed among the groups in motor activity following any of the stress treatments in the open field test. These results, thus suggested for the first time, a relationship among swim stress, cholinergic activity and avoidance memory processes.     

The effects of d-cycloserine, a partial agonist at the glycine binding site, on spatial learning and working memory in scopolamine-treated rats

Summary The present study investigated the effect of d-cycloserine, a partial agonist at the glycine binding site on NMDA receptor complex, on the performance of scopolamine-treated adult rats in a water maze task assessing spatial learning and in a delayed non-matching to position task assessing working memory in a spatial context. In the spatial learning task, scopolamine (0.4 mg/kg, i.p.) impaired acquisition (increased escape latency and distance) and increased swimming speed of rats. D-cycloserine (1.0 mg/kg, i.p.) reversed the deficits in acquisition performance but not the increases in behavioral activity. In the working memory task, scopolamine (0.2 mg/kg, i.p.) produced deficits on nonmnemonic rather than on mnemonic performance factors; scopolamine delay-independently decreased the percent correct responses and reduced behavioral activity of rats. D-cycloserine (1.0, 3.0 and 10 mg/kg, i.p.) did not reverse these performance deficits. When administered alone, the moderate to higher doses of d-cycloserine had no effects on working memory but the lower dose produced slight deficits in mnemonic performance factors; the 1.0 mg/kg dose delay-dependently decreased the percent correct responses without affecting behavioral activity of rats. In the water maze task, d-cycloserine had no effects on acquisition performance or behavioral activity of rats. These results suggest that acute, systemic administration of d-cycloserine does not improve spatial learning or working memory. However, at appropriate doses this agent may be efficacious in disease states of central cholinergic hypofunction since 1.0 mg/kg d-cycloserine was able to reverse the scopolamine-induced deficits in acquisition.     

Septo-hippocampal and nBM-cortical cholinergic neurones exhibit differential time-courses of activation as a function of both type and duration of spatial memory testing in mice

We previously showed that the initial acquisition session of a spatial discrimination (mixed reference/working memory) test in an 8-arm radial maze induced differential activations in the ascending cholinergic septo-hippocampal and nBM-cortical pathways in mice. This data showed that the duration of post-test cholinergic activation was longer in the nBM-cortical pathway than in the septo-hippocampal projection. Moreover, the post-test durations but not the immediate post-test amplitudes of activation in each pathway decreased progressively as a function of repeated daily acquisition sessions. In the present study we have thus tested the hypotheses that the time-courses of post-test cholinergic activation in the septo-hippocampal and nBM-cortical pathways may vary both as a function of the type of memory used (working vs. reference) and according to the duration of repeated daily testing. Cholinergic activity in vivo in the hippocampus or frontal cortex of mice was quantified using measures of sodium-dependent high-affinity choline uptake at two different times (30 s and 15 min) following specific spatial working or reference memory testing in an 8-arm radial maze. The memory tests were administered daily over a 13-day period to attain high levels of performance in each type of task. In comparison to control groups both types of memory testing induced significant post-test cholinergic activations in each brain region on Day 15. However, cholinergic activity remained elevated in frontal cortex at 15 min post-test following reference memory testing, whereas significantly shorter durations of cortical and hippocampal cholinergic activation were observed following working memory testing using short (1 min) retention intervals. The possible significance of these differential modifications to the time-course of the post-test activations in these cholinergic pathways in working and reference memory processes and the putative transsynaptic mechanisms involved are discussed.     

Negative and positive effects of intracerebroventricular scopolamine on memory in mice undergoing passive avoidance and escape tests

The effects of intracerebroventricular administration of scopolamine on memory and learning in the conscious, freely moving mouse were evaluated using step-down passive avoidance and water maze tests. A new technique was used that allows convenient injection into the cerebral ventricles without disturbing the animal's behavior. No significant changes in locomotor activity were observed after low doses of scopolamine (0.1 and 1.0 μg). However, 10 μg produced an increase in locomotor activity, while 100 μg caused an initial decrease followed by an increase in activity. In the passive avoidance test, scopolamine significantly impaired memory acquisition at doses higher than 1.0 μg, consolidation at a dose of 100 μg, and retrieval at doses of 10 and 100 μg. In contrast, a dose of 0.1 μg significantly improved consolidation and retrieval. In the water maze with a bridge, scopolamine either impaired memory acquisition, consolidation, and retrieval, or had no significant effect in the dose range tested. These results suggest that there are differences in the process of memory formation in the passive avoidance and escape tests.     

The locus coeruleus involves in consolidation and memory retrieval, but not in acquisition of inhibitory avoidance learning task

The locus coeruleus (LC) located at the level of the pons, is involved in cognitive functions such as learning and memory. The bilateral lidocaine-induced reversible inactivation of this nucleus has been considered in order to study its role in the phases of memory processing (acquisition, consolidation and retention) without any interference with the function of the same structure either during earlier and/or later phases of the same process. In this study, inhibitory avoidance (IA) learning task used to find the LC function in acquisition, consolidation and retrieval. Saline or lidocaine 4% (0.5 microl/side) microinjected into the LC, for assessing the acquisition (5 min before training), consolidation (5, 90 and 360 min after training) and memory retrieval, 5 min before testing. The retention test was done 24h after learning. Our results indicated that: (1) The bilateral functional inactivation of LC before training did not affect acquisition, but affected subsequent memory retention 24h later in IA task. (2) The lidocaine-induced inactivation of LC only 5 min after training impaired consolidation but did not affect it after 90 or 360 min. (3) Inactivation of the LC, 5 min before pre-retrieval test, impaired memory retrieval in IA task. In conclusion, it seems that the nucleus locus coeruleus does not affect acquisition while it involves in the memory consolidation and retrieval of inhibitory avoidance learning task.     

Intra hippocampal injection of testosterone impaired acquisition, consolidation and retrieval of inhibitory avoidance learning and memory in adult male rats

The hippocampus is essentially involved in learning and memory, and is known to be a target for androgen actions. Androgen receptors are densely expressed in CA1 of rat hippocampus, and mediate the effects of testosterone (T) on learning and memory. T depletion or administration can modulate neural function and cognitive performance. We conducted series of experiments to further investigate the effect of castration or intra hippocampal injection of T on acquisition, consolidation and retrieval of inhibitory avoidance learning and memory. Male adult rats were bilaterally cannulated into CA1 of hippocampus, and then received T (1, 10, 20, 40 and 80mug/0.5mul/side) or vehicle (DMSO), 30min before training, immediately after training and 30min before retrieval in inhibitory avoidance task. Castration was made by gonadectomy of male rats and behavioral tests performed 4 weeks later. Our results showed that gonadectomy of male rats did not influence performance on inhibitory avoidance task, as compared to sham-operated rats. We have also found that pre-training, post-training and pre-retrieval intra CA1 injections of T significantly decreased step-through latencies in inhibitory avoidance learning at doses 1 and 80, 20, and 20 and 40mug/0.5mul/side, respectively. The data suggest that intra CA1 administration of T could impair learning and memory acquisition, consolidation and retrieval, while systemic androgen's depletion have no effect on memory, in inhibitory avoidance task.     

Effects of complete immunotoxin lesions of the cholinergic basal forebrain on fear conditioning and spatial learning

Administration of muscarinic cholinergic antagonists such as scopolamine impairs the acquisition of contextual fear conditioning, but the role of the basal forebrain (BF) cholinergic system in consolidation is unclear. To test the hypothesis that BF cholinergic neurons are critical for acquisition and consolidation of fear conditioning, male Sprague-Dawley rats with 192 IgG-saporin lesions of the entire cholinergic BF made either before or after fear conditioning were tested for conditioned fear to context and tone by assessing freezing and 22 kHz ultrasonic vocalization (USV) responses. Spatial learning in a 1-day water maze task provided a comparison for effects of the BF lesions on fear conditioning. In the test phase, neither pre-training nor posttraining BF lesions affected freezing to the context or tone. During both training and testing, pre-lesioned rats were impaired in production of USVs associated with fear. Postlesioned rats emitted fewer USVs only during testing. Acquisition of a spatial water maze task was mildly impaired in lesioned rats, although probe trial and cued performance was unimpaired. Nevertheless, these data suggest that conditioned fear-induced USVs are more sensitive to the loss of BF cholinergic neurons than is conditioned fear-induced freezing. The failure of BF cholinergic lesions to impair contextual fear conditioning indicates that scopolamine-induced impairments in fear conditioning may not be mediated by affecting cholinergic input to the hippocampus and neocortex.     

Effects of pentylenetetrazol-induced brief convulsive seizures on spatial memory and fear memory

Previous studies have demonstrated that in the pentylenetetrazol (PTZ) kindling model, recurrent seizures either impair or have no effect on learning and memory. However, the effects of brief seizures on learning and memory remain unknown. Here, we found that a single injection of a convulsive dose of PTZ (50 mg/kg, ip) induced brief seizures in Sprague–Dawley rats. Administration of PTZ before training impaired the acquisition of spatial memory in the Morris water maze (MWM) and fear memory in contextual fear conditioning. However, the administration of PTZ immediately after training did not affect memory consolidation in either task. These findings suggest that brief seizures have different effects on acquisition and consolidation of spatial and fear memory.     

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.     

Chronic epigallocatechin-3-gallate ameliorates learning and memory deficits in diabetic rats via modulation of nitric oxide and oxidative stress

Due to anti-diabetic and antioxidant activity of green tea epigallocatechin gallate (EGCG) and the existence of evidence for its beneficial effect on cognition and memory, this research study was conducted to evaluate, for the first time, the efficacy of chronic EGCG on alleviation of learning and memory deficits in streptozotocin (STZ)-diabetic rats. Male Wistar rats were divided into control, diabetic, EGCG-treated-control and -diabetic groups. EGCG was administered at a dose of 20 and 40 mg/kg/day for 7 weeks. Learning and memory was evaluated using Y maze, passive avoidance, and radial 8-arm maze (RAM) tests. Oxidative stress markers and involvement of nitric oxide system were also evaluated. Alternation score of the diabetic rats in Y maze was lower than that of control and a significant impairment was observed in retention and recall in passive avoidance test (p < 0.01) and EGCG treatment (40 mg/kg) of diabetic rats significantly improved these parameters (p < 0.05). Also, diabetic animals exhibited fewer correct choices (p < 0.01) and more errors (p < 0.005) in the RAM task and EGCG (40 mg/kg) significantly ameliorated these changes (p < 0.05). Further, pretreatment with l-arginine as a substrate for nitric oxide synthase (NOS) and/or 7-nitroindazole as a neuronal NOS inhibitor attenuated and potentiated the beneficial effect of EGCG regarding learning and memory respectively. Meanwhile, increased levels of malondialdehyde (MDA) and nitrite in diabetic rats significantly reduced due to EGCG treatment (p < 0.05). In summary, chronic green tea EGCG dose-dependently could ameliorate learning and memory deficits in STZ-diabetic rats through attenuation of oxidative stress and modulation of NO.     

The influence of adenosine A3 receptor agonist: IB-MECA,on scopolamine- and MK-801-induced memory impairment

The effects of adenosine A3 agonist IB-MECA on scopolamine- and MK-801-induced impairment of spontaneous alternation and learning abilities were examined using Y-maze and passive avoidance tasks in mice. IB-MECA given 20 min before test had no effect on spontaneous alternation performance. Similarly learning abilities tested in passive avoidance were not disturbed after IB-MECA administration before training session. IB-MECA significantly diminished scopolamine- and MK-801-induced impairment of spontaneous alternation in Y-maze and learning abilities in passive avoidance task as well as reduced higher locomotor activity in MK-801-treated group. This ameliorating effect of IB-MECA was not antagonised by adenosine A1 antagonists CPX. Obtained results indicate that adenosine A3 receptor stimulation may ameliorate spatial memory and long term memory impairments in terms of cholinergic and glutamatergic deficits induced by scopolamine and MK-801, respectively.     

The effects of alpha-2 adrenoceptor antagonist, atipamezole, on spatial learning in scopolamine-treated and aged rats

Summary In order to study whether noradrenergic drugs improve age-related cognitive dysfunctions the present experiments investigated whether atipamezole, a selective and specific alpha-2 antagonist, improves spatial learning impairment due to cholinergic blockade (scopolamine 0.8 mg/kg) or aging in rats. Previously, it has been shown that atipamezole dose-dependently (0.03–3.0 mg/kg) increases the turnover of noradrenaline in rat brain. According to the present results, atipamezole (0.1, 0.3, 0.6 mg/kg) did not affect spatial learning/memory when assessed in a free swim trial of the water maze task in control rats. Furthermore, atipamezole (0.1, 0.6 mg/kg) did not improve learning deficit in scopolamine treated young rats. Higher doses (1.0 mg/kg) of atipamezole could not be tested, because they induce floating behaviour in rats. In aged rats, which were screened to be impaired in the initial acquisition of the water maze task, 0.3 mg/kg atipamezole impaired further learning of this task. Because previous studies suggest that age-related learning impairment in the water maze may be, at least partly, due to a cholinergic deficit, the present results suggest that atipamezole which increases the release of noradrenaline in brain does not alleviate this learning deficit.     

Concurrent muscarinic and beta-adrenergic blockade in rats impairs place-learning in a water maze and retention of inhibitory avoidance

These experiments examined the effects of separate and concurrent muscarinic cholinergic and beta-adrenergic blockade on inhibitory (passive) avoidance performance and spatial learning in the Morris water maze. Pretraining systemic administration of either scopolamine (0.3 or 1.0 mg/kg) or propranolol (3.0 or 10.0 mg/kg) had no significant effect on one-day retention of step-through inhibitory avoidance training. Similarly, pretraining administration of either 0.3 mg/kg scopolamine or 10 mg/kg propranolol did not affect spatial learning in the Morris water maze. However, combined administration of scopolamine and 10.0 mg/kg of propranolol impaired performance on these tasks. These findings further support a role for interactions between norepinephrine and acetylcholine in the modulation of learning and memory and implicate the participation of beta-adrenergic mechanisms in this interaction. Because cholinergic and noradrenergic deterioration is found in aging and Alzheimer's disease, these results also have implications regarding the role of age-related noradrenergic and cholinergic dysfunction in cognitive decline.     

Effects of excitotoxic median raphe lesions on scopolamine-induced working memory deficits in inhibitory avoidance

The aim of the present study was to investigate the effects of excitotoxic damage of the serotonergic cell bodies in the median raphe nucleus (MRN) on the scopolamine-induced working memory deficits in a single-trial light/dark inhibitory avoidance task. Rats were given 1 mg/kg of scopolamine hydrobromide (intraperitonal, i.p.) or saline before the inhibitory avoidance training, in which initial preference to the dark compartment (escape latency) was used to measure nonmnemonic behaviors, and response latency to enter the dark compartment immediately after the shock was used to measure working memory. It was found that scopolamine significantly reduced escape latencies in sham-lesioned rats, whereas it had no effect in the rats with MRN lesions. Although MRN lesion per se did not alter response latency, it prevented scopolamine-induced decrease in this parameter. These results suggest that the antagonistic interactive processes between serotonergic projections of the MRN and the muscarinic cholinergic system modulate nonmnemonic attentional component of working memory formation in the inhibitory avoidance.     

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.     

Improved learning and memory in aged rats with chronic administration of the nicotinic receptor agonist GTS-21

The ability of two synthetic nicotine receptor ligands, GTS-21 and DMAB, to chronically enhance the cognitive function of aged rats was evaluated in three diverse tasks and compared to the cognition-enhancing effects of nicotine administration. 15 min prior to daily behavioral testing, aged 22–24 month old rats received an i.p. injection of nicotine (0.2 mg/kg), GTS-21 (1 mg/kg), DMAB (2 mg/kg), or saline vehicle and were tested in either one-way active avoidance pole jumping, Lashley III maze, or a 17-arm radial maze. GTS-21 pretreatment was as effective as nicotine for enhancing the acquisition of aged rats in both one-way active avoidance and Lashley III maze training. In 17-arm radial maze testing, GTS-21 improved both general learning and reference (long-term) memory to the same extent as nicotine. Although DMAB pretreatment enhanced reference memory in 17-arm radial maze testing to the same extent as nicotine, it did not affect general learning in this complex task and did not exert any cognition-enhancing effects in Lashley III maze training. These results indicate that GTS-21 has cognition-enhancing abilities in aged rats that are comparable to those of nicotine in a variety of behavioral tasks. Since GTS-21 acts preferentially on brain nicotinic receptors and is less toxic than nicotine, these results further indicate that GTS-21 may have substantive therapeutic value in the treatment of age-associated memory impairment (AAMI) and/or Alzheimer's disease.     

Simultaneous modulation of retrieval by dopaminergic D(1), beta-noradrenergic, serotonergic-1A and cholinergic muscarinic receptors in cortical structures of the rat.

Retrieval of inhibitory avoidance has been recently shown to require intact glutamate receptors, protein kinases A and C and mitogen-activated protein kinase in the CA1 region of the rat hippocampus and in the entorhinal, posterior parietal and anterior cingulate cortex. These enzymatic activities are known to be modulated by dopamine D(1), beta-noradrenergic, 5HT1A and cholinergic muscarinic receptors. Here we study the effect on retrieval of this task of well-known agonists and antagonists of these receptors infused in the same brain cortical regions and into the basolateral amygdala, in rats. The drugs used were SKF38393 (D(1) agonist), noradrenaline, 8-HO-DPAT (5HT1A agonist), oxotremorine (muscarinic agonist), SCH23390 (D(1) antagonist), timolol (beta antagonist), NAN-190 (5HT1A antagonist) and scopolamine (muscarinic antagonist). All were studied at two different dose levels. The localised infusion of SKF38393, noradrenaline, NAN-190 and oxotremorine into any of the cortical structures mentioned 10 min prior to a 24-h retention test session of one-trial step-down inhibitory avoidance enhanced retention test performance. SCH2330, timolol, 8-HO-DPAT and scopolamine hindered retention test performance. In the basolateral amygdala only an enhancing effect of noradrenaline and an inhibitory effect of timolol were seen. Three hours after the infusions, retention test performance returned to normal in all cases. None of the treatments affected locomotion or rearing in an open field or behaviour in the elevated plus maze. Therefore, their effects on retention testing can be attributed to an influence on retrieval. In conclusion, memory retrieval of this apparently simple task requires the participation of CA1, entorhinal, posterior parietal and anterior cingulate cortex, and is strongly modulated by, dopaminergic D(1), beta-noradrenergic, muscarinic cholinergic and 5HT1A receptors in the four areas. The first three types of receptor enhance, and the latter inhibits, retrieval. Only beta-adrenoceptors appears to be involved in the modulation of retrieval of this task by the amygdala. The results bear on the well-known influence of emotion and mood on retrieval, and indicate that this involves many areas of the brain simultaneously. In addition, the results point to similarities and differences between the modulatory mechanisms that affect retrieval and those involved in the consolidation of the same task.     

Characteristics of memory impairment following lesioning of the basal forebrain and medial septal nucleus in rats

Memory impairment in rats with lesions of the basal forebrain (BF) and medial septal nucleus (MS) including cell bodies of the cortical and septohippocampal cholinergic systems, respectively, were compared in order to evaluate the functional contribution of the two cholinergic systems to memory. Biochemical assay revealed that lesioning of the BF and MS resulted in marked and selective decreases in both choline acetyltransferase and acetylcholinesterase activities in the cerebral cortex and hippocampus, respectively. Rats with BF lesions exhibited a severe deficit in a passive avoidance task; acquisition of passive avoidance by repeated training was sluggish, and the acquired response was rapidly eliminated in a subsequent extinction test. However, only slight impairment of passive avoidance was observed in rats with MS lesions. Memory impairment in rats with BF or MS lesions was also investigated using two spatial localization tasks, the Morris water task and the 8-arm radial maze task. Both BF and MS lesions elicited a significant impairment in the Morris water task that required reference memory, as demonstrated by an apparent increase in the latency to escape onto a hidden platform in a large water tank. The impairment was much more obvious in the BF-lesioned rats. In contrast, in the radial maze task primarily requiring working memory, rats with lesions of the MS showed severe disruption, exhibiting a marked increase in total errors, a decrease in the number of initial correct responses, and an apparent change in the strategy pattern. However, corresponding changes in the rats with BF lesions were slight. These results suggest that BF lesions may lead to substantial long-term memory impairment while MS lesions may primarily produce short-term or working memory impairment, indicating a qualitatively different contribution of the two cholinergic systems to memory. It is also suggested that these two experimental animal models may be useful for evaluation of therapeutic drugs for senile dementia of the Alzheimer type.