Behavioral impairment in the rat after colchicine lesions of the hippocampus and nucleus basalis

Rats were given bilateral injections of colchicine into the nucleus basalis (NBM; 1.0 or 2.0 micrograms/site), hippocampus (HPC; 1.25 or 2.5 micrograms/site), or both areas (COM; 1.0 NBM, 1.25 HPC) and examined for changes in locomotor activity, passive avoidance behavior, and spatial navigation in a water maze task. Colchicine injected into the HPC caused a dose-related increase in locomotor activity 7 days after treatment which declined with repeated testing. Motor activity in NBM-lesioned rats was not significantly different from control. Rats with the COM lesion were more active than controls 7 days after treatment and remained hyperactive over the 3 week testing period. Retention of a step-through passive avoidance task was examined 18 days after surgery. HPC lesions had no apparent effect on passive avoidance behavior. NBM lesions causes a dose-dependent decrease in step-through latencies, while latencies in the combined group were comparable to the low dose NBM group. In the spatial navigation task, HPC and COM lesions impaired acquisition, with little indication of learning in the combined group. NBM lesions had no effect in the water maze. These data suggest that combined lesions of the NBM and HPC cause lasting behavioral impairments and may be useful as a model for neurodegenerative disorders such as Alzheimer's disease.     

Memory impairments following basal forebrain lesions

The functional contribution of the nucleus basalis magnocellularis (NBM) and medial septal area (MSA) to memory was evaluated in 4 behavioral tasks. The tasks were postoperative acquisition of a win-stay spatial discrimination in a T-maze, a win-shift spatial discrimination on a radial arm maze, active avoidance in a shuttle box, and passive avoidance in a shuttle box. Bilateral lesions were made by injecting ibotenic acid (IBO) into the NBM or MSA. Control rats received operations in which no neurotoxin was injected. When compared to controls, rats with lesions in either the NBM or MSA had significantly impaired choice accuracy in the T-maze and radial maze tasks, took significantly fewer trials to reach criterion in the acquisition, but not the retention of an active avoidance task, and significantly more trials to reach criterion in the passive avoidance task. The results show that equivalent behavioral changes are obtained from lesions in the NBM and MSA in tasks that vary in their type of motivation, reinforcement, response-reinforcement contingency, and response. These behavioral changes suggest that the NBM and MSA may both be involved in memory.     

Comparison of quisqualic and ibotenic acid nucleus basalis magnocellularis lesions on water-maze and passive avoidance performance

The present study compares water-maze (WM) (reference and working memory) and passive avoidance (PA) (acquisition and retention) deficits induced by ibotenic (ibo) and quisqualic (quis) acid nucleus basalis magnocellularis (NBM) lesions. Ibo lesions produced a large subcortical cell loss and a decrease in frontal cortex (FR) choline acetyltransferase (ChAT) activity. Ibo lesions impaired WM acquisition and PA acquisition and retention performance. Quis NBM lesions were restricted to the ventromedial pallidum, but ChAT activity was decreased in FR. Quis NBM lesions impaired PA acquisition and retention, but had no effect on the reference or working memory WM performance.     

Enhanced detection of nucleus basalis magnocellularis lesion-induced spatial learning deficit in rats by modification of training regimen

Bilateral excitotoxic lesions of the nucleus basalis magnocellularis (NBM) in the rat cause deficits in the water maze, a spatial memory paradigm. Previous investigations aimed at reversing the water maze performance deficit with anticholinesterase treatments have been unable to demonstrate a consistent drug effect due to the relatively good acquisition of the task seen following NBM lesions. The present investigation tested three different water maze training regimens designed to separate the learning curves. F-344 rats received bilateral NBM injections of ibotenic acid; sham-operated rats served as controls. The animals were tested in three groups in the water maze as follows: (1) four trials per day with no intertrial interval (standard paradigm), (2) four trials per day with a 10-minute intertrial interval, and (3) two trials per day with no intertrial interval. Each group was tested in the water maze for five consecutive days, followed by two days of rest, and then tested for an additional five days. The two-trial per day paradigm was more difficult than the standard paradigm for both lesions and controls and yielded the most difference between lesions and controls as compared to the other two testing regimens. The 10-min intertrial interval schedule was more difficult than the standard paradigm for lesioned animals but acquisition was not affected in control rats. These data demonstrate that the nucleus basalis lesions cause a deficit in the water maze task regardless of training parameters. Further, while all rats showed some acquisition of the water maze task, training schedule affected the level of learning of both lesioned and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurochemical and behavioral recovery after colchicine lesions of the nucleus basalis magnocellularis in rats

Experimentally-induced lesions of the basal forebrain have been used to test the hypothesis that the cholinergic system plays a critical role in learning and memory. In the present study, a basal forebrain infusion of colchicine, a microtubule assembly inhibitor, was used to characterize the relationship between a cholinergic marker and behavioral function. Bilateral infusions were made in the nucleus basalis magnocellularis (NBM) of male Long-Evans rats. At 4 weeks post-lesion, behavioral assessments were made on half of the rats in each group. These rats were sacrificed 1 week later and regional choline acetyltransferase (ChAT) activity was measured. The remaining rats were behaviorally tested 11 weeks post-lesion and sacrificed 12 weeks post-lesion. The brains of additional rats were studied for Nissl-staining, ChAT-, GAD- and metEnk immunoreactivity (IR) and AChE histochemistry. At 5 weeks after colchicine infusion, there was a significant decrease in parietal and frontal cortical ChAT activity, impaired acquisition of a water maze spatial navigation task and decreased passive avoidance cross-over latency. At 12 weeks after colchicine infusion, ChAT activity was decreased in frontal but not parietal cortex; acquisition of the water maze task was not significantly different from vehicle-infused rats, and a significant deficit was observed in passive avoidance latency. ChAT-IR in the NBM showed a significant decrease at both time points, while changes in AChE-stained cortical fibers paralleled the ChAT activity. GAD- and metEnk-IR were decreased but were not different between the two time points. These data show task-specific behavioral recovery associated in time with recovery of regional cholinergic markers.     

Reversal of learning and memory impairments following lesion of the nucleus basalis magnocellularis (NBM) by concurrent noradrenergic depletion using DSP4 in the rat.

In the following study the behavioural effects of simultaneous lesion of the nucleus basalis magnocellularis (NBM) using ibotenic acid and noradrenergic depletion following a single i.p. administration of DSP4 (50 mg/kg) were examined in the rat. NBM lesion induced a deficit in acquisition of a reinforced T-maze alternation task, a working memory adaptation of a spatial navigation task in a water maze and 24 h retention in a passive avoidance task compared to sham controls. No effect of the lesion on a reference memory version of spatial navigation in a water maze task was found. Animals that received a combination of NBM lesion and DSP4 treatment showed no impairment on any of the tasks that were impaired by NBM lesion alone. This indicates a reversal of the learning and memory deficits consequent to NBM lesion by simultaneous noradrenergic depletion. NBM lesion induced a significant reduction in choline-acetyltransferase activity in the frontal cortex, and DSP4 induced a significant decrease in noradrenaline concentration in occipital cortex and hippocampus, confirming the effects of these treatments. These results suggest an interaction between central noradrenergic and cholinergic systems in learning and memory processes.     

Behavioral and morphological consequences of primary astrocytes transplanted into the rat cortex immediately after nucleus basalis ibotenic lesion

Adult male rats received transplants of dissociated 30-day old cultured cortical astrocytes into the ipsilateral frontal and parietal cortex immediately after unilateral ibotenic acid lesion of the NBM or after sham injury. We hypothesized that transplants of astrocytes into the acetylcholine-deprived cortex might provide trophic support to terminals arising from damaged NBM neurons. Twenty four hours after transplantation and every other day for 11 days post surgery, the animals were tested for locomotion and habituation in an open field. NBM lesion reduced vertical movements only as compared to no lesion and no transplant counterparts. Nine days after surgery rats with NBM lesion and astrocyte-transplants into the cortex were as impaired in the acquisition of a passive avoidance (PA) task as untreated counterparts. Animals with no lesions and transplants into the cortex also had significant PA acquisition deficits. All rats with ibotenic lesion were significantly impaired on PA retention as compared to rats with no lesions. Astrocyte-transplants survived up to 2 months after cortical implantation but these transplants produced severe laminar disruption and gliosis. This effect was greater in rats with NBM lesion than in intact animals with transplants into the cortex. These data show that astrocyte-transplants do not promote functional recovery after NBM lesion and suggest an immune rejection of the astrocyte transplants by the host brain.     

Pretraining or previous non-spatial experience improves spatial learning in the Morris water maze of nucleus basalis lesioned rats

Previous experiments have shown that infusions of ibotenic acid in the nucleus basalis magnocellularis (NBM) induce a strong impairment in spatial navigation for a hidden platform in the Morris water maze. This effect was initially attributed to a cholinergic deficit, but later studies showed that performance level did not correlate with the degree of cholinergic denervation. Therefore, this impairment is due to a combined cholinergic and non-cholinergic deficit. However, it is not clear in which particular processes the NBM is involved. In this study we have evaluated the origin of behavioural impairment in spatial navigation in the water maze after an ibotenic acid-induced lesion of NBM. In the first experiment, Wistar rats were trained preoperatively in an allocentric navigation task. Postoperatively, they were tested in the same task. All lesioned animals showed a performance level similar to controls. Lesions did not impede the acquisition of new positions in the water maze, nor did affect the ability of animals to remember new platform positions after an intertrial interval of 20s, even if animals had received only allocentric experience with the platform position, or allocentric and path integration information concurrently. Lesions also failed to affect the ability to locate a hidden platform in a new environment. However, hippocampal infusions of scopolamine (5 microg) produced a severe impairment in NBM-damaged animals, without impairing performance of controls. In the second experiment Wistar rats with the same lesion were first trained in a visual-guided task in the water maze, and subsequently evaluated in the spatial task. In both tasks lesioned animals were not different from controls. These results suggest that the NBM played an important role during acquisition phases but not in the execution of spatial navigation. Moreover, the excessive emotional response displayed by lesioned animals is postulated as a relevant cause for the impairment observed in spatial navigation after NBM damage.     

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

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

Effects of Combined Ventral Forebrain Grafts to Neocortex and Amygdala on Behavior of Rats with Damage to the Nucleus Basalis Magnocellularis

In rats with damage to the nucleus basalis magnocellularis, transplantation of the embryonic ventral forebrain to the neocortex improves behavioral performance in some behavioral tasks. The present investigation focuses on improvement of behavioral performance by combined graft placement to both neocortrex and amygdala. Male rats received unilateral microinjections of quisqualate to the nucleus basalis magnocellularis to produce cell damage. Embryonic ventral forebrain cell suspensions were placed in one group of rats in the frontal and parietal neocortex, in a second group in the amygdala, and in a third group in the frontal and parietal neocortex and in the amygdala. These groups were compared to a group of nonoperated rats and a group of rats with damage but with no grafts. Quisqualate-induced damage to the nucleus basalis magnocellularis reduced cholinergic innervation in the ipsilateral cortical hemisphere, impaired performance in the one-trial training version of passive avoidance, and increased motility and time spent in the open arms of the elevated plus maze. Combined graft placement to neocortex and amygdala normalized performance of passive avoidance and restored the normal time spent in the open arms of an elevated plus maze. These results suggest that after damage to the nucleus basalis magnocellularis, modulation of function in multiple brain regions may be necessary for optimization of adaptive behavior in situations involving induction of fear.Nucleus basalis magnocellularis (NBM), Transplantation, Neocortex, Amygdala, Learning, Fear, Passive avoidance, Elevated plus maze (EPM).     

Chronic infusion of GABA and saline into the nucleus basalis magnocellularis of rats: II. Cognitive impairments

In order to assess sensorimotor and/or cognitive modifications following chronic inhibition of nucleus basalis magnocellularis (NBM) neurons, rats trained in two radial maze paradigms (the classical version of the test and a modified version introducing a one-hour delay between the fourth and the fifth choice) received chronic infusion of gamma-aminobutyric acid (GABA) into the NBM area. GABA (10 and 50 micrograms/microliters/h) was infused for 3 days into the NBM contralateral to their preferred turning direction in the radial maze. Simultaneously, saline (NaCl 0.9%; 1 microliter/h) was infused into the contralateral NBM. GABA and saline infusions were alternated for the subsequent 3-day period. One week later, we investigated the rats' ability to learn a multiple trial passive avoidance task. At the dose of 50 micrograms/microliters, GABA infusion produced (1) a turning bias ipsilateral to the side first infused with GABA, (2) transitory cognitive impairments in radial maze tasks and (3) a deficit in the acquisition of the passive avoidance task. At the dose of 10 micrograms/microliters, the same behavioral deficits were observed except that (1) the turning bias was reversed by the contralateral GABA infusion and (2) cognitive impairments in the radial maze were observed only when a delay was inserted between the fourth and the fifth choice. Histologically, we found a dose-dependent gliosis in the NBM area first infused with GABA. These data suggest a reactivity of the NBM to GABAergic manipulations and the intervention of this structure in both sensorimotor and cognitive processes involved in the radial maze paradigms.     

Neurotoxic lesions of the nucleus basalis induced by colchicine: effects on spatial navigation in the water maze

Neuronal loss in the nucleus basalis magnocellularis (NBM) has been consistently associated with learning and memory impairments. Previous studies have used excitotoxicants such as kainic acid or ibotenic acid to examine the behavioral consequences of NBM lesions. In the present study, rats were given bilateral injections of the neurotoxicant colchicine (1.0 micrograms/site) into the NBM and examined for changes in learning and memory. Unlike excitotoxicants, which can produce extensive subcortical damage, colchicine produced a lesion limited to the site of injection. Histological studies demonstrated that colchicine decreased the number of choline acetyltransferase (ChAT)-positive cells in the NBM, and resulted in a marked loss of cortical acetylcholinesterase staining. Separate neurochemical analysis showed that colchicine lesions decreased ChAT activity in the neocortex but not the hippocampus or caudate nucleus. Similar to previous studies, rats with NBM lesions showed a large deficit in a passive avoidance task. Lesions of the NBM impaired acquisition of a reference memory task in the Morris water maze. However, the deficit was transient and with continued training lesioned rats performed as well as controls. In a reversal test in the water maze the learning deficit reappeared. These data suggest that colchicine may be useful in producing lesions of the NBM, which primarily affects the rate of acquisition of a spatial reference memory task.     

Effects of oral administration of the competitive N-methyl-D-aspartate antagonist, CGP 40116, on passive avoidance, spatial learning, and neuromotor abilities in mice

The effects were investigated of the potent competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 40116[D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] on the performance of mice in water maze and passive avoidance tasks, and in wire suspension, rotarod, and cage activity tests. The drug was administered per os (p.o.) in its anticonvulsant dose range. CGP 40116 dose-dependently impaired passive avoidance learning when given before, but not when given after training. The antagonist (5, 10, and 20 mg/kg, administered 4 h before each training session) dose-dependently affected water maze acquisition, and impaired retention test performance in both hidden- and visible-platform water maze tasks. In addition, the drug dose-dependently decreased swimming speed during water maze acquisition. Repeated administration of CGP 40116 (20 mg/kg, p.o.) persistently decreased cage activity and wire suspension test performance, whereas motor coordination and equilibrium on the rotarod apparatus remained unimpaired. In our administration protocol, no tolerance was found to the effects of the drug on passive avoidance learning and neuromotor abilities. The parallel effects of CGP 40116 on memory and motor performance are discussed, and it was concluded that the antagonist impairs neuromotor abilities and also induces memory impairments which cannot be entirely reduced to motor interference.     

Effects of concurrent nicotinic antagonist and PCPA treatments on spatial and passive avoidance learning.

The present study investigates the effects of concurrent manipulations of nicotinic cholinergic receptors (mecamylamine 10 mg/kg, i.p.) and serotonin neurons (PCPA, 400 mg on each of 4 days) on spatial navigation (water maze, WM) and passive avoidance (PA) performance. PCPA treatment had no effect on WM navigation or PA performance of intact rats, but greatly aggravated mecamylamine induced performance deficit. Either single or combined treatments with hexamethonium (5.0 mg/kg, s.c.) and PCPA had no effect on WM or PA performance. These findings may suggest that nicotinic cholinergic receptors are also importantly involved in the cholinergic-serotonergic regulation of cognitive functioning.     

Spider toxin (JSTX-3) inhibits the memory retrieval of passive avoidance tests

Summary The effect of a spider toxin (JSTX-3)—a specific blocker of quisqualate sensitive type of glutamate receptors—on learning and memory was studied in mice using passive avoidance tests (step-through and step-down tests) and the water maze test. JSTX-3 was injected into lateral ventricles of chronically cannulated mice at a dose of 22.2 pmol/brain, which did not produce any apparent behavioral changes. This chemical significantly impaired the retrieval of memory in the step-through test and showed a similar (though not statistically significant) tendency in the step-down test, but it had no effect on acquisition or consolidation of memory in both tests. In the water maze test, this chemical had no effect on escape latencies.     

Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats

Substantial information is available concerning the influence of global hippocampal lesions on spatial learning and memory, however the contributions of discrete subregions within the hippocampus to these functions is less well understood. The present investigation utilized kainic acid to bilaterally lesion specific areas of the rat hippocampus. These animals were subsequently tested on a spatial orientation task using a circular water maze, and on an associative/contextual task using passive avoidance conditioning. The results indicate that both the dorsal CA1 and the ventral CA3 subregions play important roles in learning. Specifically, CA1 lesions produced a deficit in the acquisition of the water maze task and a significant memory impairment on the passive avoidance task. CA3 lesions also caused learning deficits in the acquisition of the water maze task, and produced even greater impairments in performance on the passive avoidance task. We conclude that CA1 and CA3 hippocampal subregions each play significant roles in the overall integration of information concerning spatial and associative learning.     

Effects of cytotoxic hippocampal lesions in mice on a cognitive test battery

Mice received cytotoxic lesions which selectively removed all of the hippocampus and dentate gyrus except the most ventral portions. They were impaired on both spontaneous and rewarded discrete-trial alternation in T-mazes. Acquisition of reference memory for the location of a hidden platform in the Morris water maze was impaired in lesioned mice. On an elevated Y-maze reference memory task, in which only one arm was rewarded, lesioned mice showed no evidence of learning. In a Lashley III maze task, however, where maze rotation demonstrated that control performance was independent of distal spatial cues, acquisition in the lesioned mice was unimpaired. Control levels of continuous spontaneous alternation in a Y-maze were too low to reveal a hippocampal deficit. A small impairment in acquisition of a multiple-trial passive avoidance task was seen in lesioned mice, despite a small but significant increase in reactivity to the footshock. These results are largely consistent with findings in hippocampal lesioned rats on the same or similar tasks, and reflect a major impairment of spatial cognition, with relative sparing of non-spatial task performance.     

Spatial learning in rats: Correlation with cortical choline acetyltransferase and improvement with NGF following NBM damage

Rats display an acquisition deficit in a circular water maze following excitotoxic lesions of the nucleus basalis magnocellularis (NBM). Experiments were therefore performed to determine if acquisition behavior on this task could predict the degree of cortical cholinergic deafferentation and if the acquisition deficit could be pharmacologically reversed. Performance on acquisition was highly correlated with the lesion-induced reduction in cortical choline acetyltransferase (ChAT) activity. Accuracy of spatial behavior was highly correlated to percentage ChAT depletion (r = 0.75). Neither lesioned rats nor controls displayed a retention deficit after a 9-day interval, nor did either group display a passive-avoidance retention deficit. To test the causal relationship between cholinergic dysfunction and spatial behavior, the central nervous system cholinergic enhancer nerve growth factor (NGF) was intraventricularly infused for 4 weeks. NGF infusion resulted in improved acquisition of the water maze task compared to NBM-lesioned rats receiving vehicle infusion and untreated rats with NBM lesions. These studies indicate that the decrease in cortical ChAT activity is likely to be responsible for the observed acquisition deficit and that pharmacological manipulations can be successfully used to improve behavior following NBM lesions.     

Rat strain differences in response to galanin on the Morris water task

Galanin acts as an inhibitory modulator of cholinergic transmission in the septohippocampal pathway of the rat. Centrally administered galanin induces performance deficits on rodent learning and memory tasks, including delayed non-matching to position, T-maze delayed alternation, passive avoidance, starbust radial maze acquisition, and the Morris water task. The present study investigates differences in responsiveness to intraventricularly administered galanin across three strains of laboratory rat on acquisition of spatial learning in the Morris water task. Sprague-Dawley rats showed normal performance during training, but lack of selective quadrant search on the probe trial in response to galanin treatment. Long-Evans rats showed no effects of galanin on performance during training or probe trial. Wistar rats showed longer latencies to reach the hidden platform during training, and lack of selective quadrant search on the probe trial in response to galanin. Performance on the visible platform task and on locomotor activity in the open field was normal in rats treated with galanin. These results are consistent with an interpretation of strain differences in sensitivity to the inhibitory actions of galanin on learning and memory.     

Behavioral effects of concurrent lesions of the nucleus basalis magnocellularis and the dorsal noradrenergic bundle.

The effects of separate and concurrent lesions to the cholinergic and noradrenergic (NE) systems were assessed in two water mazes. Lesion of the nucleus basalis magnocellularis (NBM) decreased performance in a spatial memory task (Morris water maze) while lesions of the dorsal NE bundle (DNB) enhanced the acquisition of this task independent of the NBM effects. Both lesions impaired performance on a water-escape motivated T-maze; however, the deficits induced by the combined lesion did not differ from the effects of either lesion alone. Neither lesion, nor their combination, had significant effects on open field activity. Biochemical analyses revealed almost total loss of NE in the cortex and hippocampus after DNB lesion, with relatively minor changes in other catecholamines or metabolites. Choline acetyltransferase activity was not significantly altered by the DNB lesion but was decreased in the cortex by the NBM lesion. These results suggest a task-specific effect of DNB lesion that is detectable under conditions of mild stress when floor effects are minimized.