Lesions in nucleus basalis magnocellularis and medial septal area of rats produce qualitatively similar memory impairments

The functional contribution of nucleus basalis magnocellularis (NBM) and the medial septal area (MSA) to memory was evaluated in two different spatial discriminations. Preoperatively, rats were trained to a criterion level of performance in a simultaneous left/right discrimination on the stem of a T-maze (a trial-independent memory) and a discrete-trial, rewarded alternation discrimination on the arms of the T-maze (a trial-dependent memory). Bilateral lesions were made by injecting ibotenic acid (IBO) into the NBM, MSA, both NBM and MSA, or dorsal globus pallidus (DGP), and by radiofrequency current (RF) in the NBM and MSA. Control rats received operations in which either no current was passed or no neurotoxin was injected. Lesions in the NBM, MSA, or both the NBM and MSA produced a similar pattern of behavioral changes relative to the performance of controls; postoperative reacquisition of the arm discrimination was initially impaired but showed recovery to normal levels, whereas postoperative reacquisition and reversal of the stem discrimination was not impaired (except following the combined NBM and MSA lesion). Lesions of the DGP had no effect on choice accuracy in any discrimination. When the discrimination on the arms was made more difficult by increasing the delay interval during which the information had to be remembered, rats with combined NBM and MSA lesions were again impaired relative to controls and showed no signs of recovery of function. These results provide information about the behavioral functions of the basal forebrain cholinergic system and suggest that pathological changes in certain components of this system can cause disorders of memory.     

Behavior alters the uptake of [3h]choline into acetylcholinergic neurons of the nucleus basalis magnocellularis and medial septal area

Behavioral experience changed sodium-dependent high affinity choline uptake (SDHACU) in the hippocampus and frontal cortex. Rats were trained on various behavioral tasks and sacrificed after testing. SDHACU was determined in frontal cortex and hippocampus, areas that receive cholinergic innervation from the nucleus basalis magnocellularis (NBM) and the medial septal area (MSA), respectively. Untrained rats taken directly from their home cages had fairly consistent levels of SDHACU in the hippocampus (1.76 ± 0.45, X ± S.E.) and frontal cortex (1.46 ± 0.37). In the hippocampus of rats performing in a radial maze and T-maze and in rats that surpassed a criterion level in an active avoidance task, SDHACU increased significantly above Cage (untrained) group levels. In the cortex of rats performing the radial maze task, SDHACU decreased slightly. There were no other changes in frontal cortical SDHACU. After behavioral testing ceased, SDHACU in rats performing the radial maze task remained elevated above Control and Treadmill group levels for 20 days, but returned to near control levels 40 days later. Our data demonstrate that a functional differentiation exists between the MSA and NBM cholinergic systems, and that the measurement of SDHACU in central cholinergic neurons is a useful tool to identify the influences of behavior and environment upon changes in neurochemical events and neuronal activity.     

Nucleus basalis lesions: Implication of basoamygdaloid cholinergic pathways in memory

Previous studies have shown a lack of association between cortical choline acetyltransferase (ChAT) activity and severity of memory impairment following excitotoxic lesions of the nucleus basalis magnocellularis (NBM). It recently has been proposed that the differential effects of NBM injections of various excitotoxins on amygdaloid and cortical ChAT may explain this result. The present study evaluated the mnemonic effect of unilateral intra-NBM infusions of the excitotoxins phthalic acid and quisqualic acid, which decrease ChAT activity primarily in the amygdala and cortex, respectively. Rats were trained in a double Y-maze, lesioned, and allowed to recover for 1 week prior to memory assessment. Behavioral results showed impaired working but not reference memory following phthalic acid lesions, and no significant effect following quisqualic acid lesions. Biochemical analysis in a second group of subjects confirmed that phthalic acid lesions produced a large decrease in basolateral amygdaloid ChAT, but had little effect on cortical ChAT activity. Conversely, quisqualic acid lesions produced a large decrease in cortical, but not basolateral amygdaloid, ChAT activity. These results suggest that the NOM amygdalopetal cholinergic pathways play a role in mnemonic functioning.     

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.     

Unilateral AMPA lesions of nucleus basalis magnocellularis induce a sensorimotor deficit which is differentially altered by arecoline and nicotine

One week after unilateral -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) lesions of nucleus basalis magnocellularis, rats showed significant lateralised bias in spontaneous turning and in turning induced by tail pinch or by placing the rat on a 45° grid. Turning was biased to the lesioned side and this side also showed increased responsiveness to pin-prick stimulation of the skin (somaesthesia), snout and whisker stimulation and ammonia olfaction. Arecoline (0.5 mg/kg), at a dose which did not affect responses to sensorimotor stimulation in sham-operated rats, corrected the lesion-induced biased turning to tail pinch and the 45° grid test and reduced the bias in the open field. In contrast, nicotine (0.05 mg/kg), at a dose which also did not substantially affect responses to sensorimotor stimulation in sham-operated rats, switched the lesion-induced turning bias towards the contralateral side. Neither cholinoceptor agonist reduced the lesion-induced increased sensory responsiveness. The effects of nicotine were blocked by the centrally acting nicotinic antagonist, mecamylamine (1.0 mg/kg), but not by hexamethonium (1.0 mg/kg), or ondansetron (0.01 mg/kg). Amphetamine (up to 1.0 mg/kg) did not affect the lesion-induced motor asymmetry. The results confirm that the basal forebrain cholinergic system plays a role in sensorimotor cortical functions, but suggest different functional roles for muscarinic and nicotinic receptors.     

Nucleus basalis magnocellularis electrical stimulation facilitates two-way active avoidance retention, in rats

We studied the effects of post-training intracranial electrical stimulation of the nucleus basalis magnocellularis on two-way active avoidance retention. After the acquisition, rats were stimulated for 20 min, and they were tested again after 24 h or 11 days. The treatment improved memory consolidation, especially in animals with a low initial learning ability. These facilitative effects could be attributed to an enhancement of cortical and/or amygdala activation, leading to an improvement in associative processes and/or cortical plasticity.     

Place navigation in rats is impaired by lesions of medial septum and diagonal band but not nucleus basalis magnocellularis

The role of forebrain cholinergic projections in place navigation learning was assessed in two experiments. Following surgery, rats were required to learn the spatial location of an underwater platform on the basis of distal room cues. Bilateral injections of ibotenic acid into the nucleus basalis magnocellularis depleted choline acetyltransferase (ChAT) from the anterior and temporoparietal cortex but not the hippocampus. Separate histological studies confirmed the accuracy of the lesions and demonstrated a marked loss of cortical acetylcholinesterase. These rats subsequently showed no deficits in spatial learning or memory. In a second experiment, bilateral lesions of the vertical limb of the diagonal band of Broca and medial septum depleted ChAT from the hippocampus and posterior cortex but not the anterior cortex. Histological studies confirmed the accuracy of the lesion and showed a pronounced loss of acetylcholinesterase from the hippocampus. These rats were deficient in spatial learning and showed reduced spatial bias during transfer tests. The data are discussed in the light of the hypothesis that the cholinergic innervation of the hippocampus plays a key role in spatial reference memory processes involved in place navigation.     

Crossed unilateral lesions of medial forebrain bundle and either inferior temporal or frontal cortex impair object recognition memory in Rhesus monkeys

In monkeys, section of the fornix, amygdala and anterior temporal stem results in a severe anterograde amnesia. Immunolesions of the cholinergic cells of the basal forebrain suggest that this amnesia is a result of isolating the inferior temporal cortex and medial temporal lobe from their cholinergic basal forebrain afferents. In this experiment, six monkeys were trained in a delayed match-to-sample task and then received a section of the medial forebrain bundle in one hemisphere and an ablation of either the frontal or inferior temporal cortex in the opposite hemisphere. All the animals were severely impaired in the performance of this task following this surgery, and the severity of the impairment was independent of the cortical area from which the medial forebrain bundle was disconnected. These results support a model of fronto-temporal interaction via the basal forebrain in new learning, in which midbrain sites related to reward modulate the cholinergic basal forebrain activity.     

Excitotoxic basolateral amygdala lesions potentiate the memory impairment effect of muscimol injected into the medial septal area

In rats, the septo-hippocampal system is important for memory encoding. Previous reports indicate that muscimol, a specific GABAergic agonist induces learning and memory deficits when infused into the medial septal area. The basolateral nucleus of the amygdala (BLA) modulates memory encoding in other brain areas, including the hippocampus. To explore the interactions between the septo-hippocampal system and amygdala in memory, we studied the effects of intra-medial septal infusions of muscimol in rats with BLA lesions. Animals received sham surgery or excitotoxic BLA lesions and were given infusions of either vehicle or muscimol (5 nmol) into the medial septal area 5 min prior to training sessions in inhibitory avoidance and water maze tasks. In the inhibitory avoidance task, muscimol-induced memory impairment was potentiated by BLA amygdala lesions. Additionally, in the water maze task, BLA-lesioned rats given muscimol infusions into the medial septal also showed memory impairment. These findings indicate that the MSA interacts with the BLA in the processing of memory storage.     

Hiding in plain view: lesions of the medial temporal lobe impair online representation

The hippocampus is necessary for the normal formation of enduring declarative memories, but its role in cognitive processes spanning short intervals is less well understood. Within the last decade, several reports have described modest behavioral deficits in medial temporal lobe (MTL)-lesion patients when they perform tasks that do not seem likely to rely on enduring memory. An intriguing but sparsely-tested implication of such results is that the MTL is involved in the online representation of information, possibly of an associative/relational nature, irrespective of delay. We administered several tests that simultaneously presented all information necessary for accurate responses to a group of MTL-lesion patients with severe declarative memory deficits but otherwise normal cognition, and to matched brain-damaged and healthy comparison participants. MTL-lesion patients performed less well than either comparison group in the Hooper Visual Organization Test, and several patients performed outside the normal range on the Overlapping Figures Test. A novel follow-up borrowing characteristics of the Overlapping Figures Test revealed impaired identification of novel items by MTL-lesion patients when target items were obscured by distracters, and two additional novel tests of fragmented object identification further implicated the hippocampus/MTL in the integration of information across very brief intervals. These findings suggest that MTL structures including the hippocampus contribute similarly to cognition irrespective of timescale.     

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.     

Impairment in T-maze reinforced alternation performance following nucleus basalis magnocellularis lesions in rats

Rats were trained on a reinforced alternation paradigm using an elevated T-maze. After pre-surgical training subjects received either ibotenic acid (4 micrograms/0.4 microliter) or vehicle (pH 7.4, 0.4 microliter) bilaterally into the region of the nucleus basalis magnocellularis--an important source of neocortical acetylcholine projections. Acetylcholinesterase staining of sectioned brains revealed a loss of neocortical, but not hippocampal staining in lesioned animals. On the T-maze task, lesioned rats showed significantly impaired choice performance relative to controls. They also demonstrated significant side biases, the degree of which was correlated with choice performance deficit.     

Nucleus basalis lesions decrease alpha- and kappa-bungarotoxins binding in rat cortex

A unilateral ibotenic acid lesion of the nucleus basalis magnocellularis in the rat, which is known to produce a reduction in cortical choline acetyltransferase activity and acetylcholine release, produces a decrease of 125I-alpha-bungarotoxin and 125I-kappa-bungarotoxin binding sites in the frontoparietal cortex of the lesioned hemisphere. This decrease can be observed at two weeks following the lesion and persists for up to twelve weeks. The results suggest that a population of bungarotoxin binding sites may have a presynaptic localization.     

Failure of chronic physostigmine to ameliorate working memory deficits after medial septal lesions

To assess the potential usefulness of chronic acetylcholinesterase inhibition in the treatment of learning/memory disorders arising from central cholinergic deficient states, physostigmine was administered chronically to rats with medial septal lesions and the retention of a spatial/working memory task investigated. Three dose levels of physostigmine (0.025, 0.05, 0.075 mg/kg) were administered three times per day following medial septal lesions. Retention of a standard radial 8-arm maze task was assessed. Although the lesions transiently disrupted task performance, physostigmine therapy did not improve either daily performance or total recovery time. Our results suggest that chronic acetylcholinesterase inhibition is not effective in ameliorating the working memory deficits that occur after medial septal lesions.     

Spatial memory deficits in patients with lesions affecting the medial temporal neocortex

Lesion studies in monkeys suggest that neocortical subregions of the medial temporal lobe (MTL) carry memory functions independent of the hippocampal formation. The present study investigates possible differential contributions of MTL subregions to spatial memory in humans. Eye movements toward remembered spatial cues (memory-guided saccades) with unpredictably varied memorization delays of up to 30 seconds were recorded in patients with postsurgical lesions of the right MTL, either restricted to the hippocampal formation (n = 3) or including the adjacent neocortex (n = 5) and in 10 controls. Although saccadic targeting errors of patients with selective hippocampal lesions did not differ from controls, saccadic targeting errors of patients with additional neocortical involvement showed a significant and contralaterally pronounced increase at memorization delays above 20 seconds. We conclude that the human medial temporal neocortex carries spatial memory functions independent of the hippocampal formation and distinct from spatial short-term memory.     

Differences in memory impairment and response to GM1 ganglioside treatment following electrolytic or ibotenic acid lesions of the nucleus basalis magnocellularis

Alzheimer's disease is a progressive dementia associated with cholinergic cell loss in the nucleus of Meynert that induces deficiencies in cholinergic neurotransmission in the neocortex. The nucleus basalis magnocellularis (NBM) is the rodent homologue to the nucleus of Meynert in humans. In this study, we examined the effects of GM1 ganglioside, a neuroprotective agent, on morphological and functional recovery after electrolytic or ibotenic acid lesions of the NBM. In animals, GM1 ganglioside has been shown to reduce some of the behavioral deficits that follow Central Nervous System lesions. Electrolytic or ibotenic acid lesions produced deficits in passive avoidance learning, as assessed by the number of trails taken to acquire the avoidance response. Only the electrolytic lesions impaired spatial memory in the Morris Water Maze (MWM), and GM1 administration did not improve performance on this task. Facilitation of passive avoidance acquisition was observed in animals receiving GM1 treatment after electrolytic or ibotenate lesions. Both types of injuries induced equivalent amounts of damage to the nucleus basalis but the electrolytic lesions produced greater damage to adjacent structures that could be responsible for the additional deficits observed on the MWM task.     

Long-term changes in phosphoinositide hydrolysis following colchicine lesions of the nucleus basalis magnocellularis.

The effect of bilateral colchicine lesions of the nucleus basalis magnocellularis (NBM) on agonist-stimulated phosphoinositide (PI) hydrolysis was examined in cortical slices 1, 3, or 14 months after surgery. Colchicine lesions resulted in a loss of acetylcholinesterase staining in the cortex which recovered to control levels by 14 months. Choline acetyltransferase activity in the cortex was decreased by 43% one month after lesioning, but returned to control levels by 3 months. In vitro stimulation with carbachol produced a concentration-dependent increase in PI hydrolysis, which was enhanced 3 and 14 months after NBM lesions. Norepinephrine and quisqualate-stimulated PI hydrolysis was also enhanced 14 months after NBM lesions. These results suggest a slow up-regulation of postsynaptic receptor function following presynaptic loss of transmitter.     

Nucleus basalis lesions fail to induce senile plaques in the rat

Fourteen months after receiving bilateral ibotenic acid lesions of the nucleus basalis magnocellaris (NBM), male rats demonstrated impairment in spatial learning in a water maze task, increased incidence of high voltage spindles, and significant depletion of cortical choline acetyltransferase (ChAT) activity. Histological evaluation revealed decreased acetylcholinesterase (AChE) staining but no plaque-like structures in the cortex.     

The role of cortical sympathetic ingrowth in the behavioral effects of nucleus basalis magnocellularis lesions

Following cholinergic denervation of the neocortex by nucleus basalis magnocellularis (NBM) lesions, peripheral sympathetic fibers grow into the neocortex. Two experiments were performed to determine the behavioral effects of this neuronal rearrangement. Group I animals underwent training on a standard radial-8-arm maze task, while Group II animals learned a modified version (i.e. 4 arms baited). Following acquisition, NBM lesions were performed. Animals with lesions but without sympathetic ingrowth performed consistently better in both behavioral paradigms, than animals with NBM lesions and sympathetic ingrowth. These studies suggest that cortical sympathetic ingrowth can alter behavior and is detrimental to the learning of a spatial memory paradigm.     

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.