Rat Nucleus Basalis Magnocellularis Research Articles

Handling and novel object recognition modulate fear response and endocannabinoid signaling in nucleus basalis magnocellularis.

Storage of aversive memories is of utmost importance for survival, allowing animals to avoid upcoming similar stimuli. However, without reinforcement, the learned avoidance response gradually decreases over time. Although the molecular mechanisms controlling this extinction process are not well known, there is evidence that the endocannabinoid system plays a key role through CB1 receptor‐mediated modulation of cholinergic signaling. In this study, we measured fear extinction throughout 7 months using naïve rats, assessed in passive avoidance (PA) test in a non‐reinforced manner. Then, we evaluated the effect of gentle handling and non‐aversive novel object recognition test (NORT) on the extinction and expression of fear memories by measuring passive avoidance responses. Neurochemical correlates were analyzed by functional autoradiography for cannabinoid, cholinergic, and dopaminergic receptors. Despite results showing a gradual decrease of passive avoidance response, it did not fully disappear even after 7 months, indicating the robustness of this process. Meanwhile, in rats that received gentle handling or performed NORT after receiving the PA aversive stimulus, extinction occurred within a week. In contrast, gentle handling performed before receiving the aversive stimulus exacerbated fear expression and triggered escape response in PA. The neurochemical analysis showed increased cannabinoid and cholinergic activity in the nucleus basalis magnocellularis (NBM) in rats that had performed only PA, as opposed to rats that received gentle handling before PA. Additionally, a correlation between CB1 mediated‐signaling in the NBM and freezing in PA was found, suggesting that the endocannabinoid system might be responsible for modulating fear response induced by aversive memories.

Poly(ethyl cyanoacrylate) nanoparticles for brain delivery of andrographolide

The limitations imposed by the blood-brain barrier (BBB) and the non-selective distribution of drugs in the brain have hindered the effective treatment of brain diseases and may result in severe side effects on the normal brains. The aim of this work was to deliver natural molecules into nanoparticles capable to provide sustained and controlled drug release, improved biodistribution and therapeutic efficacy for Alzheimer's Disease (AD) prevention and therapy. Novel fluorescent polymeric nanoparticles to target brain tissues were designed and optimised to follow their in vivo distribution as new strategies to cross the BBB, namely ethylcyanoacrylate nanospheres (ECA-NSs) coated with polysorbate 80. They were prepared by emulsion polymerization method using fluorescein isothiocyanate linked to dextran as a florescent probe [1]. NSs were characterized in terms of dimension, polydispersity, zeta potential, morphology, encapsulation efficacy, loading capacity and stability of probe by DLS, TEM and HPLC-DAD-FLD, respectively. A study after intracerebral injection of nanoparticles in nucleus basalis magnocellularis of rats, colynergic neuronal location, evidenced that NSs did not induce inflammatory response. NSs were also administered intraperitoneally and intravenously to anaesthetized rats to evaluate their biodistribution by fluorescent microscope images. The biodistribution studies revealed that NSs were able to cross the BBB and reach brain tissue, as a consequence they were loaded with andrographolide, a major diterpenoid of Andrographis paniculata (Burm. f.) Nees, whose clinical utility for the treatment of inflammation-related neurodegenerative disorder has been demonstrated [2]. ECA-NSs were produced with good yields, suitable for the intraperitoneally administration (mean diameter ≤300nm; PDI 0.2), with a sphere-like shape and a good encapsulation efficacy. The developed nanocarriers represent a valuable targeting system for AD therapy.

Oleuropein aglycone counteracts Aβ42 toxicity in the rat brain

Previous data have shown that oleuropein aglycone (OLE), the main secoiridoid phenol present in extra virgin olive oil, counteracts in vitro aggregation of the Aβ42 peptide and protects cultured cells and model organisms against aggregates toxicity. In this study we investigated the relative tissue toxicity of Aβ42 aggregated in vitro in the presence or in the absence of OLE by injecting the nucleus basalis magnocellularis (NBM) of adult male Wistar rats with a 1.5μl solution containing OLE (450μM) or Aβ42 (50μM) aggregated in the absence (oligomers) or in the presence of 450μM OLE. Control rats were injected with vehicle (1.5μl). Thirty days after injection, the number of choline acetyltransferase (ChAT)-positive neurons, glia reaction and the Aβ peptide levels were detected by immunohistochemistry. An apparent reduction in the amount of soluble A11-positive oligomers was detected in the NBM injected with Aβ42 aggregated with OLE, as compared with the NBM injected with Aβ42 alone. In the latter case, the number of ChAT-positive neurons was significantly reduced (≈−33%) respect to that recorded in the NBM injected with phosphate buffer, OLE or Aβ42 aggregated with OLE. A markedly attenuated Aβ-induced astrocytes and microglia reaction was also found in the NBM injected with Aβ42 aggregated with OLE. Altogether, these data provide additional support to the anti-aggregation, neuroprotective and anti-inflammatory activities of this natural phenol, confirming its beneficial properties against neurodegeneration.

Selective brain region activation by histamine H3 receptor antagonist/inverse agonist ABT-239 enhances acetylcholine and histamine release and increases c-Fos expression

Histamine axons originate solely from the tuberomamillary nucleus (TMN) to innervate almost all brain regions. This feature is consistent with a function for histamine over a host of physiological processes, including regulation of appetite, body temperature, cognitive processes, pain perception and sleep–wake cycle. An important question is whether these diverse physiological roles are served by different histamine neuronal subpopulations. Here we report that systemic administration of the non-imidazole histamine H3 receptor antagonist 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile (ABT-239, 3 mg/kg) increased c-Fos expression dose-dependently in rat cortex and nucleus basalis magnocellularis (NBM) but not in the nucleus accumbens (NAcc) nor striatum, and augmented acetylcholine and histamine release from rat prefrontal cortex. To further understand functional histaminergic pathways in the brain, dual-probe microdialysis was used to pharmacologically block H3 receptors in the TMN. Perfusion of the TMN with ABT-239 (10 μM) increased histamine release from the TMN, NBM, and cortex, but not from the striatum or NAcc. When administered locally, ABT-239 increased histamine release from the NBM, but not from the NAcc. Systemic as well as intra-TMN administration of ABT-239 increased c-Fos expression in the NBM, and cortex, but not in the striatum or NAcc. Thus, as defined by their sensitivity to ABT-239, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. This implies independent functions of subsets of histamine neurons according to their terminal projections, with relevant consequences for the development of specific compounds that affect only subsets of histamine neurones, thus increasing target specificity.

Transplanted bone marrow mesenchymal stem cells improve memory in rat models of Alzheimer's disease.

The present study aims to evaluate the effect of bone marrow mesenchymal stem cells (MSCs) grafts on cognition deficit in chemically and age-induced Alzheimer's models of rats. In the first experiments aged animals (30 months) were tested in Morris water maze (MWM) and divided into two groups: impaired memory and unimpaired memory. Impaired groups were divided into two groups and cannulated bilaterally at the CA1 of the hippocampus for delivery of mesenchymal stem cells (500 × 103/μL) and PBS (phosphate buffer saline). In the second experiment, Ibotenic acid (Ibo) was injected bilaterally into the nucleus basalis magnocellularis (NBM) of young rats (3 months) and animals were tested in MWM. Then, animals with memory impairment received the following treatments: MSCs (500 × 103/μL) and PBS. Two months after the treatments, cognitive recovery was assessed by MWM in relearning paradigm in both experiments. Results showed that MSCs treatment significantly increased learning ability and memory in both age- and Ibo-induced memory impairment. Adult bone marrow mesenchymal stem cells show promise in treating cognitive decline associated with aging and NBM lesions.

Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation

Dysregulated cholinergic neurotransmission has been implicated in the pathophysiology of schizophrenia, particularly negative symptoms and cognitive deficits. The aim of the present study was to evaluate the role of neocortical cholinergic innervation and of the N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) on social interaction and novel object recognition (NOR), a declarative memory task. The cholinergic corticopetal projection was lesioned by local infusion of the immunotoxin 192 IgG-saporin into nucleus basalis magnocellularis of adult male Lister hooded rats. Behavior was assessed 2.5 weeks later in a social interaction paradigm followed by the NOR task. We found that selective cholinergic denervation of neocortex led to a significant reduction in duration of social interaction, specifically active social interaction. Acute administration of PCP (1.0 mg/kg, s.c.) caused a marked decrease of active social interaction, such that there was no longer a difference between intact and denervated animals. Neither cholinergic denervation alone, nor PCP (1.0 mg/kg, s.c.) alone blocked the ability of rats to recognize a novel object. However, when animals lacking cortical cholinergic innervation were challenged by PCP, they were no longer able to recognize a novel object. This study indicates that rats lacking cholinergic innervation of neocortex have impaired social interaction and specifically that the duration of active contact is shortened. Animals with severe cortical cholinergic hypofunction maintain the ability to perform in a declarative memory test, although the task is carried out less intensively. However, a provocation of psychosis-like behavior by a dose of PCP that does not by itself impair performance in normal animals, will abolish the ability to recognize novel objects in animals lacking cortical cholinergic innervation. The present findings support a possible role for cortical cholinergic hypofunction in the negative and cognitive symptoms of schizophrenia, and the potential for cholinergic augmentation as part of the pharmacological profile of antipsychotic drugs.

Chronic Dietary Administration of Valproic Acid Protects Neurons of the Rat Nucleus Basalis Magnocellularis from Ibotenic Acid Neurotoxicity

Valproic acid (VPA) has been used for many years as a drug of choice for epilepsy and mood disorders. Recently, evidence has been proposed for a wide spectrum of actions of this drug, including antitumoral and neuroprotective properties. Valproic acid-mediated neuroprotection in vivo has been so far demonstrated in a limited number of experimental models. In this study, we have tested the neuroprotective potential of chronic (4 + 1 weeks) dietary administration of VPA on degeneration of cholinergic and GABAergic neurons of the rat nucleus basalis magnocellularis (NBM), injected with the excitotoxin, ibotenic acid (IBO), an animal models that is relevant for Alzheimer's disease-like neurodegeneration. We show that VPA treatment significantly protects both cholinergic and GABAergic neurons present in the injected area from the excitotoxic insult. A significant level of neuroprotection, in particular, is exerted towards the cholinergic neurons of the NBM projecting to the cortex, as demonstrated by the substantially higher levels of cholinergic markers maintained in the target cortical area of VPA-treated rats after IBO injection in the NBM. We further show that chronic VPA administration results in increased acetylation of histone H3 in brain, consistent with the histone deacetylase inhibitory action of VPA and putatively linked to a neuroprotective action of the drug mediated at the epigenetic level.

Increased expression of PAD2 after repeated intracerebroventricular infusions of soluble Aβ25–35 in the Alzheimer’s disease model rat brain: Effect of memantine

Peptidylarginine deiminases (PADs) convert the arginine residues in proteins into citrulline residues in a Ca2+-dependent manner. We previously showed that a bilateral injection of ibotenic acid into the rat nucleus basalis magnocellularis elevated the PAD2 activity in the hippocampus and striatum. In this study, we examined whether repeated intracerebroventricular infusions of soluble Aβ25–35 would affect the PAD2 expression in any regions of the rat brain. We also assessed the protective effect of memantine on Aβ-induced PAD2 alterations. The infusion of Aβ25–35 increased the activity and protein level of PAD2 in the hippocampus, and co-treatment with memantine suppressed these changes. An immunohistochemical analysis showed that an increased level of PAD2 was coincident with GFAP-positive astrocytes and CD11b-positive microglia. In addition, immunofluoresecence staining revealed that citrullinepostive immunoreactivity coincided with the occurrence of GFAP-positive astrocytes. Co-treatment with memantine reversed the activation of the astrocytes and microglia, thus attenuating the PAD2 increment. These biochemical and immunohistochemical results suggest that PAD2 might play an important role in the pathology of early Alzheimer’s disease, and may correlate with the changes in glial cells that are recovered by memantine treatment.

P2-463: LXR agonist treatment of a transgenic mouse model of Alzheimer's disease: Effects on behavioral, electrophysiological and immunohistochemical markers

identified SEN12333 (WAY-317538) as a full agonist with an EC50 of 1.2 microM and selective over related receptors. In previous experiments, this new alpha7 nAChR agonists has demonstrated pro-cognitive properties in both Alzheimer disease as well as schizophrenia oriented behavioural tests in rodents. Here we describe experiments aimed to evaluate the neuroprotective property of this compound in in vivo models of neurodegeneration in comparison with nicotine and to investigate the mechanisms of neuroprotection. Results: Five microL of 0.5 M quisqualic acid solution injected into the nucleus basalis magnocellularis (NBM) of rats resulted in a highly significant decrease in the number of ChAT-positive neurons, massive reactive gliosis, involving both astrocytes and microglia, and a significant increase in p38-MAPK expression. A sub-chronic treatment with 3 mg/kg SEN12333 or 0.3 mg/kg nicotine for 7 days significantly attenuated the decrease in the number of ChAT-positive neurons in this brain region demonstrating neuroprotective effects. Conclusions: These effects may be relevant for treating neurodegenerative diseases such as Alzheimer’s disease. The ability of nicotinic agonist-treatments to protect brain tissues from gliosis and inflammation will be discussed.

Selective cholinergic lesions in the rat nucleus basalis magnocellularis with limited damage in the medial septum specifically alter attention performance in the five-choice serial reaction time task

Selective immunotoxic cholinergic lesions in the nucleus basalis magnocellularis (NBM) impair visuospatial attention performance in a 5-choice serial reaction time task (5-CSRT task). The features of the reported deficits, however, do not perfectly match among studies, in which some lesions may have been too weak while others largely encroached onto the septal region. Using the 5-CSRT task, we therefore re-assessed the effects of NBM lesions that produced minimal septal damage. Long-Evans adult male rats were trained to stable 5-CSRT task performance (stimulus duration: 0.5 s) and subsequently subjected to intra-NBM injections of 192 IgG-saporin (200 ng/side). The lesions induced more than 90% loss of choline acetyltransferase–positive neurons in the NBM vs. only 28% in the medial septum. The decrease of the optical density of acetylcholinesterase reaction products was significant in the cortex (−91%), not in the hippocampus. In the 5-CSRT task, the lesions resulted in increased omissions (from 10% to 30%) and decreased correct responses (from 80% to 60%), with negligible or no effects on all other usually collected variables. This deficit disappeared with lengthened stimulus duration (i.e. 0.5–1 and then 5 s). Furthermore, overall performance levels decreased when the stimulus duration was shortened (i.e. 0.5–0.2 s) or its intensity attenuated, and rats with cholinergic lesions remained consistently impaired vs. controls. These results show that disruption of sustained visual attention functions by damage to the NBM cholinergic neurons can be evidenced despite weak or no effects on variables accounting for motivational, locomotion- or impulsivity-related biases. Discrepancies with previously reported results are discussed in terms of differences in lesion extent/specificity and training levels.

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.

Betahistine increases ACh release from the cortex, but not histamine release from the nucleus basalis magnocellularis of freely-moving rats.

Betahistine increases ACh release from the cortex, but not histamine release from the nucleus basalis magnocellularis of freely-moving rats.

Change of central cholinergic receptors following lesions of nucleus basalis magnocellularis in rats: search for an imaging index suitable for the early detection of Alzheimer's disease

Cholinergic system in the central nervous system is involved in the memory function. Thus, because the dysfunction of cholinergic system that project to the cerebral cortex from nucleus basalis of Meynert (nbM) would be implicated in the memory function deficits in Alzheimer's disease (AD), evaluating cholinergic function may be useful for the early detection of AD. In this study, because the nucleus basalis magnocellularis (NBM) in rats is equivalent to nbM in human, we investigated the change in cholinergic receptors in the frontal cortex of rats with unilateral lesion to the NBM to find an appropriate index for the early detection of AD using techniques of nuclear medicine. The right NBM was injected with ibotenic acid. [ 18F]FDG-PET images were obtained 3 days later. Some rats were sacrificed at 1 week, whereas others were subjected to a second [ 18F]FDG-PET at 4 weeks then sacrificed for membrane preparation. The prepared membranes were subjected to radioreceptor assays to measure the density of nicotinic and muscarinic acetylcholine receptors. Glucose metabolism had decreased on the damaged side compared to the control side at 3 days, but at 4 weeks, there was no difference between the sides. Nicotinic acetylcholine receptors had significantly decreased in density compared to the control side at both 1 and 4 weeks. However, muscarinic receptors were not affected. These results suggested that neuronal dysfunction in AD could be diagnosed at an early stage by imaging nicotinic acetylcholine receptors.

Verapamil prevents, in a dose-dependent way, the loss of ChAT-immunoreactive neurons in the cerebral cortex following lesions of the rat nucleus basalis magnocellularis

In the present study we analysed the neuroprotective effect of the L-type voltage-dependent calcium channel antagonist verapamil on cholineacetyltransferase (ChAT)-immunoreactive neurons in the cerebral cortex of rats with bilateral electrolytic lesions of the nucleus basalis magnocellularis (NBM). Treatment with verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg/12 h i.p.) started 24 h after NBM lesions and lasted 8 days. Animals were sacrificed on day 21 after NBM-lesions. The bilateral NBM-lesions produced significant loss of ChAT-immunoreactive neurons in frontal, parietal and temporal cortex. Although the number of ChAT-positive neurons was significantly higher in NBM-lesioned animals treated with verapamil at a dose of 2.5, 5.0 and 10.0 mg/kg than in saline treated ones, the most significant effect was obtained at a dose of 5 mg/kg. This is, to our knowledge, the first report showing an inverted U-shape mode of neuroprotective action of the calcium antagonist verapamil, at morphological level in this particular model of brain damage. The demonstrated beneficial effect of verapamil treatment suggests that the regulation of calcium homeostasis during the early period after NBM lesions might be a possible treatment to prevent neurodegenerative processes in the rat cerebral cortex.

Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation

Altered cholinergic function is considered as a potential contributing factor in the pathogenesis of schizophrenia. We hypothesize that cortical cholinergic denervation may result in changes in glutamatergic activity. Therefore, we lesioned the cholinergic corticopetal projections by local infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of rats. Possible effects of this lesion on glutamatergic systems were examined by phencyclidine-induced locomotor activity, and also by N-methyl-D-aspartate receptor binding. We find that cholinergic lesioning of neocortex leads to enhanced sensitivity to phencyclidine in the form of a dramatic increase in horizontal activity. Further, N-methyl-D-aspartate receptor binding is unaffected in denervated rats. These results suggest that aberrations in cholinergic function might lead to glutamatergic dysfunctions, which might be of relevance for the pathophysiology for schizophrenia.

Effect of Polygala tenuifolia root on behavioral disorders by lesioning nucleus basalis magnocellularis in rat

We investigated whether an aqueous extract of Polygala tenuifolia Willd (PTW) could improve the rats’ memory and behavioral disorders produced by lesioning nucleus basalis magnocellularis (NBM) in rats. The animals were divided into four groups for surgery, and following that they were orally administered PTW extract for 7 and 21 days. Each group consisted of eight male Sprague-Dawley rats and were treated as follows: Control: no surgery ( n = 8), PBS: 1 M (mol/L) phosphate buffered saline ( n = 8), IBO: 0.12 M ( n = 8), QUIS: 0.12 M ( n = 8). Two 0.5 μL injections were made in the vicinity of the bilateral side of the nucleus basalis magnocellularis (NBM). All rats were tested in the neurological tests and the step-through passive avoidance memory test during pre-surgery, surgery and post-surgery drug treatment. The results suggest that PTW extract has some repairing effects on the memory and behavioral disorders produced by lesioning of the NBM in rats.

Effect of memantine on the levels of glial cells, neuropeptides, and peptide-degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's disease model

It has been implicated that glia activation plays a critical role in the progression of Alzheimer's disease (AD). However, the precise mechanism of glia activation is not clearly understood yet. In our present studies, we confirmed our previous results where change the levels of neuropeptides and peptidases in ibotenic acid (IBO) infusion into the rat nucleus basalis magnocellularis, an animal model of AD. Furthermore, we extended our study to investigate a possible protection effect of co-administration on the changes of neuropeptides, and neuronal and glial cells in IBO-infused rat brain by memantine treatment. The levels of substance P and somatostatin were decreased in the striatum and frontal cortex 1 week after IBO infusion, and recovered to the control level by memantine treatment, indicating the involvement of neuropeptides in AD pathology. Furthermore, the immunohistochemical and enzymatic studies of GFAP and CD 11b, and peptidylarginine deiminase, markers of glia, in the striatum and frontal cortex showed the increase in IBO-treated rat brain as compared with controls, while co-administration of memantine and IBO no increase of astrocytes and microglia activation was observed. The present biochemical and immunohistochemical results suggest that glia activation might play an important role to the pathology of AD, and correlate with the changes of neuropeptide levels in AD brain that is recovered by memantine treatment.

Effect of memantine on the levels of glial cells, neuropeptides, and peptide-degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's disease model

It has been implicated that glia activation plays a critical role in the progression of Alzheimer's disease (AD). However, the precise mechanism of glia activation is not clearly understood yet. In our present studies, we confirmed our previous results where change the levels of neuropeptides and peptidases in ibotenic acid (IBO) infusion into the rat nucleus basalis magnocellularis, an animal model of AD. Furthermore, we extended our study to investigate a possible protection effect of co-administration on the changes of neuropeptides, and neuronal and glial cells in IBO-infused rat brain by memantine treatment. The levels of substance P and somatostatin were decreased in the striatum and frontal cortex 1 week after IBO infusion, and recovered to the control level by memantine treatment, indicating the involvement of neuropeptides in AD pathology. Furthermore, the immunohistochemical and enzymatic studies of GFAP and CD 11b, and peptidylarginine deiminase, markers of glia, in the striatum and frontal cortex showed the increase in IBO-treated rat brain as compared with controls, while co-administration of memantine and IBO no increase of astrocytes and microglia activation was observed. The present biochemical and immunohistochemical results suggest that glia activation might play an important role to the pathology of AD, and correlate with the changes of neuropeptide levels in AD brain that is recovered by memantine treatment.

Selective Behavioral and Neurochemical Effects of Cholinergic Lesions Produced by Intrabasalis Infusions of 192 IgG-Saporin on Attentional Performance in a Five-Choice Serial Reaction Time Task

The effects of the cholinergic immunotoxin 192 IgG-saporin (SAP) (0.0, 0.15, or 0.45 microg/microl; 0.5 microl/hemisphere) infused into the area of the nucleus basalis magnocellularis (NBM) of rats were tested in a five-choice serial reaction time task (5CSRTT) designed to assess visual attention. The effects of this manipulation on acetylcholine efflux in the medial frontal cortex were determined using in vivo microdialysis during the 5CSRTT. Rats with extensive lesions of the NBM (SAP HIGH) showed an array of behavioral deficits in the 5CSRTT hypothesized to represent deficits in central executive function that were associated with severe deficits in accuracy. Lengthening the stimulus duration ameliorated these deficits. Rats with restricted lesions of the NBM (SAP LOW) showed impairments over time on task when tested under standard conditions that were exacerbated by increases in the event rate. The number of choline acetyltransferase-immunoreactive cells in the area of the NBM but not the vertical limb of the diagonal band correlated significantly with accuracy in the task. SAP HIGH rats had significantly lower levels of cortical acetylcholine (ACh) efflux relative to SHAM both before and during the 5CSRTT. SAP LOW rats showed significantly higher levels of cortical ACh efflux before but not during the 5CSRTT. Cortical ACh efflux increased in all rats with the onset of the attentional task. These data provide the first direct evidence for a relationship between selective damage in the basal forebrain with decreased cortical ACh efflux and impaired attentional function.

MRNA expression alterations of inward rectifier potassium channels in rat brain with cholinergic impairment

Potassium channel dysfunction has been indicated in Alzheimer's disease. In the present study, spatial memory, the activity of cortical acetylcholinesterase (AChE) and the expressions of inward rectifier potassium channels (Kir) were measured after ibotenic acid lesions of nucleus basalis magnocellularis (nbm) in rats. Expressions of Kir (Kir2.1, Kir3.1, Kir6.1 and Kir6.2) at mRNA level were assessed using reverse transcription-polymerase chain reaction. At 28 days after ibotenic acid injection, the spatial memory of rats was significantly impaired accompanied by a 32% reduction of cortical AChE activity. Furthermore, the expression of Kir6.2 was increased by 79.3% in cortex, and that of Kir6.1 was increased by 172.1% in hippocampus, while no obvious changes in the mRNA expression of Kir2.1 and Kir3.1 were detected. This study indicated that the expression of adenosine triphosphate-sensitive potassium channel was area and channel subtype specifically increased following nbm lesions.