ABSTRACT
As most COVID-19 patients only receive thoracic CT scans, but body composition, which is relevant to detect sarcopenia, is determined in abdominal scans, this study aimed to investigate the relationship between thoracic and abdominal CT body composition parameters in a cohort of COVID-19 patients. This retrospective study included n = 46 SARS-CoV-2-positive patients who received CT scans of the thorax and abdomen due to severe disease progression. The subcutaneous fat area (SF), the skeletal muscle area (SMA), and the muscle radiodensity attenuation (MRA) were measured at the level of the twelfth thoracic (T12) and the third lumbar (L3) vertebra. Necessity of invasive mechanical ventilation (IMV), length of stay, or time to death (TTD) were noted. For statistics correlation, multivariable linear, logistic, and Cox regression analyses were employed. Correlation was excellent for the SF (r = 0.96) between T12 and L3, and good for the respective SMA (r = 0.80) and MRA (r = 0.82) values. With adjustment (adj.) for sex, age, and body-mass-index the variability of SF (adj. r2 = 0.93; adj. mean difference = 1.24 [95% confidence interval (95% CI) 1.02-1.45]), of the SMA (adj. r2 = 0.76; 2.59 [95% CI 1.92-3.26]), and of the MRA (adj. r2 = 0.67; 0.67 [95% CI 0.45-0.88]) at L3 was well explained by the respective values at T12. There was no relevant influence of the SF, MRA, or SMA on the clinical outcome. If only thoracic CT scans are available, CT body composition values at T12 can be used to predict abdominal fat and muscle parameters, by which sarcopenia and obesity can be assessed.
Subject(s)
COVID-19 , Sarcopenia , Abdomen , Body Composition , COVID-19/diagnosis , COVID-19/diagnostic imaging , Humans , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Retrospective Studies , SARS-CoV-2 , Sarcopenia/diagnostic imaging , Sarcopenia/pathology , Tomography, X-Ray ComputedABSTRACT
Somatostatin is implicated in a number of physiological functions in the CNS. These effects are elicited through the activation of at least five receptor subtypes. Among them, sst2 receptors appear the most widely expressed in the cortex and hippocampal region. However, the specific role of this somatostatin receptor subtype in these regions is largely undetermined. In this study, we investigated the role of the sst2 receptor in the hippocampus using mice invalidated for the sst2 gene (sst2 KO mice). Complementary experimental approaches were used. First, mice were tested in behavioral tests to explore the consequences of the gene deletion on learning and memory. Spatial discrimination learning in the radial maze was facilitated in sst2 KO mice, while operant learning of a bar-pressing task was slightly altered. Mice were then processed for electrophysiological study using the ex vivo hippocampal slice preparation. Extracellular recordings in the CA1 area showed an enhancement in glutamatergic (AMPA and NMDA) responses in sst2 KO mice which displayed an increase in the magnitude of the short-term potentiation and long-term depression. In contrast, long-term potentiation was not significantly altered. Taken together, these data demonstrate that somatostatin, acting via sst2 hippocampal receptors, may contribute to a global decrease in glutamate efficiency and consequently alter glutamate-dependent plasticity and spatial learning.
Subject(s)
Hippocampus/physiology , Maze Learning/physiology , Neuronal Plasticity/genetics , Receptors, Somatostatin/deficiency , Spatial Behavior/physiology , Animals , Behavior, Animal , Conditioning, Operant , Discrimination Learning/physiology , Electric Stimulation , Excitatory Postsynaptic Potentials/physiology , In Vitro Techniques , Long-Term Potentiation/physiology , Male , Memory/physiology , Mice , Mice, Knockout , Motivation , Neural Inhibition/physiology , Receptors, AMPA/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, Somatostatin/genetics , Synapses/physiologyABSTRACT
Somatostatin (SRIF) controls many physiological and pathological processes in the central nervous system but the respective roles of the five receptor isotypes (sst1-5) that mediate its effects are yet to be defined. In the present study, we attempted to identify functions of the sst2 receptor using mice with no functional copy of this gene (sst2 KO mice). In contrast with control 129Sv/C57Bl6 mice, sst2 mRNA was no longer detectable in the brain of sst2 KO mice; 125I-labeled Tyr0DTrp8-SRIF14 binding was also greatly reduced in almost all brain structures except for the hippocampal CA1 area, demonstrating that sst2 accounts for most SRIF binding in mouse brain. Invalidation of this subtype generated an increased anxiety-related behaviour in a number of behavioural paradigms, while locomotor and exploratory activity was decreased in stress-inducing situations. No major motor defects could be detected. sst2 KO mice also displayed increased release of pituitary ACTH, a main regulator of the stress response. Thus, somatostatin, via sst2 receptor isotype pathways, appears involved in the modulation of locomotor, exploratory and emotional reactivity in mice.
Subject(s)
Brain/metabolism , Emotions/physiology , Exploratory Behavior/physiology , Motor Activity/physiology , Receptors, Somatostatin/deficiency , Somatostatin/metabolism , Adrenocorticotropic Hormone/metabolism , Animals , Brain/cytology , Growth Hormone/metabolism , Mice , Mice, Knockout/abnormalities , Mice, Knockout/genetics , Mice, Knockout/metabolism , Neurons/cytology , Neurons/metabolism , Pituitary Gland/metabolism , Radioligand Assay , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Histological analyses were performed on the brains of APP(V717F) transgenic (Tg)mice previously studied in a battery of behavioral tests. We describe here the regional and age-dependent deposition of amyloid in both heterozygous and homozygous Tg mice. We also report that Tg mice show significant and age-dependent changes in synaptic density measured by synaptophysin immunoreactivity. Surprisingly, a rather marked hippocampal atrophy is observed as early as 3 months of age in Tg mice (20-40%). Statistical analyses revealed that the deficits in object recognition memory are related to the number of amyloid deposits in specific brain regions, whereas deficits in spatial reference and working memory are related to the changes in synaptic density and hippocampal atrophy. Our study suggests that the behavioral deficits observed in Tg mice are only in part related to amyloid deposition, but are also related to neuroanatomical alterations secondary to overexpression of the APP(V717F) transgene and independent of amyloid deposition.
Subject(s)
Alzheimer Disease/pathology , Behavior, Animal/physiology , Brain/pathology , Age Factors , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/analysis , Animals , Disease Models, Animal , Immunohistochemistry , Memory Disorders/pathology , Memory Disorders/physiopathology , Mice , Mice, Transgenic , Synaptophysin/analysisABSTRACT
Both the beta-amyloid precursor protein (APP) and the apoliprotein E (apoE) genes are involved in the pathogenesis of Alzheimer's disease (AD). We previously showed that mice over-expressing a human mutated form of APP (APP(V717F)) display age-dependent recognition memory deficits associated with the progression of amyloid deposition. Here, we asked whether 10- to 12-month-old APP(V717F) mice lacking the apoE gene, which do not present obvious amyloid deposition, differ from APP(V717F) mice in the object recognition task. The recognition performance is decreased in both transgenic mouse groups compared to control groups. Moreover, some behavioral disturbances displayed by APP mice lacking apoE are even more pronounced than those of APP mice expressing apoE. Our results suggest that the recognition memory deficits are related to high levels of soluble Abeta rather than to amyloid deposits.
Subject(s)
Amyloid beta-Protein Precursor/genetics , Apolipoproteins E/deficiency , Behavior, Animal/physiology , Mental Disorders/genetics , Mutation/physiology , Amyloid/metabolism , Animals , Apolipoproteins E/genetics , Brain/metabolism , Humans , Mice , Mice, Inbred Strains , Mice, Transgenic/genetics , Motor Activity/physiology , Pattern Recognition, Visual/physiology , Tissue DistributionABSTRACT
Intensive investigation towards the understanding of the biology and physiological functions of the beta-amyloid precursor protein (APP) have been supported since it is known that a 39-43 amino acid fragment of APP, called the beta-amyloid protein (Abeta), accumulates in the brain parenchyma to form the typical lesions associated with Alzheimer's disease (AD). It emerges from extensive data that APP and its derivatives show a wide range of contrasting physiological properties and therefore might be involved in distinct physiological functions. Abeta has been shown to disrupt neuronal activity and to demonstrate neurotoxic properties in a wide range of experimental procedures. In contrast, both in vitro and in vivo studies suggest that APP and/or its secreted forms are important factors involved in the viability, growth and morphological and functional plasticity of nerve cells. Furthermore, several recent studies suggest that APP and its derivatives have an important role in learning and memory processes. Memory impairments can be induced in animals by intracerebral treatment with Abeta. Altered expression of the APP gene in aged animals or in genetically-modified animals also leads to memory deficits. By contrast, secreted forms of APP have recently been shown to facilitate learning and memory processes in mice. These interesting findings open novel perspectives to understand the involvement of APP in the development of cognitive deficits associated with AD. In this review, we summarize the current data concerning the biology and the behavioral effects of APP and its derivatives which may be relevant to the roles of these proteins in memory and in AD pathology.
Subject(s)
Amyloid beta-Protein Precursor/analogs & derivatives , Amyloid beta-Protein Precursor/physiology , Learning/physiology , Memory/physiology , Alzheimer Disease/psychology , Animals , Cognition Disorders/physiopathology , HumansABSTRACT
The effects of immediate post-training administration of drugs interacting with group I and/or group II glutamate metabotropic receptors (mGluRs) were determined on the retention performance of a partially acquired lever-press learning task in mice. The antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) dose-dependently (0. 1-100 nmol/mouse, i.c.v.) impairs the retention performance evaluated 24 h post-training. The retention deficit induced by 100 nmol MCPG is related to the selective suppression of a time-dependent spontaneous improvement of performance between the two sessions. This phenomenon appears progressively within 24 h post-training in control mice and is thought to reflect post-training processing of memory traces. The coadministration of either (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), the group I mGluR agonist (R,S)3,5-dihydroxyphenylglycine (DHPG), or the group II mGluR agonist LY354740, completely blocked MCPG-induced deficits at a dose of 0.1 nmol for each agonist. These results suggest that selective activation of either group I or group II mGluRs is able to prevent the memory retention deficits induced by MCPG.
Subject(s)
Benzoates/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glycine/analogs & derivatives , Learning/drug effects , Memory Disorders/chemically induced , Receptors, Metabotropic Glutamate/agonists , Retention, Psychology/drug effects , Animals , Bridged Bicyclo Compounds/pharmacology , Cycloleucine/analogs & derivatives , Cycloleucine/pharmacology , Dose-Response Relationship, Drug , Eating/drug effects , Excitatory Amino Acid Agonists/pharmacology , Glycine/pharmacology , Male , Memory Disorders/psychology , Mice , Mice, Inbred Strains , Neuroprotective Agents/pharmacology , Protein Isoforms/agonists , Resorcinols/pharmacology , Time FactorsABSTRACT
PDAPP transgenic mice have been shown to develop age dependently much of the cerebral histopathology associated with Alzheimer's disease. PDAPP mice (3-10 months old) were tested in a battery of memory tasks to determine whether they develop memory-behavioral deficits and whether these deficits occur before or after amyloid deposition. PDAPP mice manifest robust impairments in a radial-maze spatial discrimination task at all ages tested. Mild deficits were observed in a barpress learning task in 3-month-old PDAPP mice. In contrast, PDAPP mice show an age-dependent decrease in spontaneous object-recognition performance that appears to be severe at ages when amyloid deposition is known to occur. Thus, the PDAPP mouse shows severe deficits in the radial maze well before amyloid plaque deposition, whereas object-recognition performance decreases with age and may be associated with amyloid deposition.
Subject(s)
Amyloid beta-Protein Precursor/genetics , Conditioning, Operant/physiology , Maze Learning/physiology , Memory/physiology , Motor Activity/physiology , Reinforcement, Psychology , Age Factors , Alzheimer Disease/genetics , Animals , Behavior, Animal/physiology , Male , Mice , Mice, TransgenicABSTRACT
The effects of post-training administration of GF 109203X (5 and 50 ng i.c.v.), a selective inhibitor of protein kinase C, on retention performance were investigated in a positively reinforced lever press task, in male Swiss mice. Both doses of GF 109203X suppressed the spontaneous improvement of performance observed in control animals between the last 5 min of the acquisition session and the first 5 min of the retention session 24 h later. GF 109203X had no effect on food intake and locomotor activity. These data suggest that GF 109203X selectively interferes with mechanisms underlying post-training organization of information and that protein kinase C is involved in this memory process.
Subject(s)
Conditioning, Operant/drug effects , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Maleimides/pharmacology , Protein Kinase C/antagonists & inhibitors , Retention, Psychology/drug effects , Animals , Feeding Behavior/drug effects , Male , Mice , Motor Activity/drug effectsABSTRACT
The steroids dehydroepiandrosterone sulfate (DHEA-S) and pregnenolone sulfate (Preg-S) are naturally synthetized in the brain. They improve short term and long term memory performances in a variety of learning tasks and models of amnesia in rodents. DHEA-S and Preg-S modulate GABAergic and glutamatergic synaptic transmission through direct interactions with GABA-A, NMDA and/or sigma 1 membrane receptors. In addition, these two neurosteroids facilitate the release of acetylcholine and modulate synaptic plasticity phenomena in cerebral structures, such as the hippocampus, known to play a role in learning and memory processes. The possible links between these actions and the promnestic effects of DHEA-S and Preg-S are discussed in the present review.
Subject(s)
Brain/physiology , Dehydroepiandrosterone Sulfate/pharmacology , Learning/physiology , Memory/physiology , Pregnenolone/pharmacology , Amnesia , Animals , Brain/drug effects , Hippocampus/drug effects , Hippocampus/physiology , Humans , Learning/drug effects , Memory/drug effects , Mice , Models, Neurological , Models, Psychological , Pregnenolone/physiology , RatsABSTRACT
Cognitive deficits are frequently associated with Duchenne muscular dystrophy (DMD). They might be due to a deficiency in the brain isoforms of the 427 kDa full-length dystrophin, and/or to altered expression of other C-terminal dystrophin-gene products (Dp71, Dp140) also found in brain. Mdx mice, which only lack full-length dystrophin in both muscle and brain, were previously shown to have moderate learning and memory deficits. In the present study, we investigated behavioral responses in mdx3cv mutants, which have altered expression of all the dystrophin-gene products. Contrary to the original mdx mice, mdx3cv mice showed enhanced anxiety-related behaviors and reduced locomotion as compared to control mice. Although those perturbations might be related to the lack in C-terminal dystrophins, they do not seem sufficient to induce strong learning deficits in this mutant. Indeed, we showed that mdx3cv mice may display similar or weaker deficits during the learning of a bar-pressing task, as compared to mdx mice. The relevance of the mdx3cv mutant as a model to study the cognitive deficits associated with DMD is discussed.
Subject(s)
Behavior, Animal/physiology , Dystrophin/deficiency , Muscular Dystrophy, Animal/genetics , Animals , Conditioning, Operant , Dystrophin/genetics , Emotions/physiology , Extinction, Psychological , Female , Learning/physiology , Male , Maze Learning/physiology , Memory/physiology , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Motor Activity/physiology , Motor Skills/physiology , Protein Isoforms/deficiency , Protein Isoforms/geneticsABSTRACT
The contribution of the cytoskeletal membrane-associated protein dystrophin in glutamatergic transmission and related plasticity was investigated in the hippocampal CA1 area of wild-type and dystrophin-deficient (mdx) mice, using extracellular recordings in the ex vivo slice preparation. Presynaptic fiber volleys and field excitatory postsynaptic potentials (fEPSPs) mediated through N-methyl-D-Aspartate receptors (NMDAr) or non-NMDAr were compared in both strains. Comparable synaptic responses were observed in wild-type and mdx mice, suggesting that basal glutamatergic transmission is not altered in the mutants. By contrast, the synaptic strengthening induced by a conditioning stimulation of either 10, 30, or 100 Hz was significantly greater in mdx mice during the first minutes posttetanus. Because the posttetanic potentiation induced in the presence of the NMDAr antagonist D-APV was not affected in the mutants, a critical role of NMDAr in this increase was suggested. The magnitude of the potentiation induced by a 30 Hz stimulation in mdx mice was normalized as compared to wild-type mice by increasing the extracellular magnesium concentration from 1.5 to 3 mM. Moreover, the transitory depression of fEPSPs induced by bath-applied NMDA (50 microM for 30s) was more sensitive to an increased extracellular magnesium concentration in wild-type than in mdx mice. Our results suggest that the absence of dystrophin may facilitate NMDAr activation in the CA1 hippocampal subfield of mdx mice, which may be partly due to a reduction of the voltage-dependent block of this receptor by magnesium.
Subject(s)
Dystrophin/deficiency , Hippocampus/physiopathology , Neuronal Plasticity/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Synapses/physiology , Animals , Electric Stimulation , Excitatory Postsynaptic Potentials/physiology , Extracellular Space/metabolism , Magnesium/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Osmolar ConcentrationABSTRACT
In the present study, we examined whether the relative levels of regional brain [14C]2-deoxyglucose (2-DG) uptake are altered in a transgenic mouse model of Alzheimer's disease which overexpresses a mutated form of the human beta-amyloid precursor protein (mutation V717F). We show that the relative levels of 2-DG uptake are significantly reduced in the septum, thalamus, dentate gyrus and parietal cortex of 3-month-old transgenic mice as compared with wild-type littermates. In 10-month-old transgenic mice, these alterations also extend to the CA3 hippocampal region, the cingulate, retrosplenial, occipital and temporal cortices, suggesting an age-dependent decrease in the regional 2-DG uptake. These results suggest that expression of a mutated APP gene induces an early regional cerebral hypometabolism independently of amyloid deposition per se.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Glucose/metabolism , Mice, Transgenic/metabolism , Prosencephalon/metabolism , Age Factors , Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Animals , Cerebrovascular Circulation/physiology , Deoxyglucose/pharmacology , Mice , Time FactorsABSTRACT
Convergent data indicate that certain substances that interact with N-methyl-D-aspartate (NMDA) receptors or metabotropic glutamate receptors (mGluRs) do not affect acquisition processes per se, or retrieval, but interfere specifically with the formation of memory traces. This action differs widely in its amplitude and time-course according to the learning task used. We showed that systemic injection of the competitive NMDA receptor antagonists, gamma-L-glutamyl-L-aspartate (gamma-LGLA) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), or intracerebroventricular infusion of D-2-amino-5-phosphonovalerate (D-AP5), immediately following acquisition of a Y-maze avoidance learning task in mice, deeply impaired retention of the temporal component of the task (leaving the start alley within the first 5 s of a trial), which significantly improved in controls during the hours following acquisition. In contrast the same substances had no or only slight effects on retention of the discrimination component (choice of the correct alley), which did not improve over time in control animals. This retention deficit did not appear to be due to an action on acquisition, retrieval and/or forgetting processes, or to state-dependent effects. Moreover, gamma-LGLA, CPP or AP5, when administered immediately after partial acquisition of a food-reinforced bar-press task, suppressed the spontaneous improvement in post-training performance observed in control mice 24 h after the training session. (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG), an antagonist of mGluRs, also suppressed the post-training performance increment and its effects were antagonized by the co-administration of trans-ACPD, an agonist of mGluRs. Post-training improvement of performance over time is thought to reflect an active and dynamic process, leading to the organization of memory traces. According to this hypothesis, our results suggest that synaptic plasticity mediated by NMDA receptors and/or mGluRs activation is involved in mechanisms underlying long-term consolidation of memory traces.
Subject(s)
Memory/physiology , Receptors, Glutamate/physiology , Animals , Avoidance Learning/physiology , Maze Learning/physiology , Mice , Mice, Inbred Strains/physiology , Receptors, Metabotropic Glutamate/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Time FactorsABSTRACT
When administered intracerebroventricularly to mice performing various learning tasks involving either short-term or long-term memory, secreted forms of the beta-amyloid precursor protein (APPs751 and APPs695) have potent memory-enhancing effects and block learning deficits induced by scopolamine. The memory-enhancing effects of APPs were observed over a wide range of extremely low doses (0.05-5,000 pg intracerebroventricularly), blocked by anti-APPs antisera, and observed when APPs was administered either after the first training session in a visual discrimination or a lever-press learning task or before the acquisition trial in an object recognition task. APPs had no effect on motor performance or exploratory activity. APPs695 and APPs751 were equally effective in the object recognition task, suggesting that the memory-enhancing effect of APPs does not require the Kunitz protease inhibitor domain. These data suggest an important role for APPss on memory processes.
Subject(s)
Amyloid beta-Protein Precursor/pharmacology , Memory/physiology , Amnesia/chemically induced , Amyloid beta-Protein Precursor/administration & dosage , Animals , Injections, Intraventricular , Male , Mice , Motor Activity , Scopolamine/pharmacology , Visual PerceptionABSTRACT
Duchenne muscular dystrophy is frequently associated with a non-progressive cognitive deficit attributed to the absence of 427,000 mol. wt brain dystrophin, or to altered expression of other C-terminal products of this protein, Dp71 and/or Dp140. To further explore the role of these membrane cytoskeleton-associated proteins in brain function, we studied spatial learning and ex vivo synaptic plasticity in the mdx mouse, which lacks 427,000 mol. wt dystrophin, and in the mdx3cv mutant, which shows a dramatically reduced expression of all the dystrophin gene products known so far. We show that reference and working memories are largely unimpaired in the two mutant mice performing a spatial discrimination task in a radial maze. However, mdx3cv mice showed enhanced emotional reactivity and developed different strategies in learning the task, as compared to control mice. We also showed that both mutants display apparently normal levels of long-term potentiation and paired-pulse facilitation in the CA1 field of the hippocampus. On the other hand, an increased post-tetanic potentiation was shown by mdx, but not mdx3cv mice, which might be linked to calcium-regulatory defects. Otherwise, immunoblot analyses suggested an increased expression of a 400,000 mol. wt protein in brain extracts from both mdx and mdx3cv mice, but not in those from control mice. This protein might correspond to the dystrophin-homologue utrophin. The present results suggest that altered expression of dystrophin or C-terminal dystrophin proteins in brain did not markedly affect hippocampus-dependent spatial learning and CA1 hippocampal long-term potentiation in mdx and mdx3cv mice. The role of these membrane cytoskeleton-associated proteins in normal brain function and pathology remains to be elucidated. Furthermore, the possibility that redundant mechanisms could partially compensate for dystrophins' deficiency in the mdx and mdx3cv models should be further considered.
Subject(s)
Discrimination Learning/physiology , Dystrophin/deficiency , Hippocampus/physiology , Maze Learning , Neuronal Plasticity/physiology , Neurons/physiology , Synapses/physiology , Animals , Dendrites/physiology , Dystrophin/genetics , Emotions/physiology , Hippocampus/physiopathology , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Nerve Fibers/physiology , Space PerceptionABSTRACT
We investigated the effects of immediate post-training systemic administration of gamma-L-glutamyl-L-aspartate (gamma-LGLA) and 3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonate (CPP), antagonists at the N-methyl-D-aspartate receptor, in a lever-press task in two inbred strains of mice. When retention performance was tested in control animals 24 h after partial acquisition of the task. BALB/c mice exhibited a spontaneous performance improvement whereas C57BL/6J mice did not gamma-LGLA at doses of 2.5 and 25 mumol/kg and CPP at doses ranging between 0.025 and 2.5 mumol/kg blocked the spontaneous performance improvement found in BALB/c mice but had no apparent effects on the retention performance of C57BL/6J mice. These data suggest that retention impairment induced by CPP and gamma-LGLA in BALB/c mice results from an interference with posttraining memory processes.
Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Retention, Psychology/drug effects , Animals , Conditioning, Operant/drug effects , Dipeptides/pharmacology , Generalization, Psychological/drug effects , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Piperazines/pharmacology , Retention, Psychology/physiology , Species SpecificityABSTRACT
The purpose of the present study was to design an object recognition task in mice and characterize the effects of scopolamine in this paradigm. This task consisted of exposing mice for 6 or 10 min to an object in an open field (trial 1) and, after a delay (1-24 h), testing mice for 10 min with the object and a novel object (trial 2). Mice explored the novel object more than the familiar object as the inter-trial delay decreased and/or the duration of trial 1 increased. Administration of scopolamine (0.3, 1 and 3 mg kg-1, s.c.) before trial 1 reduced recognition performance on trial 2 after a 3 h inter-trial delay and induced other behavioural effects, including an increase in locomotor activity on trial 1. Methylscopolamine (1 mg kg-1) had no effect on recognition performance. The present results show that this task is a useful model to test recognition memory in mice and that blocking the central cholinergic system impairs this form of memory.
Subject(s)
Blood-Brain Barrier/physiology , Muscarinic Antagonists/pharmacology , Pattern Recognition, Visual/drug effects , Scopolamine Derivatives/pharmacology , Scopolamine/pharmacology , Analysis of Variance , Animals , Drug Evaluation, Preclinical , Male , Mice , Motor Activity/drug effects , Muscarinic Antagonists/pharmacokinetics , N-Methylscopolamine , Scopolamine/pharmacokinetics , Scopolamine Derivatives/pharmacokineticsABSTRACT
The effects of the neurosteroid pregnenolone sulfate (PS) on learning as well as on scopolamine-induced learning deficits were studied in Swiss mice using an appetitively reinforced Go-No Go visual discrimination task. Subcutaneous (SC) administration of scopolamine (0.3-3 mg/kg) after the first session of training dose-dependently impairs learning during the following sessions in this task. Moreover, intracerebroventricular (ICV) administration of PS (0.01-10 nmol) dose-dependently blocks learning deficits induced by scopolamine (3 mg/kg), with the most potent effects at the dose of 0.5 nmol PS. In addition to antagonizing the amnestic effects of scopolamine, PS (0.5 nmol ICV) has a memory-enhancing effect, when administered alone after the first training session. Scopolamine (3 mg/kg SC) also produced substantial deficits on retrieval performance in the Go-No Go visual discrimination task, and caused motor disturbances, when administered 15 min before testing. PS (0.5 nmol ICV) also reduced scopolamine-induced deficits on retrieval but had no effect on scopolamine-induced motor impairments in the traction reflex test. Such a rapid effect of PS on memory processes may be mediated via NMDA and/or GABAA receptors.
Subject(s)
Learning/drug effects , Pregnenolone/pharmacology , Scopolamine/pharmacology , Animals , Discrimination, Psychological/drug effects , Dose-Response Relationship, Drug , Eating/drug effects , Injections, Intraventricular , Male , Memory/drug effects , Mice , Scopolamine/antagonists & inhibitorsABSTRACT
The neurosteroid pregnenolone sulfate (PREG-S) has been shown to modulate positively NMDA receptor activity and to have memory enhancing properties in mice. The present study was designed to evaluate the effects of post-training administration of PREG-S, alone or in combination with D-2-amino-5-phosphonovalerate (D-AP5), a competitive NMDA receptor antagonist, in Y-maze avoidance and appetitively motivated lever-press learning tasks and in a traction reflex test in mice. Intracerebroventricular (i.c.v.) administration of PREG-S (0.01-0.1 nmol/mouse) blocked the selective retention deficits induced by 0.02 nmol D-AP5 in the Y-maze avoidance task. PREG-S (0.1 nmol, i.c.v.) also blocked the retention deficits induced by 0.02 nmol D-AP5 in the lever-press task. Post-training administration of PREG-S alone (0.001-0.1 nmol, i.c.v.) had no effect on retention performance in the Y-maze and the lever-press tasks. PREG-S (1-10 nmol, i.c.v.) significantly reduced the impairment of the traction reflex induced by 2 nmol D-AP5. The ability of PREG-S to block retention performance deficits as well as motor impairment induced by D-AP5 is in agreement with its positive modulatory action at NMDA receptors.