Hippocampal LTP and memory in mouse strains: is there evidence for a causal relationship?

The mechanisms underlying memory are under intense investigation. One of the most promising candidates at the cellular level is long-term potentiation (LTP). Numerous pharmacological and molecular genetic manipulations have led to alteration in both LTP and memory. However, the causal relationship between these phenotypical changes is debated. The problem of causality can be addressed in numerous ways. One suggestion is to investigate natural variation in both LTP and memory performance in mouse strains. If variation in synaptic and behavioral phenomena is found, correlation between these traits may be investigated. The advantages and disadvantages of this approach are discussed. An empirical example using four mouse strains is also presented to highlight some general problems. The following arguments are made. First, multiple electrophysiological and behavioral paradigms with idiosyncratic condition characteristics should be conducted to avoid false-positive findings due to alterations unrelated to memory and its mechanisms. Multiple stimulation and memory protocols may also allow one to study the complexity and multiplicity of processes. Second, analysis of a large number of mouse strains may be needed to avoid false interpretation of results due to spurious gene associations and/or linkage disequilibrium. Third, quantitative genetic analysis using, for example, diallele crosses, may be employed to properly investigate biologically meaningful, i.e., genetic, effects. It is concluded that with the use of additional methods (e.g., QTL analysis, gene expression arrays, and biochemical analysis) providing converging evidence, analysis of mouse strains will be instrumental in addressing the question regarding the role LTP may play in memory.     

Effects of polygonatum sibiricum polysaccharide on learning and memory in a scopolamine-induced mouse model of dementia★

BACKGROUND： Learning and memory processes are accompanied by complex neuropathological and biochemical changes. Free radicals play an important role in learning and memory damage. OBJECTIVE： To observe the effects of polygonatum sibiricum polysaccharide （PSP） in comparison with vitamin 12 on inhibiting free radical damage, as well as improving the degree of cerebral ischemia and learning and memory in a scopolamine-induced mouse model of dementia. DESIGN： Randomized controlled animal study. SETTINGS： Department of Pharmacology, Taishan Medical College; Shandong Jewim Pharmaceutical Co., Ltd. MATERIALS： A total of 105 healthy Kunming mice, comprising 90 males and 15 females that were clean grade, were provided by the Animal Center of Taishan Medical College. PSP （extracted and purified by Huangjing, Taishan） was provided by the Department of Traditional Chinese Medicine, Taishan Medical College （purity of 79.6% by using a phenol-concentrated sulphate acid method）, and hydrogen bromine acid scopolamine injection solution （SCO） by Shanghai Hefeng Pharmaceutical Co., Ltd. METHODS： This study was performed at the Pharmacological Laboratory of Taishan Medical College from March to June 2007. （1） A total of 75 healthy Kunming male mice of clean grade were randomly divided into a normal control group, positive control group, and low-dosage and high-dosage PSP groups, with 15 mice in each group. Mice in both the low-dosage and high-dosage PSP groups were intragastrically administered 0.5 g/kg and 2.0 g/kg PSP, respectively. Mice in the positive control group were intragastrically administered 0.5 g/kg vitamin 12. In addition, mice in both the normal control group and model group were intragastrically administered the same volume of saline, respectively, once a day for 7 consecutive days. One hour after the final administration on day 6, mice in the positive control group, model group, low-dosage and high-dosage PSP groups were subcutaneously injected with 3.0 mg/kg SCO, while mice in the no     

Auricular transcutaneous vagus nerve stimulation improves memory persistence in naïve mice and in an intellectual disability mouse model

BackgroundVagus nerve stimulation (VNS) using non-invasive approaches have attracted great attention due to their anti-epileptic, anti-depressive and pro-cognitive effects. It has been proposed that auricular transcutaneous VNS (atVNS) could benefit intellectual disability disorders, but preclinical data supporting this idea is limited.ObjectiveTo develop an atVNS device for mice and to test its efficacy on memory performance in naïve mice and in a mouse model for intellectual disability.MethodsNaïve outbreed CD-1 mice and a model for fragile X syndrome, the Fmr1 knockout (Fmr1KO), were used to assess the effect of atVNS in the novel object-recognition memory performance.ResultsWe found that atVNS significantly improves memory persistence in naïve mice. Notably, atVNS was efficacious in normalizing the object-recognition memory deficit in the Fmr1KO model.ConclusionOur data show that atVNS improves memory persistence in naïve mice and in a model of intellectual disability and support further studies taking advantage of preclinical mouse models of cognitive disorders.     

Long-term treatment with lithium alleviates memory deficits and reduces amyloid-β production in an aged Alzheimer's disease transgenic mouse model

The glycogen synthase kinase-3β (GSK3β) pathway plays a central role in Alzheimer's disease (AD) and its deregulation accounts for many of the pathological hallmarks of AD. Lithium, which modulates GSK3β activity, has been shown to reduce amyloid production and tau phosphorylation in pre-pathological AD mouse models. In this study, we investigated the effects of chronic LiCl treatment in aged double transgenic mice (AβPPSwe/PS1A246E). We found that chronic lithium treatment decreased the γ-cleavage of amyloid-β protein precursor, further reduced amyloid-β production and senile plaque formation, accompanied by the improvement in spatial learning and memory abilities. Because autophagy may play an important role in the pathology of AD, we also assessed the autophagy activity and found that the chronic lithium treatment attenuated the autophagy activation in this AD mouse model. Our results suggest that prolonged lithium treatment, even during the later stages of AD, could be an effective therapeutics.     

Do age differences in odour memory depend on differences in verbal memory?

Studies of human odour memory have in most cases been obscured by the experimental designs utilised, in which verbal memory played a crucial role in the subjects' performance. Previously, attempts have been made to minimise verbal mediation in the assessment of odour memory by the use of incidental or implicit learning, which is how odours are learned in everyday life; it is still under debate whether this form of learning is age-dependent or not. In this experiment we make use of very uncommon odours and show that incidental learning of odours is as good in elderly people as in the young, whereas intentional learning is better in young people.     

Can postictal memory predict postoperative memory in patients with temporal lobe epilepsy?

We investigated the contribution of postictal memory testing for lateralizing the epileptic focus and predicting memory outcome after surgery for temporal lobe epilepsy (TLE). Forty‐five patients with TLE underwent interictal, postictal, and postoperative assessment of verbal and nonverbal memory. Surgery consisted of anterior temporal lobectomy (36), selective isolated amygdalohippocampectomy (6), or amygdalohippocampectomy coupled to lesionectomy (3). Postictal and postoperative but not interictal memory were significantly lower in left TLE than in right TLE. Nonverbal memory showed no significant difference in left TLE versus right TLE in all conditions. Postictal memory was significantly correlated with postoperative memory, but the effect disappeared when the lateralization of the focus was considered. Postictal verbal memory is a useful bedside tool that can help lateralize the epileptic focus. Larger studies are needed to further estimate its predictive value of the postoperative outcome.     

Panic disorder and memory: does panic disorder result from memory dysfunction?

It is proposed that patients with panic disorder have a defect in fear-relevant episodic memory, and their panic attacks arise from automaticity in recollecting fear-relevant emotional-autonomic cluster. The cluster as a component of fear appears to have been dissociated from cognitive structure (episodic or informative memory trace) or from "information structure". A special method was created for testing this hypothesis where 30 panic disorder patients, 12 healthy controls, and 32 patients with other psychiatric diagnoses were asked to recall and describe a fearful experience. None of the patients in the panic disorder group could recall any fearful event or episode in their past. All but one subject among healthy controls and all the subjects in the non-panic group could recall one or more fearful event or episode. Possible theoretical implications of these results are discussed in the context of some classical concepts.     

Delayed recognition memory in Parkinson's disease: a role for working memory?

Immediate and delayed recognition memory for words was examined in a sample of 16 non-demented patients with Parkinson's disease and 16 normal control participants of equivalent age and educational attainment. The patients, relative to control participants, had intact immediate but impaired delayed recognition memory performance. Patients were also impaired on tests of free and cued recall, working memory and a measure of psychomotor processing speed. Processing speed was a significant covariate for delayed recognition, free and cued recall and working memory performance, but not for immediate recognition performance. These results suggest that the same cognitive processes which support performance on tests of recall and working memory also support performance on tests of delayed recognition.     

A butyrolactone derivative 3BDO alleviates memory deficits and reduces amyloid-β deposition in an AβPP/PS1 transgenic mouse model

Excessive extracellular deposition of amyloid- peptide (Aβ) in the brain is the pathological hallmark of Alzheimer's disease (AD). Cumulative evidence indicates that autophagy is involved in the metabolism of Aβ and pathogenesis of AD. However, the molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. We recently found that long-term treatment with a butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran- 2(3 H)-one (3BDO) increased levels of insulin-degrading enzyme and neprilysin, suppressed autophagy via an mTOR pathway, lowered levels of Aβ, and prevented AD-like cognitive deficits in the AβPP/PS1 double transgenic mouse model. Therefore, our findings suggest that 3BDO may be beneficial in the prevention and treatment of AD.     

Do memory complaints represent impaired memory performance in patients with major depressive disorder?

Memory complaints are found to be associated with depression. However, the question is, “How much these subjective complaints indicate objective memory impairments?” The aim of this study is to determine whether subjective memory complaints represent objective memory impairments and to establish the demographic and clinical characteristics of patients with major depressive disorder (MDD) and subjective memory complaints. Sixty‐four patients with MDD were assessed for objective memory performance through subtests of the Wechsler Memory Scale‐III. Memory complaints also were assessed in these patients with a structured interview. Thirty healthy controls were also included in the study to compare memory performance among groups. The Hamilton Rating Scale for Depression was used to measure the severity and characteristics of depression. Patients with MDD who had longer duration and earlier onset of depression reported more memory complaints. MDD patients with memory complaints had more hypochondriac concerns but not more depression severity compared with those without memory complaints. There was no relationship between subjective memory complaints and objective memory performance in MDD patients. Patients with MDD with and without memory complaints had lower scores on the Wechsler Memory Scale‐III than the control group. Subjective memory complaints are not a valid indictor of objective memory impairments, and the diagnostic value of self‐reported memory is being questioned in patients with MDD. The cognitive status of MDD patients should be assessed routinely, regardless of the patient awareness of his or her cognitive deficits. Depression and Anxiety, 2008. © 2007 Wiley‐Liss, Inc.     

Basic fibroblast growth factor improves learning and memory deficits in a mouse model of vascular dementia Associated with the role of free radicals clearance?

BACKGROUND:Basic fibroblast growth factor(bFGF)exhibits neuroprotective functions,but the possible mechanisms of bFGF on vascular dementia remain unclear.OBJECTIVE:To explore the neureprotective effects of bFGF on a mouse model of vascular dementia,with focus on oxidative damage.DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at the Medical College of Beihua University from March to December 2008.MATERIALS:bFGF was purchased from Peprotech,USA.METHODS:A total of 80 healthy,Kunming mice were randomly assigned to control,sham-surgery,model,and bFGF groups.The model and bFGF groups were used to establish vascular dementia models by repetitive cerebral ischemia-reperfusion in a conscious state.In addition,bFGF group mice were intraperitoneally injected with bFGF(100 μg/kg)following model establishment,once a day for 7 consecutive days.MAIN OUTCOME MEASURES:The Morris water maze was used to determine the influence of bFGF on learning and memory abilities in vascular dementia mice.The pathomorphological changes in hippocampal CA1 neurons were observed by Nissl staining.Superoxide dismutase and malondialdehyde changes were analyzed using biochemical analysis methods.Annexin V-FITC/PI-double-labeled flow cytometry was used to detect neuronal apoptosis.RESULTS:Learning and memory functions in model mice significantly decreased,as characterized by prolonged latency and reduced time and number of platform crossings(P < 0.01,P < 0.05).Superoxide dismutase activity was significantly reduced,malondialdehyde content was significantly increased(P < 0.01),and hippocampal neuronal apoptosis was increased(P < 0.01)following vascular dementia,bFGF increased superoxide dismutase activity,decreased malondialdehyde content,and reduced hippocampal neuronal apoptosis(P < 0.01),which resulted in improved learning and memory in mice with vascular dementia.CONCLUSION:bFGF improved learning and memory deficits in mice with vascular dementia by reducing free radical injury and inhibiting hippocampal neuronal apoptosis.     

4-O-methylhonokiol attenuated memory impairment through modulation of oxidative damage of enzymes involving amyloid-β generation and accumulation in a mouse model of Alzheimer's disease

Accumulations of amyloid-β (Aβ) and oxidative damage are critical pathological mechanisms in the development of Alzheimer's disease (AD). We previously found that 4-O-methylhonokiol, a compound extracted from Magnolia officinalis, improved memory dysfunction in Aβ-injected and presenilin 2 mutant mice through the reduction of accumulated Aβ. To investigate mechanisms of the reduced Aβ accumulation, we examined generation, degradation, efflux and aggregation of Aβ in Swedish AβPP AD model (AβPPsw) mice pre-treated with 4-O-methylhonokiol (1.0 mg/kg) for 3 months. 4-O-methylhonokiol treatment recovered memory impairment and prevented neuronal cell death. This memory improving activity was associated with 4-O-methylhonokiol-induced reduction of Aβ1-42 accumulation in the brains of AβPPsw mice. According to the reduction of Aβ1-42 accumulation, 4-O-methylhonkiol modulated oxidative damage sensitive enzymes. 4-O-methylhonkiol decreased expression and activity of brain beta-site AβPP cleaving enzyme (BACE1), but increased clearance of Aβ in the brain through an increase of expressions and activities of Aβ degradation enzymes; insulin degrading enzyme and neprilysin. 4-O-methylhonkiol also increased expression of Aβ transport molecule, low density lipoprotein receptor-related protein-1 in the brain and liver. 4-O-methylhonkiol decreased carbonyl protein and lipid peroxidation, but increased glutathione levels in the brains of AβPPsw mice suggesting that oxidative damage of protein and lipid is critical in the impairment of those enzyme activities. 4-O-methylhonokiol treatment also prevented neuronal cell death in the AβPPsw mousee brain through inactivation of caspase-3 and BAX. These results suggest that 4-O-methylhonokiol might prevent the development and progression of AD by reducing Aβ accumulation through an increase of clearance and decrease of Aβ generation via antioxidant mechanisms.     

The role of the hippocampus in long-term memory: is it memory store or comparator?

Several attempts have been made to reconcile a number of rival theories on the role of the hippocampus in long-term memory. Those attempts fail to explain the basic effects of the theories from the same point of view. We are reviewing the four major theories, and shall demonstrate, with the use of mathematical models of attention and memory, that only one theory is capable of reconciling all of them by explaining the basic effects of each theory in a unified fashion, without altogether sacrificing their individual contributions. The key issue here is whether or not a memory trace is ever stored in the hippocampus itself, and there is no reconciliation unless the answer to that question is that there is not. As a result of the reconciliation that we are proposing, there is a simple solution to several outstanding problems concerning the neurobiology of memory such as: consolidation and reconsolidation, persistency of long term memory, novelty detection, habituation, long-term potentiation, and the multifrequency oscillatory self-organization of the brain.     

Effects of Acanthopanax senticosus on learning and memory in a mouse model of Alzheimer’s disease and protection against free radical injury to brain tissue *☆

BACKGROUND： Acanthopanax senticosus, a plant of the Araliaceae family, is used in traditional Chinese medicine. It can be used to replenish Qi, strengthen the spleen, tonify the kidney, and relieve mental strain.
OBJECTIVE： To observe effects ofAcanthopanax senticosus on learning and memory in a mouse model of Alzheimer＇s disease and abnormal biochemical changes in the brain tissue. DESIGN： A completely randomized grouping, controlled animal experiment. SETTING： Department of Preventive Medicine, School of Basic Medical Sciences, Yanbian University.
MATERIALS： A total of 50 Kunming mice, aged 1-1.5 months, equal numbers of males and females, were provided by the Laboratory Animal Center, Yanbian University Medical College. The study was performed in accordance with ethical guidelines for the use and care of animals. Acanthopanax was provided by Yanbian Chengda Pharmaceutical Co., Ltd. Acanthopanax senticosus （0.5 kg） was soaked in water for 1 hour and transferred to 1.5 kg distilled water for extraction. It was boiled for 1 hour and extracted after 1 hour of boiling. The procedure was repeated 3 times. The extract was condensed to 500 mL and then adjusted to 500 and 1000 g/L with water. Piracetam tablets were produced by Shandong Luoxin Pharmaceutical Corporation, China. Malonaldehyde （MDA）, superoxide dismutase （SOD）, and acetylcholinesterase （ACHE） kits were purchased from Nanjing Jiancheng Bioengineering Co., Ltd., China. METHODS： This study was performed at the Department of Preventive Medicine, School of Basic Medical Sciences, Yanbian University from January to June 2007. All mice were randomly divided into 5 groups with 10 mice in each： control group, model group, low-, and high-dose Acanthopanax senticosus-treated groups, and piracetam-treated group. All groups were administered 0.1 mL/10 g. In the control and model groups, mice were intragastrically administered saline each morning for 5 days prior to experimentation. Five days later, they were intraperitoneally perfus     

Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AβPP containing the wild-type β-secretase site sequence

Therapeutic agents that improve the memory loss of Alzheimer's disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have β-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AβPP containing the WT β-secretase site sequence and the London γ-secretase site (AβPPWT/Lon mice). Knockout of the CatB gene in the AβPPWT/Lon mice improved memory deficits and altered the pattern of Aβ-related biomarkers in a manner consistent with CatB having WT β-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.     

Are memory traces localized or distributed?

Evidence supports the view that "memory traces" are formed in the hippocampus and in the cerebellum in classical conditioning of discrete behavioral responses (e.g. eyeblink conditioning). In the hippocampus, learning results in long-lasting increases in excitability of pyramidal neurons that appear to be localized to these neurons (i.e. changes in membrane properties and receptor function). However, these learning-altered pyramidal neurons are distributed widely throughout CA3 and CA1. Although it plays a key role in certain aspects of classical conditioning, the hippocampus is not necessary for learning and memory of the basic conditioned responses. The cerebellum and its associated brain stem circuitry, on the other hand, does appear to be essential (necessary and sufficient) for learning and memory of the conditioned response. Evidence to date is most consistent with a localized trace in the interpositus nucleus and multiple localized traces in cerebellar cortex, each involving relatively large ensembles of neurons. Perhaps "procedural" memory traces are relatively localized and "declarative" traces more widely distributed.     

How are memory complaints in functional memory disorder related to measures of affect, metamemory and cognition?

Objective

Memory complaints are a common finding in outpatients, especially in psychosomatic and neurological practice. In a substantial group of patients persistent memory complaints are found in the absence of abnormal neuropsychology. Different labels such as “functional memory complaint” have been suggested for this phenomenon. We characterise a group of patients with such memory complaints, which we termed functional memory disorder (FMD). The aim of the present study is to describe patients with FMD.

Methods

Thirty-nine patients with FMD were compared to 38 control subjects. Data were collected on the German version of the Rey Auditory Verbal Learning test and the Zahlenverbindungstest (cognitive speed), subscales of the Metamemory in Adulthood questionnaire (MIA), the Perceived Stress Questionnaire (PSQ), the Global Severity Index (GSI) of the Symptom Checklist, the Beck Depression Inventory (BDI), and other psychological questionnaire measures.

Results

We found significant group differences on all psychological questionnaire measures, with more pathological scores in the patient group. GSI and PSQ were the best predictors of memory self-efficacy. MIA-Memory Self-Efficacy (MSE), MIA-Achievement, and BDI were the best predictors of group membership (FMD vs. control group). When MSE was excluded, MIA-Achievement and BDI or GSI were the only predictors of group membership. Neuropsychological measures predicted neither MSE nor group membership.

Conclusions

Pathological scores on measures of metamemory, stress, and depression are typical of FMD. Low MSE and a high memory-related achievement motivation seem to be key features of FMD. Other important features are increased perceived stress, general psychosomatic complaint, and elevated depression scores. Neuropsychological test performance is not associated with FMD symptoms.     

Recognition memory for hand positions and spatial locations in patients with Huntington's disease: differential visuospatial memory impairment?

Allocentric and egocentric memory was investigated in patients with Huntington's disease (HD) and matched controls. Patients with HD and age- and education-matched healthy normal controls (NC) were administered two visuospatial recognition memory tasks, one assessing memory for hand positions (egocentric) and the other assessing memory for spatial locations (allocentric). HD patients showed normal primacy and recency effects, but their overall performance was impaired relative to controls on both tasks. Correlation analyses indicated that HD patients' performance on the Hand Position Memory task, but not the Spatial Location Memory task, was associated with global cognitive status (Mattis Dementia Rating Scale) and disease severity (Shoulson and Fahn Rating Scale), and HD patients' performances on the two tasks were not associated. Results provide preliminary support for the role of the caudate nucleus in both allocentric and egocentric spatial memory.