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remote memory [keywords]
- Effects of field-realistic doses of glyphosate on honeybee appetitive behaviour. [JOURNAL ARTICLE]
- J Exp Biol 2014 Jul 25.
Glyphosate (GLY) is a broad spectrum herbicide used for weed control. Presently, sub-lethal impact of GLY on non-target organisms such as insect pollinators has not been evaluated yet. Apis mellifera is the main pollinator in agricultural environments and a well-known model for behavioural research. Moreover, honeybees are accurate biosensors of environmental pollutants and their appetitive behavioural response is a suitable tool to test sub-lethal effects of agrochemicals. We studied the effects of field-realistic doses of GLY on honeybees exposed chronically or acutely to it. We focused on sucrose sensitivity, elemental and non-elemental associative olfactory conditioning of the proboscis extension response (PER) and on foraging related behaviour. We found a reduced sensitivity to sucrose and learning performance for the groups chronically exposed to GLY concentrations within the range of recommended doses. When olfactory PER conditioning was performed with sucrose reward with the same GLY concentrations (acute exposure), elemental learning and short-term memory retention decreased significantly compared to controls. Non-elemental associative learning was also impaired by an acute exposure to GLY traces. Altogether, these results imply that GLY at concentrations found in agro-ecosystems due to standard spraying can reduce sensitivity to nectar reward and impair associative learning in honeybees. However, no effect on foraging related behaviour was found. Therefore, we speculate that successful forager bees could become a source of constant inflow of nectar with GLY traces that could then be distributed among nest mates, stored in the hive and have long-term negative consequences on colony performance.
- Two inhibitors of the ubiquitin proteasome system enhance long-term memory formation upon olfactory conditioning in the honeybee (Apis mellifera). [JOURNAL ARTICLE]
- J Exp Biol 2014 Jul 25.
In honeybees (Apis mellifera) the proteasome inhibitor Z-Leu-Leu-Leu-CHO (MG132) enhances long-term memory (LTM) formation. Studies in vertebrates using different inhibitors of the proteasome demonstrate the opposite, namely an inhibition of memory formation. The reason for this contradiction remains unclear. MG132 is an inhibitor of the proteasome, but also blocks other proteases. Accordingly, one possible explanation might be that other proteases affected by MG132 are responsible for the enhancement of LTM formation. We test this hypothesis by comparing the effect of MG132 and the more specific proteasome inhibitor clasto-lactacystin beta-lactone (β-lactone). We show that these two inhibitors block the activity of the proteasome in honeybee brains to a similar extent, do not affect the animals' survival but do enhance LTM retention upon olfactory conditioning. Thus, the enhancement of LTM formation is not due to MG132-specific side effects, but to inhibition of a protease targeted by MG132 and β-lactone, i.e. the proteasome.
- Circadian modulation of memory and plasticity gene Products in a diurnal species. [JOURNAL ARTICLE]
- Brain Res 2014 Jul 22.
Cognition is modulated by circadian rhythms, in both nocturnal and diurnal species. Rhythms of clock gene expression occur in brain regions that are outside the master circadian oscillator of the suprachiasmatic nucleus and that control cognitive functions, perhaps by regulating the expression neural-plasticity genes such as brain derived neurotrophic factor (BDNF) and its high affinity receptor, tyrosine kinase B (TrkB). In the diurnal grass rat (Arvicanthis niloticus), the hippocampus shows rhythms of clock genes that are 180° out of phase with those of nocturnal rodents. Here, we examined the hypothesis that this reversal extends to the optimal phase for learning a hippocampal-dependent task and to the phase of hippocampal rhythms in BDNF/TrkB expression. We used the Morris water maze (MWM) to test for time of day differences in reference memory and monitored daily patterns of hippocampal BDNF/TrkB expression in grass rats. Grass rats showed superior long-term retention of the MWM, when the training and testing occurred during the day as compared to the night, at a time when nocturnal laboratory rats show superior retention; acquisition of the MWM was not affected by time of day. BDNF/TrkB expression was rhythmic in the hippocampus of grass rats, and the phase of the rhythms was reversed compared to that of nocturnal rodents. Our findings provide correlational evidence for the claim that the circadian regulation of cognition may involve rhythms of BDNF/TrkB expression in the hippocampus and that their phase may contribute to species differences in the optimal phase for learning.
- Role of Cognitive Enhancer Therapy in Alzheimer's Disease with Concomitant Cerebral White Matter Disease: Findings from a Long-Term Naturalistic Study. [JOURNAL ARTICLE]
- Drugs R D 2014 Jul 26.
Evidence is lacking for cognitive enhancer therapy in patients with Alzheimer's disease (AD) and concomitant cerebrovascular disease (mixed AD) as such patients would have been excluded from clinical trials. Earlier studies of mixed AD have focused on large vessel cerebrovascular disease. The influence of small vessel cerebrovascular disease (svCVD) in the form of white matter hyperintensity (WMH) on treatment outcomes in mixed AD has not been addressed.In this long-term naturalistic study, we evaluated the effectiveness of cognitive enhancers in patients with mixed AD with svCVD.We conducted a retrospective analysis of a prospective clinical database from a memory clinic of a tertiary hospital. Magnetic resonance imaging WMH was used as a marker of svCVD. Demographic, cognitive, and treatment data were analysed. Linear mixed models with patient-specific random effects were used to evaluate cognitive outcomes over time while adjusting for confounders.Patients with mixed AD (n = 137) or AD without svCVD (pure AD) (n = 28) were studied over a median duration of 28.7 months. Patients with mixed AD had a higher prevalence of hypertension (62.8 vs. 35.7 %, p = 0.011). The majority (75.2 %) of the study sample were managed with monotherapy. Mini Mental State Examination (MMSE) scores decreased over time (-0.04, p = 0.007), and the decrease was similar for both diagnosis groups (-0.03, p = 0.246). Annual estimated mean MMSE decline was 0.84 for pure AD and 0.48 for mixed AD. Similar trends were observed with Montreal Cognitive Assessment (MoCA) scores, with annual estimated mean reduction of 0.72 and 0.48 for pure AD and mixed AD, respectively.Cognitive enhancers are effective in slowing the rate of cognitive decline in patients with AD with svCVD. These findings would need to be confirmed in randomized clinical trials.
- Novel interactive effects of darkness and retinoid signaling in the ability to form long-term memory following aversive operant conditioning. [JOURNAL ARTICLE]
- Neurobiol Learn Mem 2014 Jul 22.
The vitamin A metabolite, retinoic acid, is important for memory formation and hippocampal synaptic plasticity in vertebrate species. In our studies in the mollusc Lymnaea stagnalis, we have shown that retinoic acid plays a role in memory formation following operant conditioning of the aerial respiratory behaviour. Inhibition of either retinaldehyde dehydrogenase (RALDH) or the retinoid receptors prevents long-term memory (LTM) formation, whereas synthetic retinoid receptor agonists promote memory formation by converting intermediate-term memory (ITM) into LTM. In this study, animals were exposed to constant darkness in order to test whether light-sensitive retinoic acid would promote memory formation. However, we found that exposure to constant darkness alone (in the absence of retinoic acid) enhanced memory formation. To determine whether the memory-promoting effects of darkness could override the memory-inhibiting effects of the retinoid signaling inhibitors, we exposed snails to RALDH inhibitors or a retinoid receptor antagonist in constant darkness. We found that darkness overcame the inhibitory effects of RALDH inhibition, but did not overcome the inhibitory effects of the retinoid receptor antagonist. We also tested whether constant darkness and training affected the mRNA levels of the retinoid metabolic enzymes RALDH and Cyp26, or the mRNA levels of the retinoid receptors, but found no significant effect. Overall, these data demonstrate an interaction between environmental light conditions and the retinoid signaling pathway, which influence long-term memory formation in a mollusc.
- Influence of mild traumatic brain injury during pediatric stage on short-term memory and hippocampal apoptosis in adult rats. [Journal Article]
- J Exerc Rehabil 2014 Jun; 10(3):148-54.
Traumatic brain injury (TBI) is a leading cause of neurological deficit in the brain, which induces short- and long-term brain damage, cognitive impairment with/without structural alteration, motor deficits, emotional problems, and death both in children and adults. In the present study, we evaluated whether mild TBI in childhood causes persisting memory impairment until adulthood. Moreover, we investigated the influence of mild TBI on memory impairment in relation with hippocampal apoptosis. For this, step-down avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and immunohistochemistry for caspase-3 were performed. Male Sprague-Dawley rats were used in the experiments. The animals were randomly divided into two groups: sham-operation group and TBI-induction group. The mild TBI model was created with an electromagnetic contusion device activated at a velocity of 3.0 m/sec. The results showed that mild TBI during the pediatric stage significantly decreased memory retention. The numbers of TUNEL-positive and caspase-3-positive cells were increased in the TBI-induction group compared to those in the sham-operation group. Defective memory retention and apoptosis sustained up to the adult stage. The present results shows that mild TBI induces long-lasting cognitive impairment from pediatric to adult stages in rats through the high level of apoptosis. The finding of this study suggests that children with mild TBI may need intensive treatments for the reduction of long-lasting cognitive impairment by secondary neuronal damage.
- A novel Fibroblast Growth Factor Receptor family member promotes neuronal outgrowth and synaptic plasticity in Aplysia. [JOURNAL ARTICLE]
- Amino Acids 2014 Jul 25.
Fibroblast Growth Factor (FGF) Receptors (FGFRs) regulate essential biological processes, including embryogenesis, angiogenesis, cellular growth and memory-related long-term synaptic plasticity. Whereas canonical FGFRs depend exclusively on extracellular Immunoglobulin (Ig)-like domains for ligand binding, other receptor types, including members of the tropomyosin-receptor-kinase (Trk) family, use either Ig-like or Leucine-Rich Repeat (LRR) motifs, or both. Little is known, however, about the evolutionary events leading to the differential incorporation of LRR domains into Ig-containing tyrosine kinase receptors. Moreover, although FGFRs have been identified in many vertebrate species, few reports describe their existence in invertebrates. Information about the biological relevance of invertebrate FGFRs and evolutionary divergences between them and their vertebrate counterparts is therefore limited. Here, we characterized ApLRRTK, a neuronal cell-surface protein recently identified in Aplysia. We unveiled ApLRRTK as the first member of the FGFRs family deprived of Ig-like domains that instead contains extracellular LRR domains. We describe that ApLRRTK exhibits properties typical of canonical vertebrate FGFRs, including promotion of FGF activity, enhancement of neuritic outgrowth and signaling via MAPK and the transcription factor CREB. ApLRRTK also enhanced the synaptic efficiency of neurons known to mediate in vivo memory-related defensive behaviors. These data reveal a novel molecular regulator of neuronal function in invertebrates, provide the first evolutionary linkage between LRR proteins and FGFRs and unveil an unprecedented mechanism of FGFR gene diversification in primeval central nervous systems.
- Differential hippocampal gene expression and pathway analysis in an etiology-based mouse model of major depressive disorder. [JOURNAL ARTICLE]
- Am J Med Genet B Neuropsychiatr Genet 2014 Jul 25.
We have recently reported the creation and initial characterization of an etiology-based recombinant mouse model of a severe and inherited form of Major Depressive Disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with MDD in individuals from families with recurrent, early-onset MDD (RE-MDD). In the current study, we explored the effect of the pathogenic Creb1 allele on gene expression in the mouse hippocampus, a brain region that is altered in structure and function in MDD. Mouse whole-genome profiling was performed using the Illumina MouseWG-6 v2.0 Expression BeadChip microarray. Univariate analysis identified 269 differentially-expressed genes in the hippocampus of the mutant mouse. Pathway analyses highlighted 11 KEGG pathways: the phosphatidylinositol signaling system, which has been widely implicated in MDD, Bipolar Disorder, and the action of mood stabilizers; gap junction and long-term potentiation, which mediate cognition and memory functions often impaired in MDD; cardiac muscle contraction, insulin signaling pathway, and three neurodegenerative brain disorders (Alzheimer's, Parkinson's, and Huntington's Diseases) that are associated with MDD; ribosome and proteasome pathways affecting protein synthesis/degradation; and the oxidative phosphorylation pathway that is key to energy production. These findings illustrate the merit of this congenic C57BL/6 recombinant mouse as a model of RE-MDD, and demonstrate its potential for highlighting molecular and cellular pathways that contribute to the biology of MDD. The results also inform our understanding of the mechanisms that underlie the comorbidity of MDD with other disorders. © 2014 Wiley Periodicals, Inc.
- Neurodevelopmental and behavioral effects of nonylphenol exposure during gestational and breastfeeding period on F1 rats. [JOURNAL ARTICLE]
- Neurotoxicology 2014 Jul 21.
Nonylphenols (NP) are endocrine-disruptors known to be widely present in our environment. This study evaluated the effects of 4-n-NP on neurobehavioral development and memory capacity after perinatal exposure on the offspring rats. Dams were gavaged with 4-n-NP (0, 50 and 200 mg/kg/day) from gestational day 5 to postnatal day (PND) 21. Dams exposed to the higher dose lost weight during gestation and had a longer gestational duration. Juvenile female pups of the 200 mg 4-n-NP/kg/day group were lighter. Their thyroid somatic index (TSI) was also affected. For male pups, a decrease of TSI at weaning for the 200 mg 4-n-NP/kg/day group and an increase of GSI for the 50 mg 4-n-NP/kg/day group were observed. Physical maturation (incisives and eyes) were likewise affected. In open field (OF) tests, females were more active than males. In the first OF (PND 36), a treatment effect was observed only for males, particularly for the high dose group, which became as active as females. The second OF (PND 71) showed few differences between groups (treated vs control), the gender difference whatever the dose was not abolished. In the Morris water maze test, the study of the first 30 s showed that females (200 mg/kg/day) were mainly affected. Their performances were improved by 4-n-NP. These effects were particularly important for the first short-term memory test and observed to a lesser extent in the second evaluation of the long-term memory (PND 69). These data showed that perinatal 4-n-NP exposure induced behavioral and neuro-developmental impairments from 50 mg/kg/day.
- eIF2α Dephosphorylation in Basolateral Amygdala Mediates Reconsolidation of Drug Memory. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):10010-21.
Maladaptive memories elicited by exposure to environmental stimuli associated with drugs of abuse are often responsible for relapse among addicts. Interference with the reconsolidation of drug memory can inhibit drug seeking. Previous studies have indicated that the dephosphorylation of the eukaryotic initiation factor 2 α-subunit (eIF2α) plays an important role in synaptic plasticity and long-term memory consolidation, but its role in the reconsolidation of drug memory remains unknown. The amygdala is required for the reconsolidation of a destabilized drug memory after retrieval of drug-paired stimuli. Here, we used conditioned place preference (CPP) and self-administration procedures to determine whether amygdala eIF2α dephosphorylation is required for the reconsolidation of morphine and cocaine memories in rats. We found that the levels of eIF2α phosphorylation (Ser51) and activating transcription factor 4 (ATF4) were decreased after reexposure to a previously morphine- or cocaine-paired context (i.e., a memory retrieval procedure) in the basolateral amygdala (BLA) but not in the central amygdala. Intra-BLA infusions of Sal003, a selective inhibitor of eIF2α dephosphorylation, immediately after memory retrieval disrupted the reconsolidation of morphine- or cocaine-induced CPP, leading to a long-lasting suppression of drug-paired stimulus-induced craving. Advanced knockdown of ATF4 expression in the BLA by lentivirus-mediated short-hairpin RNA blocked the disruption of the reconsolidation of morphine-induced CPP induced by Sal003 treatment. Furthermore, inhibition of eIF2α dephosphorylation in the BLA immediately after light/tone stimulus retrieval decreased subsequent cue-induced heroin-seeking behavior in the self-administration procedure. These results demonstrate that eIF2α dephosphorylation in the BLA mediates the memory reconsolidation of drug-paired stimuli.