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remote memory [keywords]
- Dopamine D2 receptor controls hilar mossy cells excitability. [JOURNAL ARTICLE]
- Hippocampus 2014 Apr 18.
Hippocampal control of memory formation is regulated by dopaminergic signaling. Whereas the role of dopamine D1 receptors is well documented in such regulations, functions of dopamine D2 receptors (DRD2) are not fully understood. Using fluorescence in situ hybridization we demonstrate that Drd2 expression in the hippocampus of wild-type mice is limited to glutamatergic hilar mossy cells. Using whole cell electrophysiological recordings in hippocampal slice preparations, we provide evidence that unlike in basal ganglia, activation of DRD2 by the selective agonist, quinpirole, induces a long-lasting increase in excitability of hilar mossy cells, which can be blocked by the DRD2 antagonist raclopride. Such activity is mediated by the Akt/GSK pathway, as application of specific inhibitors such as A1070722 or SB216763 prevented quinpirole activity. Long-term effects of acute DRD2 activation in vitro suggest that, volume transmission of dopamine may modulate mossy cell activities in vivo. This is supported by the presence of dense tyrosine hydroxylase positive varicosities in the hilus, which are rarely seen in the vicinity of mossy cell dendrites. From these data we discuss how dopamine could control mossy cell activity and thus dentate gyrus functions. © 2014 Wiley Periodicals, Inc.
- The maintenance of long-term memory in the hippocampus depends on the interaction between N-Ethylmaleimide-Sensitive factor and Glua2. [JOURNAL ARTICLE]
- Hippocampus 2014 Apr 20.
The maintenance of established memories has recently been shown to involve the stabilization of GluA2-containing AMPA receptors (GluA2/AMPARs) at postsynaptic membranes. Previous studies have suggested that N-ethylmaleimide-sensitive factor (NSF) regulates the stabilization of AMPARs at the synaptic membrane. We therefore disrupted the interaction between GluA2 and NSF in the dorsal hippocampus and examined its effect on the maintenance of object location and contextual fear memory. We used two interference peptides, pep2m and pepR845A, that have been shown to block the binding of NSF to GluA2 and reduce GluA2 synaptic content. Either peptide disrupted consolidated memory, and these effects persisted for at least 5 or 28 d after peptide administration. Following peptide administration and long-term memory disruption, rats were able to acquire new memories. Memory acquisition or consolidation was not impaired when pepR845A was given immediately before the training sessions. Blocking GluA2 endocytosis with the peptide GluA23Y prevented the memory impairment effect of pepR845A. Taken together, our results indicate that the persistence of long-term memory depends on the maintenance of a steady-state level of synaptic GluA2/AMPARs, which requires the interaction of NSF with GluA2. © 2014 Wiley Periodicals, Inc.
- The role of self-generated odor cues in contextual representation. [JOURNAL ARTICLE]
- Hippocampus 2014 Apr 17.
As first demonstrated in the patient H.M., the hippocampus is critically involved in forming episodic memories, the recall of "what" happened "where" and "when." In rodents, the clearest functional correlate of hippocampal primary neurons is the place field: a cell fires predominantly when the animal is in a specific part of the environment, typically defined relative to the available visuospatial cues. However, rodents have relatively poor visual acuity. Furthermore, they are highly adept at navigating in total darkness. This raises the question of how other sensory modalities might contribute to a hippocampal representation of an environment. Rodents have a highly developed olfactory system, suggesting that cues such as odor trails may be important. To test this, we familiarized mice to a visually cued environment over a number of days while maintaining odor cues. During familiarization, self-generated odor cues unique to each animal were collected by re-using absorbent paperboard flooring from one session to the next. Visual and odor cues were then put in conflict by counter-rotating the recording arena and the flooring. Perhaps surprisingly, place fields seemed to follow the visual cue rotation exclusively, raising the question of whether olfactory cues have any influence at all on a hippocampal spatial representation. However, subsequent removal of the familiar, self-generated odor cues severely disrupted both long-term stability and rotation to visual cues in a novel environment. Our data suggest that odor cues, in the absence of additional rule learning, do not provide a discriminative spatial signal that anchors place fields. Such cues do, however, become integral to the context over time, and exert a powerful influence on the stability of its hippocampal representation. © 2014 Wiley Periodicals, Inc.
- Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging. [JOURNAL ARTICLE]
- Hippocampus 2014 Apr 17.
Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 hours at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-hour retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation. © 2014 Wiley Periodicals, Inc.
- Dynamic expression of the polysialyltransferase PST in adult rat hippocampus performing an olfactory associative task. [JOURNAL ARTICLE]
- Hippocampus 2014 Apr 18.
Neural cell adhesion molecule (NCAM) is associated with polysialic acid (PSA), and its function is highly dependent on the extent of polysialylation through the activity of two polysialyltransferases, STX and PST. PSA-NCAM plays an important role in synaptic plasticity in the hippocampus. The involvement of STX and PST during mnesic processes was assessed in the adult rat hippocampus. We investigated whether different levels in learning and memory using an olfactory associative task influenced STX and PST gene expression in the hippocampus using semi-quantitative RT-PCR. Then, NCAM polysialylation and cell proliferation were quantified in the dentate gyrus of a "Learning and Memory" group using immunohistochemistry. We found that only the expression level of PST mRNA increased with learning performance and returned to an initial level when learned associations were consolidated in long-term memory, while STX mRNA levels remained unchanged. This phenomenon was accompanied by an increase in PSA on NCAM but not by cell proliferation in the dentate gyrus. Our results suggest a different involvement for STX and PST in neural plasticity: while STX is probably involved in the proliferation of neural progenitor cells, PST could play a key role in synaptic plasticity of mature neural networks. The expression of the STX and PST genes could therefore be useful markers of neurobiological plasticity in the brain, allowing to follow chronological events in limbic and cortical structures related first to learning and memory processes (for PST) and, second, to adult neurogenesis processes (for STX). © 2014 Wiley Periodicals, Inc.
- Progesterone in transient ischemic stroke: a dose-response study. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2014 Apr 22.
Previous studies demonstrate the neuroprotective effects of progesterone in numerous animal injury models, but a systematic dose-response study in a transient ischemic stroke model is lacking.We investigated the effects of progesterone at different doses on post-stroke brain infarction and functional deficits in middle-aged rats.Cerebral ischemia was induced in 13-month-old male Sprague-Dawley rats by right middle cerebral artery occlusion for 2 h followed by reperfusion. Rats received intraperitoneal injections of 8, 16, or 32 mg/kg of progesterone (P8, P16, P32) or vehicle at 2 h post-occlusion followed by subcutaneous injections at 6 h and every 24 h post-injury for 7 days. Functional recovery was evaluated at intervals over 22 days using motor, sensory, and cognitive tests. Infarct size was evaluated at 22 days post-stroke.Repeated-measures ANOVA showed significant group effects on grip strength, rotarod, and sensory neglect. All progesterone-treated groups had improved (p < 0.05) spatial memory performance. The P8 and P16 groups showed maximum improvement in long-term memory compared to vehicle. Significant (p < 0.05) gait impairments were observed in the vehicle group compared to shams. Animals receiving the P8 dose showed maximum gait improvement compared to vehicle. Post hoc analysis revealed that the P8 and P16 groups showed significant attenuation in infarct volume compared to vehicle. Animals receiving the P32 dose did not show any effect on infarct volume.Although all doses were somewhat effective, progesterone given at 8 mg/kg led to the most consistent improvements across a panel of behavioral/functional tests and reduced the severity of ischemic infarct injury.
- Cognitive decline in patients with Alzheimer's disease and its related factors in a memory clinic setting, shanghai, china. [Journal Article]
- PLoS One 2014; 9(4):e95755.
Progressive cognitive decline is a characteristic hallmark of AD. It is important to identify prognostic markers to improve patient care and long-term planning. We aimed to identify the characteristics of disease progression in AD patients, focusing on cognitive decline and its related factors.Clinically diagnosed AD patients in a memory clinic were followed. The mini-mental state examination (MMSE) and a battery of other neuropsychological tests were performed to assess the rate of cognitive decline and to analyze the related factors.A total of 165 AD patients were analyzed for cognitive changes. The MMSE scores declined at a rate of 1.52 points per year. Most neuropsychological test scores deteriorated significantly over time. Younger and early-onset AD patients deteriorated more rapidly than older and late-onset patients in global cognition and executive function. Men declined faster in memory but slower in attention than women. Higher education was associated with more rapid deterioration in visuo-spatial ability. Family history, hypertension and cerebral vascular disease were also associated with disease progression.Attention, executive and visuo-spatial functions deteriorate at faster rates than other cognitive functions in AD patients. Age and age at onset were the main factors that associated with deterioration.
- Discovery of prognostic biomarker candidates of lacunar infarction by quantitative proteomics of microvesicles enriched plasma. [Journal Article]
- PLoS One 2014; 9(4):e94663.
Lacunar infarction (LACI) is a subtype of acute ischemic stroke affecting around 25% of all ischemic stroke cases. Despite having an excellent recovery during acute phase, certain LACI patients have poor mid- to long-term prognosis due to the recurrence of vascular events or a decline in cognitive functions. Hence, blood-based biomarkers could be complementary prognostic and research tools.Plasma was collected from forty five patients following a non-disabling LACI along with seventeen matched control subjects. The LACI patients were monitored prospectively for up to five years for the occurrence of adverse outcomes and grouped accordingly (i.e., LACI-no adverse outcome, LACI-recurrent vascular event, and LACI-cognitive decline without any recurrence of vascular events). Microvesicles-enriched fractions isolated from the pooled plasma of four groups were profiled by an iTRAQ-guided discovery approach to quantify the differential proteome. The data have been deposited to the ProteomeXchange with identifier PXD000748. Bioinformatics analysis and data mining revealed up-regulation of brain-specific proteins including myelin basic protein, proteins of coagulation cascade (e.g., fibrinogen alpha chain, fibrinogen beta chain) and focal adhesion (e.g., integrin alpha-IIb, talin-1, and filamin-A) while albumin was down-regulated in both groups of patients with adverse outcome.This data set may offer important insight into the mechanisms of poor prognosis and provide candidate prognostic biomarkers for validation on larger cohort of individual LACI patients.
- Long-Term Follow-up of a Novel Anastomotic Device in a Canine Model. [Journal Article]
- Surg Innov 2014 Apr; 21(2):198-203.
Construction of intestinal anastomosis is a fundamental general surgery skill. New constraints in creating safe, effective anastomoses are faced, however, even as minimally invasive surgery techniques continue to gain popular and scientific support. We present our experience in developing and testing a novel anastomotic device (AD) constructed of a shape memory metal, with long-term follow-up in a canine model. This device has the potential for both laparoscopic and endoscopic delivery because of its unique design and adaptable deployment system. Eight canines had gastroduodenal and jejunojejunal anastomoses formed with the AD: the gastroduodenal anastomosis by transecting the stomach immediately distal to the pylorus and forming a side-to-side functional end-to-end anastomosis and the jejunojejunal anastomosis similarly following transection in the mid-jejunum. Four animals were survived for 6 months, and 4 for 12 months. At the study's end, the animals were euthanized and the anastomotic sites harvested for both gross and microscopic pathology. Two animals developed postoperative complications: one a mechanical bowel obstruction from bedding ingestion that required laparotomy, and one an ileus that conservative management resolved. All animals survived to their endpoints, displaying normal growth and development. All jejunojejunal anastomoses had AD passage and microscopic evidence of complete healing. Meanwhile, none of the gastroduodenal devices passed, with microscopy demonstrating incomplete mucosalization. This AD is highly effective in forming jejunojejunal anastomoses. Gastroduodenal anastomoses, while highly functional, retained the device without complete healing. Future studies using a more human-like animal model and an anastomotic technique avoiding the thick pylorus muscle should yield better results.
- Cognition and Hippocampal Plasticity in the Mouse Is Altered by Monosomy of a Genomic Region Implicated in Down Syndrome. [JOURNAL ARTICLE]
- Genetics 2014 Apr 21.
Down syndrome (DS) is due to increased copy number of human chromosome 21. The contribution of different genetic regions has been tested using mouse models. As shown previously, the Abcg1-U2af1 genetic region contributes to cognitive defects in working and short-term recognition memory in Down syndrome mouse models. Here we analyzed the impact of monosomy of the same genetic interval using a new mouse model, named Ms2Yah. We used several cognitive paradigms, and did not detect defects in the object recognition nor the Morris water maze tests. However, surprisingly, Ms2Yah mice displayed increased associative memory in a pure contextual fear conditioning test, and decreased social novelty interaction along with a larger long term potentiation recorded in the CA1 area following stimulation of Schaffer collaterals. Whole genome expression studies carried out on hippocampus showed that only the transcription of a small number of genes is affected, mainly from the genetic interval (Cbs, Rsph1, Wdr4), with a few additional ones, including the postsynaptic Gabrr2, Gabbr1, Grid2p, Park2 and Dlg1 and the components of the Ubiquitin mediated proteolysis (Anapc1, Rnf7, Huwe1, Park2). The Abcg1-U2af1 region is undeniably encompassing dosage sensitive genes or elements whose change in copy number directly impact learning and memory, synaptic function and autistic related behavior.