Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus

The perforant path projecting from the entorhinal cortex to the hippocampal dentate gyrus is a particularly vulnerable target to the early deposition of amyloid beta (Abeta) peptides in Alzheimer's brain. The authors previously showed that brief applications of Abeta at subneurotoxic concentrations suppressed the early-phase long-term potentiation (E-LTP) in rat dentate gyrus. The current study further examines the effect of Abeta on the late-phase LTP (L-LTP) in this area. Using multiple high-frequency stimulus trains, a stable L-LTP lasting for at least 3 h was induced in the medial perforant path of rat hippocampal slices. Bath application of Abeta(1-42) (0.2-1.0 microM) during the induction trains attenuated both the initial and late stages of L-LTP. On the other hand, Abeta(1-42) perfusion within the first hour following the induction primarily impaired the late stage of L-LTP, which resembled the action of the protein synthesis inhibitor emetine. Blockade of calcineurin activity with FK506 or cyclosporin A completely prevented Abeta-induced L-LTP deficits. These results suggest that Abeta(1-42) impaired both the induction and maintenance phase of dentate L-LTP through calcineurin-dependent mechanisms. In the concentration range effective for inhibiting L-LTP, Abeta(1-42) also reduced the amplitude of NMDA receptor-mediated synaptic currents in dentate granule cells via a postsynaptic mechanism. In addition, concurrent applications of Abeta(1-42) with the protein synthesis inhibitor caused no additive reduction of L-LTP, indicating a common mechanism underlying the action of both. Thus, inhibition of NMDA receptor channels and disruption of protein synthesis were two possible mechanisms contributing to Abeta-induced L-LTP impairment.     

Contribution of acetylcholine to visual cortex plasticity

Acetylcholine is involved in a variety of brain functions. In the visual cortex, the pattern of cholinergic innervation varies considerably across different mammalian species and across different cortical layers within the same species. The physiological effects of acetylcholine in the visual cortex display complex responses, which are likely due to cholinergic receptor subtype composition in cytoplasm membrane as well as interaction with other transmitter systems within the local neural circuitry. The functional role of acetylcholine in visual cortex is believed to improve the signal-to-noise ratio of cortical neurons during visual information processing. Available evidence suggests that acetylcholine is also involved in experience-dependent visual cortex plasticity. At the level of synaptic transmission, activation of muscarinic receptors has been shown to play a permissive role in visual cortex plasticity. Among the muscarinic receptor subtypes, the M(1) receptor seems to make a predominant contribution towards modifications of neural circuitry. The signal transduction cascade of the cholinergic pathway may act synergistically with that of the NMDA receptor pathway, whose activation is a prerequisite for cortical plasticity.     

LTP诱导期向维持或转化过程中的突触形态学特征

该研究探讨了视皮层LTP由诱导期向维持期转化过程的突触形态学特征。实验选用18-30天龄的健康SD大鼠,分实验组、空白对照组及实验对照组进行电镜观测和图象分析。结果发现,在常规LTP实验程序中强直刺激后有LTP产生并记录80分钟的实验组脑片标片,局部有界面曲率大于2的较大U型突触形成,这种突触多有两个以上活性区。图象分析结果显示,实验组与对照组相比较,突触的界面曲率明显增大（P＜0．05）,活性区的长度明显加长（＜0．05）。     

Recollection reduces unitised familiarity effect

Two types of encoding tasks have been employed in previous research to investigate the beneficial effect of unitisation on familiarity-based associative recognition (unitised familiarity effect), namely the compound task and the interactive imagery task. Here we show how these two tasks could differentially engage subsequent recollection-based associative recognition and consequently lead to the turn-on or turn-off of the unitised familiarity effect. In the compound task, participants studied unrelated word pairs as newly learned compounds. In the interactive imagery task, participants studied the same word pairs as interactive images. An associative recognition task was used in combination with the Remember/Know procedure to measure recollection-based and familiarity-based associative recognition. The results showed that the unitised familiarity effect was present in the compound task but was absent in the interactive imagery task. A comparison of the compound and the interactive imagery task revealed a dramatic increase in recollection-based associative recognition for the interactive imagery task. These results suggest that unitisation could benefit familiarity-based associative recognition; however, this effect will be eliminated when the memory trace formed is easily accessed by strong recollection without the need for a familiarity assessment.     

Contextual cueing is not flexible

Target detection is faster when search displays repeat, but properties of the memory representations that give rise to this contextual cueing effect remain uncertain. We adapted the contextual cueing task using an ABA design and recorded the eye movements of healthy young adults to determine whether the memory representations are flexible. Targets moved to a new location during the B phase and then returned to their original locations (second A phase). Contextual cueing effects in the first A phase were reinstated immediately in the second A phase, and response time costs eventually gave way to a repeated search advantage in the B phase, suggesting that two target-context associations were learned. However, this apparent flexibility disappeared when eye tracking data were used to subdivide repeated displays based on B-phase viewing of the original target quadrant. Therefore, memory representations acquired in the contextual cueing task resist change and are not flexible.     

Simple Co‐Occurrence Statistics Reproducibly Predict Association Ratings

What determines human ratings of association? We planned this paper as a test for association strength (AS) that is derived from the log likelihood that two words co‐occur significantly more often together in sentences than is expected from their single word frequencies. We also investigated the moderately correlated interactions of word frequency, emotional valence, arousal, and imageability of both words (r's ≤ .3). In three studies, linear mixed effects models revealed that AS and valence reproducibly account for variance in the human ratings. To understand further correlated predictors, we conducted a hierarchical cluster analysis and examined the predictors of four clusters in competitive analyses: Only AS and word2vec skip‐gram cosine distances reproducibly accounted for variance in all three studies. The other predictors of the first cluster (number of common associates, (positive) point‐wise mutual information, and word2vec CBOW cosine) did not reproducibly explain further variance. The same was true for the second cluster (word frequency and arousal); the third cluster (emotional valence and imageability); and the fourth cluster (consisting of joint frequency only). Finally, we discuss emotional valence as an important dimension of semantic space. Our results suggest that a simple definition of syntagmatic word contiguity (AS) and a paradigmatic measure of semantic similarity (skip‐gram cosine) provide the most general performance‐independent explanation of association ratings.     

Interference between cues requires a causal scenario: Favorable evidence for causal reasoning models in learning processes

In an interference-between-cues design (IbC), the expression of a learned Cue A–Outcome 1 association has been shown to be impaired if another cue, B, is separately paired with the same outcome in a second learning phase. The present study examined whether IbC could be caused by associative mechanisms independent of causal reasoning processes. This was achieved by testing participants in two different learning situations. In the Causal Scenario condition, participants learned in a diagnostic situation in which a common cause (Outcome 1) caused two disjoint effects, namely Cues A and B. In the Non-Causal Scenario condition, the same IbC design and stimulus conditions were used. However, instructions provided no causal frame to make sense of how cues and outcomes were related. IbC was only found in the Causal Scenario condition. This result is consistent with Causal Reasoning Models of causal learning and raises important difficulties for associative explanations of IbC.     

Spatial learning in the holeboard impairs an early phase of long-term potentiation in the rat hippocampal CA1-region

Long-term potentiation (LTP) and depression (LTD) are considered as cellular models for learning and memory. We studied the impact of holeboard training on LTP in the rat CA1 hippocampal region. In 7-week-old Wistar rats a recording electrode was chronically implanted into the hippocampal pyramidal cell layer of the CA1 of the right hemisphere and a stimulation electrode into the contralateral CA3 region.Two groups of animals received a spatial holeboard training of 10 or 15 trials over 2 days on a fixed pattern of baited holes. The last trial was performed 15 min after a primed burst stimulation of the contralateral CA3, which resulted in LTP in the ipsilateral CA1. A pseudo-trained group that received a 10 trial training with changing patterns of baited holes after each trial and a group that remained in the recording chambers during the experiments served as controls. Experimental rats significantly improved their spatial performance with increasing numbers of trials, indicated by decreasing times to pick up all food pellets and by decreasing numbers of reference memory errors. A learning-related impairment of CA1-LTP measured in both the population-spike amplitude as well as the fEPSP could be noted. These results show that specific (pattern-training), but not unspecific (pseudo-training) spatial information processing prior to electrical stimulation can severely affect LTP in hippocampal area CA1.     

Inverted-U shape relationship between cortisol and learning in ground squirrels

Adrenal hormones regulate glucose levels, responses to unpredictable stressors and modulate cognition. Glucocorticoids can have an inverted-U shape relationship with cognition, as very low or high levels impair, whereas moderate elevations facilitate, acquisition and retention of memories. To date these relationships have been tested with humans and rodents in laboratory settings rather than with wild animals in biologically relevant contexts. This study examined whether the elevated cortisol observed in juvenile Belding’s ground squirrels (Spermophilus beldingi) at natal emergence might promote both acquisition of adaptive responses to this species’ two alarm calls warning of predators and memory of the spatial configuration of mothers’ territories. Both experimentally increased and decreased basal cortisol levels interfere with acquisition and retention of an association between a warning call and the appropriate response compared with naturally occurring moderately elevated cortisol. Further, decreased cortisol impairs learning of a novel, complex spatial maze. Thus in the field the brief elevation of cortisol at emergence might facilitate acquisition of spatial memory of a three-dimensional environment and responses to alarm calls during a sensitive period of learning. This novel demonstration of the inverted-U shape function in a wild animal suggests that natural selection has favored a hormonal profile facilitating rapid acquisition of important survival behaviors.