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To efficiently process information, the brain shifts between encoding and retrieval states, prioritizing bottom-up or top-down processing accordingly. Expectation violation before or during learning has been shown to trigger an adaptive encoding mechanism, resulting in better memory for unexpected events. Using fMRI, we explored (1) whether this encoding mechanism is also triggered during retrieval, and if so, (2) what the temporal dynamics of its mnemonic consequences are. Male and female participants studied object images, then, with new objects, they learned a contingency between a cue and a semantic category. Rule-abiding (expected) and violating (unexpected) targets and similar foils were used at test. We found interactions between previous and current similar events' expectation, such that when an expected event followed a similar but unexpected event, its performance was boosted, underpinned by activation in the hippocampus, midbrain, and occipital cortex. In contrast, a sequence of two unexpected similar events also triggered occipital engagement; however, this did not enhance memory performance. Taken together, our findings suggest that when the goal is to retrieve, encountering surprising events engages an encoding mechanism, supported by bottom-up processing, that may enhance memory for future related events. SIGNIFICANCE STATEMENT Optimizing the balance between new learning and the retrieval of existing knowledge is an ongoing process, at the core of human cognition. Previous research into memory encoding suggests experiencing surprise leads to the prioritization of the learning of new memories, forming an adaptive encoding mechanism. We examined whether this mechanism is also engaged when the current goal is to retrieve information. Our results demonstrate that an expectation-driven shift toward an encoding state, supported by enhanced perceptual processing, is beneficial for the correct identification of subsequent expected similar events. These findings have important implications for our understanding of the temporal dynamics of the adaptive encoding of information into memory.

Although reconsolidation-based interventions constitute a promising new avenue to treating fear and anxieties disorders, the success of the intervention is not guaranteed. The initiation of memory reconsolidation is dependent on whether a mismatch between the experienced and predicted outcome-a prediction error (PE)-occurs during fear memory reactivation. It remains, however, elusive whether any type of PE renders fear memories susceptible to reconsolidation disruption. Here, we investigated whether a value PE, elicited by an outcome that is better or worse than expected, is necessary to make fear memories susceptible to reconsolidation disruption or whether a model-based identity PE, i.e., a PE elicited by an outcome equally aversive but different than expected, would be sufficient. Blocking beta-adrenergic receptors with propranolol HCl after reactivation did, however, not reduce the expression of fear after either type of PE. Instead, we observed intact fear memory expression 24 h after reactivation in the value-, identity- and a no-PE control group. The present results do not corroborate our earlier findings of reconsolidation disruption and point towards challenges that the field is currently facing in observing evidence for memory reconsolidation at all. We provide potential explanations for the unexpected failure of replicating reconsolidation disruption and discuss future directions.

Orientadores: Elenice Aparecida de Moraes Ferrari, Luiz Roberto Giorgetti Britto Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: O presente estudo investigou os efeitos do antagonista do receptor NMDA, MK-801 na expressão do produto do zenk no hipocampo (Hp) de pombos, submetidos ao condicionamento clássico aversivo. Antes do treino, administrou-se MK-801, i.p, para o grupo condicionado MK (GCMK, n=6), salina para o grupo condicionado salina (GCS, n=6) e nenhum tratamento para os grupos-controle: randômico (GCR, n=6), contexto (GCC=7) e manipulação (GM=4). GCMK e GCS receberam três associações de som (1000-Hz, 83 dB,1 s) e choque (10 mA, 35ms) numa sessão de 20 min. Para GCR os estímulos foram aleatórios e o GCC não recebeu estímulos. O teste de re-exposição ao contexto ocorreu 24 h após o treino. A análise de freezing no treino mostrou maior ocorrência para o GCS em comparação ao GCC (p

Brain lactate formation, intercellular exchange and utilization has been implicated in memory formation. However, the individual role of either neuronal or astroglial monocarboxylate transporters for the acquisition and consolidation of information remains incomplete. Using novel transgenic mice and a viral vector approach to decrease the expression of each transporter in a cell-specific manner within the dorsal hippocampus, we show that both neuronal MCT2 and astroglial MCT4 are required for spatial information acquisition and retention (at 24 h post-training) in distinct hippocampus-dependent tasks. Intracerebral infusion of lactate rescued spatial learning in mice with reduced levels of astroglial MCT4 but not of neuronal MCT2, suggesting that lactate transfer from astrocytes and utilization in neurons contribute to hippocampal-dependent learning. In contrast, only neuronal MCT2 was shown to be required for long-term (7 days post training) memory formation. Interestingly, reduced MCT2 expression levels in mature neurons result in a heterologous effect as it blunts hippocampal neurogenesis associated with memory consolidation. These results suggest important but distinct contributions of both neuronal MCT2 and astroglial MCT4 in learning and memory processes, going beyond a simple passive role as alternative energy substrate suppliers or in waste product disposal.

Acute physical exercise improves memory functions by increasing neural plasticity in the hippocampus. In animals, a single session of physical exercise has been shown to boost anandamide (AEA), an endocannabinoid known to promote hippocampal plasticity. Hippocampal neuronal networks encode episodic memory representations, including the temporal organization of elements, and can thus benefit motor sequence learning. While previous work established that acute physical exercise has positive effects on declarative memory linked to hippocampal plasticity mechanisms, its influence on memory for motor sequences, and especially on neural mechanisms underlying possible effects, has been less investigated.Here we studied the impact of acute physical exercise on motor sequence learning, and its underlying neurophysiological mechanisms in humans, using a cross-over randomized within-subjects design. We measured behavior, fMRI activity, and circulating AEA levels in fifteen healthy participants while they performed a serial reaction time task (SRTT) before and after a short period of exercise (moderate or high intensity) or rest.We show that exercise enhanced motor sequence memory, significantly for high intensity exercise and tending towards significance for moderate intensity exercise. This enhancement correlated with AEA increase, and dovetailed with local increases in caudate nucleus and hippocampus activity.These findings demonstrate that acute physical exercise promotes sequence learning, thus attesting the overarching benefit of exercise to hippocampus-related memory functions.

Contains fulltext : 218973.pdf (Publisher’s version ) (Open Access) Aging is associated with cognitive decline, specifically in episodic memory. However, there are large individual differences in the extent of this decline and previous research suggests that these are associated with differences in executive functioning (EF). These EF differences, and associated differences in the encoding and retrieval of episodic information, have been linked to differences in the activation of particular brain regions. The "encoding/retrieval flip" (E/R flip) framework assumes deactivation and activation of specific brain regions during successful encoding and retrieval, respectively. The present study assessed whether this framework can be used to explain EF-based individual differences in memory performance of young and older participants. Young adults (N = 19) and older adults (N = 39) performed an incidental semantic encoding and memory recognition task in an fMRI setting, focusing on brain regions that show the E/R flip. The association between an index of EF and fMRI activity in brain regions showing the E/R flip was tested in each age group. EF predicted E/R flip activity in the older, but not young adults. These findings underscore the importance of individual differences in ageing research and provide empirical evidence for the association between EF and the E/R flip. 5 p.

OBJECTIVE: To summarise the current research on the effectiveness of the Amsterdam Memory and Attention Training for Children (Amat-c).METHODS: A literature search was conducted to find articles published about the Amat-c, using PubMed, psychINFO, and PsychBITE databases. Relevant search terms included Amat-c, attention and memory, and childhood ABI.RESULTS: Our literature search identified 7 articles that described 5 separate studies including 61 children in total (mostly TBI). Only one study had a control group. All results indicated positive effects on memory and attention, although in three of the studies, these results were not statistically tested. Positive results were generally maintained six months follow up.CONCLUSIONS: This review showed that the Amat-c is effective for treating attention and memory disturbances in children with ABI. However, evidence is limited and training material is outdated. We suggest that the Amat-c should be digitised and implemented in a school setting and further evaluated.

OBJECTIVE: To summarise the current research on the effectiveness of the Amsterdam Memory and Attention Training for Children (Amat-c). METHODS: A literature search was conducted to find articles published about the Amat-c, using PubMed, psychINFO, and PsychBITE databases. Relevant search terms included Amat-c, attention and memory, and childhood ABI. RESULTS: Our literature search identified 7 articles that described 5 separate studies including 61 children in total (mostly TBI). Only one study had a control group. All results indicated positive effects on memory and attention, although in three of the studies, these results were not statistically tested. Positive results were generally maintained six months follow up. CONCLUSIONS: This review showed that the Amat-c is effective for treating attention and memory disturbances in children with ABI. However, evidence is limited and training material is outdated. We suggest that the Amat-c should be digitised and implemented in a school setting and further evaluated.

Introduction: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.Methods: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.Results: Eight metabolites were associated with amyloid b and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.Discussion: PFAMs have been found increased and associated with amyloid b burden in CSF and clinical measures. Crown Copyright (C) 2019 Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

It is well documented that women have an increased risk of emotional disorders, such as anxiety and depression. Such disorders are typically characterized by intrusive memories and rumination of past events, but findings are mixed as to whether women have enhanced access to memories of emotional events. Some studies have found that women, compared with men, report more frequent and more intense memories of emotionally stressful events, whereas other studies have failed to replicate this effect. These conflicting findings may reflect the use of different memory sampling techniques (e.g., retrospective vs. experimental data) and limited control for factors associated with both gender and emotional memory. The purpose of the present study was to investigate gender differences in memory for emotionally negative events, using three different sampling methods, while at the same time controlling for parameters that might co-vary with gender. Consistent with some previous studies, we found that women and men did not differ in their frequencies of emotionally negative involuntary memories. However, women rated their memories as more intense and arousing than men did, and women also reported higher increases in state anxiety after retrieval. Female gender accounted for unique variance in the emotional intensity and subjective arousal associated with negative memories, when controlling for other theoretically derived variables. The findings provide evidence that female gender is associated with a stronger emotional response to memories of negative events, but not that women remember such events more frequently than men do.

Objective A body of experimental, neuropsychological, and neuroanatomical evidence suggests a relationship between autobiographical memory and the ability to generate mental images. This study investigated this relationship in Alzheimer's disease (AD). Method Twenty six AD participants and 28 control participants were asked to retrieve 2 autobiographical events. They were also administered measures of visual imagery (i.e., the taller/wider task), and spatial imagery (i.e., the clock angles task). Results Analysis showed preserved autobiographical memory and visual imagery but compromised spatial imagery in AD. Significant correlations were observed between autobiographical memory and visual and spatial imagery in AD and control participants. However, autobiographical memory was predicted by visual but not by spatial imagery. Conclusions The ability to retrieve (i.e., visual imagery) and manipulate mental images (i.e., spatial imagery) seems to be related with autobiographical recall in AD. In particular, visual imagery may contribute to autobiographical retrieval in AD participants by providing them with visual cues that increase the ease and speed of search through the hierarchical structure of autobiographical memory. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer's disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Understanding the emerging roles of astrocytes in cognitive function and dysfunction will open up a large array of new therapeutic opportunities.

The adipocyte plasma membrane-associated protein APMAP is expressed in the brain where it associates with γ-secretase, a protease responsible for the generation of the amyloid-β peptides (Aβ) implicated in the pathogenesis of Alzheimer’s disease (AD). In this study, behavioral investigations revealed spatial learning and memory deficiencies in our newly generated mouse line lacking the protein APMAP. In a mouse model of AD, the constitutive deletion of APMAP worsened the spatial memory phenotype and led to increased Aβ production and deposition into senile plaques. To investigate at the molecular level the neurobiological functions of APMAP (memory and Aβ formation) and a possible link with the pathological hallmarks of AD (memory impairment and Aβ pathology), we next developed a procedure for the high-grade purification of cellular APMAP protein complexes. The biochemical characterization of these complexes revealed a series of new APMAP interactomers. Among these, the heat shock protein HSPA1A and the cation-dependent mannose-6-phosphate receptor (CD-M6PR) negatively regulated APP processing and Aβ production, while clusterin, calnexin, arginase-1, PTGFRN and the cation-independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) positively regulated APP and Aβ production. Several of the newly identified APMAP interactomers contribute to the autophagy-lysosome system, further supporting an emergent agreement that this pathway can modulate APP metabolism and Aβ generation. Importantly, we have also demonstrated increased alternative splicing of APMAP and lowered levels of the Aβ controllers HSPA1A and CD-M6PR in human brains from neuropathologically verified AD cases. Electronic supplementary material The online version of this article (10.1186/s40478-019-0660-3) contains supplementary material, which is available to authorized users.

Whether a novel stimulus is expected or unexpected may have implications for the kind of ensuing encoding and the type of subsequent memory. Pupil response was used in the present study to explore the way expected and unexpected stimuli are encoded and whether encoding-linked pupil response is modulated by expectation. Participants first established a contingency relationship between a series of symbols and the type of stimulus (man-made or natural) that followed each one. At encoding, some of the target stimuli violated the previously established relationship (i.e., unexpected), while the majority conformed to this relationship (i.e., expected). Expectation at encoding had opposite effects on familiarity and recollection, the two types of memory that support recognition, and modulated differently the way pupil responses predicted subsequent memory. Encoding of unexpected novel stimuli was associated with increased pupil dilation as a predictor of subsequent memory type and strength. In contrast, encoding of expected novel stimuli was associated with decreased pupil response (constriction), which was predictive of subsequent memory type and strength. The findings support the close link between pupil response and memory formation, but critically indicate that this is modulated by the type of novelty as defined by expectation. These novel findings have important implications for the encoding mechanisms involved when different types of novelty are detected and is proposed to indicate the operation of different neurotransmitters in memory formation.

Summary Novelty facilitates memory formation and is detected by both the dorsal and ventral hippocampus. Although dentate granule cells (GCs) in the dorsal hippocampus are known to mediate the formation of novelty-induced contextual memories, the required pathways and mechanisms remain unclear. Here we demonstrate that a powerful excitatory pathway from mossy cells (MCs) in the ventral hippocampus to dorsal GCs is necessary and sufficient for driving dorsal GC activation in novel environment exploration. In vivo Ca2+ imaging in freely moving mice indicated that this pathway relays environmental novelty. Furthermore, manipulation of ventral MC activity bidirectionally regulates novelty-induced contextual memory acquisition. Our results show that ventral MC activity gates contextual memory formation through an intra-hippocampal interaction activated by environmental novelty., Graphical Abstract, Highlights • Mossy cells in ventral hilus directly excite granule cells in dorsal hippocampus • Activity of ventral mossy cells positively correlates with environmental novelty • Inhibiting ventral mossy cells disrupts novelty-induced contextual fear memory • Exciting ventral mossy cells enhances contextual memory in a familiar environment, Novelty facilitates memory formation. Fredes et al. show that mossy cells in the ventral dentate gyrus detect environmental novelty. This information is conveyed to dorsal dentate granule cells and is necessary for novelty-induced contextual memory formation. Conversely, activating this pathway enhances contextual memory in a familiar environment.

Background: The positive relationship between cognitive and physical performance has been widely established. The influence of brain structure on both domains has been shown as well. Objective: We studied whether the relationship between brain structure and physical performance is independent of cognitive performance. Methods: This was a cross-sectional analysis of 297 middle-aged to older adults (mean age ± SD 65.4 ± 6.8 years). Memory function, executive function and physical performance measured by the Tandem Stance Test, Chair Stand Test, 4-meter walk and 25-meter walk were assessed. Magnetic resonance imaging was available in 237 participants and used to determine the (sub)cortical gray matter, white matter, hippocampal and basal ganglia volumes and the presence of cerebral small-vessel disease, i.e. white matter hyperintensities, cerebral microbleeds (CMBs) and lacunar infarcts (LIs). Regression analysis was used adjusting for age, gender, education and whole-brain volume. A Bonferroni correction was applied considering p values Results: Poor memory function was associated with a slower 4-meter walking speed (p < 0.01). No association was found between brain structure and cognitive performance. The presence of CMBs and LIs was associated with a slower 25-meter walking speed (p < 0.001). This result did not change after additional adjustment for cognitive performance. Conclusions: In middle-aged to older adults, CMBs and LIs are associated with walking speed independent of cognitive performance. This emphasizes the clinical relevance of identifying each of the possible underlying mechanisms of physical performance, which is required for the development of timely and targeted therapies.

Summary Hippocampal neurons activated during encoding drive the recall of contextual fear memory. Little is known about how such ensembles emerge during acquisition and eventually form the cellular engram. Manipulating the activity of granule cells (GCs) of the dentate gyrus (DG) we reveal a mechanism of lateral inhibition that modulates the size of the cellular engram. GCs engage somatostatin positive interneurons that inhibit the dendrites of surrounding GCs. Our findings reveal a microcircuit within the DG that controls the size of the cellular engram and the stability of contextual fear memory.

Studying the sources of errors in memory recall has proven invaluable for understanding the mechanisms of working memory (WM). While one-dimensional memory features (e.g., color, orientation) can be analyzed using existing mixture modeling toolboxes to separate the influence of imprecision, guessing, and misbinding (the tendency to confuse features that belong to different memoranda), such toolboxes are not currently available for two-dimensional spatial WM tasks.Here we present a method to isolate sources of spatial error in tasks where participants have to report the spatial location of an item in memory, using two-dimensional mixture models. The method recovers simulated parameters well and is robust to the influence of response distributions and biases, as well as number of nontargets and trials.To demonstrate the model, we fit data from a complex spatial WM task and show the recovered parameters correspond well with previous spatial WM findings and with recovered parameters on a one-dimensional analogue of this task, suggesting convergent validity for this two-dimensional modeling approach. Because the extra dimension allows greater separation of memoranda and responses, spatial tasks turn out to be much better for separating misbinding from imprecision and guessing than one-dimensional tasks.Code for these models is freely available in the MemToolbox2D package and is integrated to work with the commonly used MATLAB package MemToolbox.

Highlights • First investigation of the role of NMNAT1 in the early stage of tauopathies in mice. • htau mice display a robust deficit in food burrowing prior to onset of cognitive symptoms. • NMNAT1 overexpression rescues this behavioral abnormality., NAD metabolism and the NAD biosynthetic enzymes nicotinamide nucleotide adenylyltransferases (NMNATs) are thought to play a key neuroprotective role in tauopathies, including Alzheimer’s disease. Here, we investigated whether modulating the expression of the NMNAT nuclear isoform NMNAT1, which is important for neuronal maintenance, influences the development of behavioral and neuropathological abnormalities in htau mice, which express non-mutant human tau isoforms and represent a model of tauopathy relevant to Alzheimer’s disease. Prior to the development of cognitive symptoms, htau mice exhibit tau hyperphosphorylation associated with a selective deficit in food burrowing, a behavior reminiscent to activities of daily living which are impaired early in Alzheimer’s disease. We crossed htau mice with Nmnat1 transgenic and knockout mice and tested the resulting offspring until the age of 6 months. We show that overexpression of NMNAT1 ameliorates the early deficit in food burrowing characteristic of htau mice. At 6 months of age, htau mice did not show neurodegenerative changes in both the cortex and hippocampus, and these were not induced by downregulating NMNAT1 levels. Modulating NMNAT1 levels produced a corresponding effect on NMNAT enzymatic activity but did not alter NAD levels in htau mice. Although changes in local NAD levels and subsequent modulation of NAD-dependent enzymes cannot be ruled out, this suggests that the effects seen on behavior may be due to changes in tau phosphorylation. Our results suggest that increasing NMNAT1 levels can slow the progression of symptoms and neuropathological features of tauopathy, but the underlying mechanisms remain to be established.

ObjectiveStroke patients often suffer from delayed disturbances of mood and cognition. In rodents, the prefrontal cortex (PFC) is involved in both higher order cognition and emotion. Our objective was to determine if bilateral focal ischaemic lesions restricted to the medial prefrontal cortex (mPFC) could be used to model post-stroke anxiety and/or cognitive deficits.MethodsGroups of adult male Sprague-Dawley rats (n=9) received bilateral injections of either endothelin-1 (ET-1) (400 pmol) or vehicle (artificial cerebrospinal fluid) into the mPFC and were tested at various times using both a test of temporal order memory and in an elevated plus maze. Lesions were verified histologically.ResultsET-1 lesioned rats had reduced mobility on post-surgery day 8 that had resolved by day 29 at which time they spent significantly more time in the closed arm of the plus mazeConclusionWe conclude that ischaemic lesions localised to the mPFC can be used to model post-stroke anxiety in rats.

Cognitive deficits are clearly associated with poor everyday life functioning in persons diagnosed with schizophrenia. However, previous studies have primarily used questionnaires to assess everyday life functioning. We developed a computerized real-life activity task (shopping task), where participants are required to shop for a list of seven grocery store items. Thirty individuals diagnosed with schizophrenia and 30 healthy controls were administered an extensive battery of cognitive tests and the computerized shopping task. Performances on the computerized shopping task significantly differentiated patients and healthy controls for several variables. Moreover, performance on the shopping task was significantly correlated with verbal episodic memory, cognitive flexibility, planning, processing speed, and inhibition. Finally, performance on the computerized shopping task was significantly correlated with various clinical variables and with a global measure of social functioning. These findings suggest that the computerized task used in the present study provides an indication of the level of everyday life functioning and cognitive functioning of persons diagnosed with schizophrenia, and, therefore, may be viewed as a valuable instrument in both an evaluation and remediation context. (JINS, 2010, 16, 180–189.)

Postnatal hippocampal neurogenesis induces network remodeling and may participate to mechanisms of learning. In turn, the maturation and survival of newborn neurons is regulated by their activity. Here, we tested the effect of a cell-autonomous overexpression of synaptic adhesion molecules on the maturation and survival of neurons born postnatally and on hippocampal-dependent memory performances. Families of adhesion molecules are known to induce pre- and post-synaptic assembly. Using viral targeting, we overexpressed three different synaptic adhesion molecules, SynCAM1, Neuroligin-1B and Neuroligin-2A in newborn neurons in the dentate gyrus of 7- to 9-week-old mice. We found that SynCAM1 increased the morphological maturation of dendritic spines and mossy fiber terminals while Neuroligin-1B increased spine density. In contrast, Neuroligin-2A increased both spine density and size as well as GABAergic innervation and resulted in a drastic increase of neuronal survival. Surprisingly, despite increased neurogenesis, mice overexpressing Neuroligin-2A in new neurons showed decreased memory performances in a Morris water maze task. These results indicate that the cell-autonomous overexpression of synaptic adhesion molecules can enhance different aspects of synapse formation on new neurons and increase their survival. Furthermore, they suggest that the mechanisms by which new neurons integrate in the postnatal hippocampus conditions their functional implication in learning and memory.

IntroductionIn phenylketonuria (PKU), a gene mutation in the phenylalanine metabolic pathway causes accumulation of phenylalanine (Phe) in blood and brain. Although early introduction of a Phe-restricted diet can prevent severe symptoms from developing, patients who are diagnosed and treated early still experience deficits in cognitive functioning indicating shortcomings of current treatment. In the search for new and/or additional treatment strategies, a specific nutrient combination (SNC) was postulated to improve brain function in PKU. In this study, a long-term dietary intervention with a low-Phe diet, a specific combination of nutrients designed to improve brain function, or both concepts together was investigated in male and female BTBR PKU and WT mice.Material & methods48 homozygous wild-types (WT, +/+) and 96 PKU BTBRPah2 (-/-) male and female mice received dietary interventions from postnatal day 31 till 10 months of age and were distributed in the following six groups: high Phe diet (WT C-HP, PKU C-HP), high Phe plus specific nutrient combination (WT SNC-HP, PKU SNC-HP), PKU low-Phe diet (PKU C-LP), and PKU low-Phe diet plus specific nutrient combination (PKU SNC- LP). Memory and motor function were tested at time points 3, 6, and 9 months after treatment initiation in the open field (OF), novel object recognition test (NOR), spatial object recognition test (SOR), and the balance beam (BB). At the end of the experiments, brain neurotransmitter concentrations were determined.ResultsIn the NOR, we found that PKU mice, despite being subjected to high Phe conditions, could master the task on all three time points when supplemented with SNC. Under low Phe conditions, PKU mice on control diet could master the NOR at all three time points, while PKU mice on the SNC supplemented diet could master the task at time points 6 and 9 months. SNC supplementation did not consistently influence the performance in the OF, SOR or BB in PKU mice. The low Phe diet was able to normalize concentrations of norepinephrine and serotonin; however, these neurotransmitters were not influenced by SNC supplementation.ConclusionThis study demonstrates that both a long-lasting low Phe diet, the diet enriched with SNC, as well as the combined diet was able to ameliorate some, but not all of these PKU-induced abnormalities. Specifically, this study is the first long-term intervention study in BTBR PKU mice that shows that SNC supplementation can specifically improve novel object recognition.

Disorientation is frequent after brain damage. It is a constituent component of post traumatic amnesia and was part of the original definition of the Korsakoff syndrome together with amnesia and confabulations. Orbitofrontal reality filtering is a pre conscious memory control process that has been held accountable for disorientation and a specific type of spontaneous confabulation that patients act upon. A recent study questioned the specificity of this process and suggested that confabulating patients who failed in orbitofrontal reality filtering similarly failed to monitor the precise content of memories a critical step within the strategic retrieval account which describes a series of processes leading up to the recollection of memories. In the present study we combined the proposed experimental requirements of both processes in a single continuous recognition task and tested a group of 21 patients with a matched deficit of delayed free recall. We found that only deficient reality filtering but not content monitoring significantly correlated with disorientation and distinguished between confabulators and non confabulators. Thus reality confusion as evident in disorientation and behaviourally spontaneous confabulation primarily reflects an inability to monitor memories' relation with ongoing reality rather than to monitor their precise content.

Item does not contain fulltext Unlike prospective time perception paradigms, in which participants are aware that they have to estimate forthcoming time, little is known about retrospective time perception in normal aging and Alzheimer's disease (AD). Our paper addresses this shortcoming by comparing prospective and retrospective time estimation in younger adults, older adults, and AD patients. In four prospective tasks (lasting 30 s, 60 s, 90 s, or 120 s) participants were asked to read a series of numbers and to provide a verbal estimation of the reading time. In four other retrospective tasks, they were not informed about time judgment until they were asked to provide a verbal estimation of four elapsed time intervals (lasting 30 s, 60 s, 90 s, or 120 s). AD participants gave shorter verbal time estimations than older adults and younger participants did, suggesting that time is perceived to pass quickly in these patients. For all participants, the duration of the retrospective tasks was underestimated as compared to the prospective tasks and both estimations were shorter than the real time interval. Prospective time estimation was further correlated with mental time travel, as measured with the Remember/Know paradigm. Mental time travel was even higher correlated with retrospective time estimation. Our findings shed light on the relationship between time perception and the ability to mentally project oneself into time, two skills contributing to human memory functioning. Finally, time perception deficits, as observed in AD patients, can be interpreted in terms of dramatic changes occurring in frontal lobes and hippocampus

A 57-year-old man suffered severe amnesia and disorientation, accompanied by content-specific confabulation, due to an alcoholic Wernicke-Korsakoff syndrome. For months, he was deeply concerned about a single obligation that he thought he had to respond to, but which he had already assumed 20 years previously. This monothematic, prospective confabulation was associated with failures of reality filtering as previously documented in behaviorally spontaneous confabulation and disorientation: the patient failed to suppress the interference of currently irrelevant memories and to abandon anticipations that were no longer valid (impaired extinction capacity). Magnetic resonance imaging showed damage to the mamillary bodies and the dorsomedial thalamic nucleus. Positron emission tomography (FDG-PET) showed extended orbitofrontal hypometabolism. We suggest that isolated prospective confabulation shares the core feature (acts and thoughts based on currently irrelevant memory), mechanism (failure of reality filtering), and anatomical basis (orbitofrontal dysfunction) with behaviorally spontaneous confabulations.

The Morris water maze (MWM) spatial learning task has been demonstrated to involve a cognitive switch of action control to serve the transition from an early towards a late learning phase. However, the molecular mechanisms governing this switch are largely unknown. We employed MALDI MS imaging (MSI) to screen for changes in expression of small proteins in brain structures implicated in the different learning phases. We compared mice trained for 3days and 30days in the MWM, reflecting an early and a late learning phase in relation to the acquisition of a spatial learning task. An ion with m/z of 6724, identified as PEP-19/pcp4 by top-down tandem MS, was detected at higher intensity in the dorsal striatum of the late learning phase group compared with the early learning phase group. In addition, mass spectrometric analysis of synaptosomes confirmed the presence of PEP-19/pcp4 at the synapse. PEP-19/pcp4 has previously been identified as a critical determinant of synaptic plasticity in locomotor learning. Our findings extend PEP-19/pcp4 function to spatial learning in the forebrain and put MSI forward as a valid and unbiased research strategy for the discovery and identification of the molecular machinery involved in learning, memory and synaptic plasticity. publisher: Elsevier articletitle: MS imaging and mass spectrometric synaptosome profiling identify PEP-19/pcp4 as a synaptic molecule involved in spatial learning in mice journaltitle: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics articlelink: http://dx.doi.org/10.1016/j.bbapap.2016.10.007 content_type: article copyright: © 2016 Elsevier B.V. All rights reserved. ispartof: Biochimica et Biophysica Acta vol:1865 issue:7 pages:936-945 ispartof: location:Netherlands status: published

Complex social behaviors lie at the heart of many of the challenges facing evolutionary biology, sociology, economics, and beyond. For evolutionary biologists the question is often how group behaviors such as collective action, or decision making that accounts for memories of past experience, can emerge and persist in an evolving system. Evolutionary game theory provides a framework for formalizing these questions and admitting them to rigorous study. Here we develop such a framework to study the evolution of sustained collective action in multi-player public-goods games, in which players have arbitrarily long memories of prior rounds of play and can react to their experience in an arbitrary way. We construct a coordinate system for memory-m strategies in iterated n-player games that permits us to characterize all cooperative strategies that resist invasion by any mutant strategy, and stabilize cooperative behavior. We show that, especially when groups are small, longer-memory strategies make cooperation easier to evolve, by increasing the number of ways to stabilize cooperation. We also explore the co-evolution of behavior and memory. We find that even when memory has a cost, longer-memory strategies often evolve, which in turn drives the evolution of cooperation, even when the benefits for cooperation are low.

In this issue of Neuron, Oettl et al. (2016) show how oxytocin can boost processing of olfactory information in female rats by a top-downregulation from the anterior olfactory nucleus onto the main olfactory bulb. As a result, interactions with juvenile conspecifics receive more attention and are longer memorized.

Introduction: Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory clinic populations. Methods: We prospectively enrolled 3868 patients (50% women, age 66 +/- 11 years, mini mental state examination 25 +/- 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain. Results: A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect. Discussions: The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics. (C) 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

How are words represented in the human brain and can these representations be qualitatively assessed with respect to their structure and properties? Recent research demonstrates that neurophysiological signatures of individual words can be measured when subjects do not focus their attention on speech input. These automatic activations, which take the form of negative deflections of event-related potentials, can appear surprisingly early (within ~ 200 ms) and are based on robust connections within neuronal memory circuits encoding individual words that ignite even when attentional resources are scarce. A new and critical prediction of this framework is that words with high frequency of occurrence have especially strong connections of their underlying memory circuits and should thus yield more negative ERPs compared with rarer words. We tested this prediction by presenting our subjects, in passive non-attend conditions, with acoustically matched high- and low-frequency words along with pseudo-words. Using factorial and correlation analyses, we found that already at ~ 120 ms after the spoken stimulus information was available, amplitude of brain responses was modulated by the words' lexical frequency. Topographic mapping and source analysis suggested that this early automatic frequency effect originates from the left inferior-frontal cortices. While, at this early latency, lexical differences between words and pseudo-words (more negative-going potential for meaningful words) could be seen only for the most frequent word stimuli, later-on (~ 270 ms), a more global lexicality effect with bilateral perisylvian sources was found for all stimuli, suggesting faster access to more frequent lexical entries. Our results support the account of word memory traces as interconnected neuronal circuits, and suggest that speed and magnitude of their activation are determined by their internal connection strength, which, in turn, is determined by the everyday language use.

Recent studies indicated that the human medial temporal lobe (MTL) may not only be important for long-term memory consolidation but also for certain forms of short-term memory. In this study, we explored the interplay between short- and long-term memory using high-density event-related potentials. We found that pictures immediately repeated after an unfilled interval were better recognized than pictures repeated after intervening items. After 30 min, however, the immediately repeated pictures were significantly less well recognized than pictures repeated after intervening items. This processing advantage at immediate repetition but disadvantage for long-term storage had an electrophysiological correlate: spatiotemporal analysis showed that immediate repetition induced a strikingly different electrocortical response after 200-300 ms, with inversed polarity, than new stimuli and delayed repetitions. Inverse solutions indicated that this difference reflected transient activity in the MTL. The findings demonstrate behavioral and electrophysiological dissociation between recognition during active maintenance and recognition after intervening items. Processing of novel information seems to immediately initiate a consolidation process, which remains vulnerable during active maintenance and increases its effectiveness during off-line processing.

Momentary fluctuations of baseline activity have been shown to influence responses to sensory stimulation both behaviorally and neurophysiologically. This suggests that perceptual awareness does not solely arise from physical stimulus properties. Here we studied whether the momentary state of the brain immediately before stimulus presentation indicates how a physically unique but perceptually ambiguous stimulus will be perceived. A complex Necker cube was intermittently presented and subjects indicated whether their perception changed with respect to the preceding presentation. EEG was recorded from 256 channels. The prestimulus brain-state was defined as the spatial configuration of the scalp potential map within the 50 ms before stimulus arrival, representing the sum of all momentary ongoing brain processes. Two maps were found that doubly dissociated perceptual reversals from perceptual stability. For EEG sweeps classified as either map, distributed inverse solutions were computed and statistically compared. This yielded activity confined to a region in right inferior parietal cortex that was significantly more active before a perceptual reversal. In contrast, no significant topographic differences of the evoked potentials elicited by stable vs. reversed Necker cubes were found. This indicates that prestimulus activity in right inferior parietal cortex is associated with the perceptual change.

Severe disease associated with cytomegalovirus (CMV) infection is still a major problem in patients who undergo transplantation. Support of the patients' immune defense against the virus is a major goal in transplantation medicine. We have used the murine model of CMV (MCMV) to investigate the potential of a cell-based strategy to support the humoral antiviral immune response. Immunocompetent C57BL/6 mice were infected with MCMV, and memory B cells from the immune animals were adoptively transferred into T-cell– and B-cell–deficient RAG-1−/− mice. Following MCMV infection, a virus-specific IgG response developed within 4 to 7 days in the recipient animals. Concomitantly, a significant reduction in viral titers and DNA copies in several organs was observed. In addition, the memory B-cell transfer provided long-term protection from the lethal course of the infection that is invariably seen in immunodeficient animals. Transfer of memory B cells was also effective in protecting from an already ongoing viral infection, indicating a therapeutic potential of virus-specific memory B cells. T cells were not involved in this process. Our data provide evidence that a cell-based strategy to support the humoral immune response can be effective to combat infectious pathogens in severely immunodeficient hosts.

This preliminary study integrated previous findings of the distribution of autobiographical memories in the later age according to their age of occurrence, with the overgeneral memory bias predictive of depression. Twenty-five non-demented, Israeli participants between 65–89 years of age provided autobiographical memories to 4 groups of word cues reflecting events from childhood, adolescence, adulthood and late age. Their autobiographical responses were coded for degree of specificity of mentioning people, place and time. They additionally completed the Geriatric Depression Scale (Sheikh & Yesavage, 1986). We found that specificity of memories for adolescence cue-words (“the reminiscence bump”) was significantly and inversely correlated with depression ( r = −0.61), and this remained significant after controlling for gender and education. The study's limitations and the possibility that puberty hormones may be involved in memory and later age depression are discussed.

Background: Group III metabotropic glutamate receptors (mGlu4, mGlu7, mGlu8) display differential brain distribution, which suggests different behavioral functions. However, comparison across the available animal studies remains methodologically hazardous and controversial. The present report directly compares knockouts for each group III receptor subtype using a single behavioral test battery and multivariate analysis. Methods: The behavioral phenotypes of C57BL/6J mice lacking mGlu4, mGlu7, or mGlu8 and their respective littermates were examined using a multimetric test battery, which included elements of neuromotor performance, exploratory behavior, and learning and memory. Multivariate statistical methods were used to identify subtype-specific behavioral profiles and variables that distinguished between these mouse lines. Results: It generally appears that mGlu7 plays a significant role in hippocampus-dependent spatial learning and in some fear-related behaviors, whereas mGlu4 is most clearly involved in startle and motivational processes. Excepting its influence on body weight, the effect of mGlu8 deletion on behavior appears more subtle than that of the other group III receptors. These receptors have been proposed as potential drug targets for a variety of psychopathological conditions. Conclusion: On the basis of these controlled comparisons, we presently conclude that the different group III receptors indeed have quite distinct behavioral functions.

BACKGROUND: There is a need to find very early markers for pre-clinical Alzheimer's disease as interventions early in the disease process are thought to be most effective. OBJECTIVE: The present study aimed to address the potential relation between cerebrospinal fluid (CSF) biomarkers and reduced cognitive function in a relatively young cohort of memory clinic patients with subjective cognitive decline. METHODS: 122 patients (mean age 63 years) with subjective cognitive decline were recruited from two university memory clinics and followed for two years. RESULTS: The main finding was that the subgroup with objective memory decline during the study period had significantly higher T-tau at baseline than the group with improved memory. Baseline CSF variables showed a trend toward more pathological values in the patients with memory decline compared to those who improved or remained stable. The baseline memory score of those who declined was significantly better than the baseline score of those who improved over two years. The general trend for the whole group was improved memory and executive test scores. There were no differences in cognitive scores based on CSF quartiles at baseline, nor were there differences in cognitive outcome for patients with early amnestic mild cognitive impairment versus average cognitive function at baseline. CONCLUSIONS: The main finding that T-tau rather than amyloid-β was associated with memory decline do not support the prevailing opinion about the chain of events assumed to take place in Alzheimer's disease. In addition, memory decline was not associated with poor baseline memory score. Thus, a memory cut-off indicating low baseline memory would not would have identified the declining group.