RGS14 (414)-mediated prevention of an episodic memory loss: a study of molecular mechanism

A large proportion of human populations suffer memory impairments either caused by normal aging or afflicted by diverse neurological and neurodegenerative diseases. Memory enhancers and other drugs tested so far against memory loss have failed to produce therapeutic efficacy in clinical trials and thus, there is a need to find remedy for this mental disorder. In search for cure of memory loss, our laboratory discovered a robust memory enhancer called RGS14(414). A treatment in brain with its gene produces an enduring effect on memory that lasts for lifetime of rats. Therefore, current thesis work was designed to investigate whether RGS14(414) treatment can prevent memory loss and furthermore, explore through biological processes responsible for RGS-mediated memory enhancement. We found that RGS14(414) gene treatment prevented episodic memory loss in rodent models of normal aging and Alzheimer´s disease. A memory loss was observed in normal rats at 18 months of age; however, when they were treated with RGS14(414) gene at 3 months of age, they abrogated this deficit and their memory remained intact till the age of 22 months. In addition to normal aging rats, effect of memory enhancer treatment in mice model of Alzheimer´s disease (AD-mice) produced a similar effect. AD-mice subjected to treatment with RGS14(414) gene at the age of 2 months, a period when memory was intact, showed not only a prevention in memory loss observed at 4 months of age but also they were able to maintain normal memory after 6 months of the treatment. We posit that long-lasting effect on memory enhancement and prevention of memory loss mediated through RGS14(414) might be due to a permanent structural change caused by a surge in neuronal connections and enhanced neuronal remodeling, key processes for long-term memory formation. A neuronal arborization analysis of both pyramidal and non-pyramidal neurons in brain of RGS14(414)-treated rats exhibited robust rise in neurites outgrowth of both kind of cells, and an increment in number of branching from the apical dendrite of pyramidal neurons, reaching to almost three times of the control animals. To further understand of underlying mechanism by which RGS14(414) induces neuronal arborization, we investigated into neurotrophic factors. We observed that RGS14 treatment induces a selective increase in BDNF. Role of BDNF in neuronal arborization, as well as its implication in learning and memory processes is well described. In addition, our results showing a dynamic expression pattern of BDNF during ORM processing that overlapped with memory consolidation further support the idea of the implication of this neurotrophin in formation of long-term memory in RGS-animals. On the other hand, in studies of expression profiling of RGS-treated animals, we have demonstrated that 14-3-3ζ protein displays a coherent relationship to RGS-mediated ORM enhancement. Recent studies have demonstrated that the interaction of receptor for activated protein kinase 1 (RACK1) with 14-3-3ζ is essential for its nuclear translocation, where RACK1-14-3-3ζ complex binds at promotor IV region of BDNF and promotes an increase in BDNF gene transcription. These observations suggest that 14-3-3ζ might regulate the elevated level of BDNF seen in RGS14(414) gene treated animals. Therefore, it seems that RGS-mediated surge in 14-3-3ζ causes elevated BDNF synthesis needed for neuronal arborization and enhanced ORM. The prevention of memory loss might be mediated through a restoration in BDNF and 14-3-3ζ protein levels, which are significantly decreased in aging and Alzheimer’s disease. Additionally, our results demonstrate that RGS14(414) treatment could be a viable strategy against episodic memory loss.

A novel episodic associative memory model for enhanced classification accuracy

A novel approach to Episodic Associative Memory (EAM), known as Episodic Associative Memory with a Neighborhood Effect (EAMwNE) is presented in this paper. It overcomes the representation limitations of existing episodic memory models and increases the potential for their use in practical application.

fMRI evidence of word frequency and strength effects in recognition memory

We used event-related fMRI to investigate the neural correlates of encoding strength and word frequency effects in recognition memory. At test, participants made Old/New decisions to intermixed low (LF) and high frequency (HF) words that had been presented once or twice at study and to new, unstudied words. The Old/New effect for all hits vs. correctly rejected unstudied words was associated with differential activity in multiple cortical regions, including the anterior medial temporal lobe (MTL), hippocampus, left lateral parietal cortex and anterior left inferior prefrontal cortex (LIPC). Items repeated at study had superior hit rates (HR) compared to items presented once and were associated with reduced activity in the right anterior MTL. By contrast, other regions that had shown conventional Old/New effects did not demonstrate modulation according to memory strength. A mirror effect for word frequency was demonstrated, with the LF word HR advantage associated with increased activity in the left lateral temporal cortex. However, none of the regions that had demonstrated Old/New item retrieval effects showed modulation according to word frequency. These findings are interpreted as supporting single-process memory models proposing a unitary strength-like memory signal and models attributing the LF word HR advantage to the greater lexico-semantic context-noise associated with HF words due to their being experienced in many pre-experimental contexts.

Event memory: A theory of memory for laboratory, autobiographical, and fictional events.

An event memory is a mental construction of a scene recalled as a single occurrence. It therefore requires the hippocampus and ventral visual stream needed for all scene construction. The construction need not come with a sense of reliving or be made by a participant in the event, and it can be a summary of occurrences from more than one encoding. The mental construction, or physical rendering, of any scene must be done from a specific location and time; this introduces a "self" located in space and time, which is a necessary, but need not be a sufficient, condition for a sense of reliving. We base our theory on scene construction rather than reliving because this allows the integration of many literatures and because there is more accumulated knowledge about scene construction's phenomenology, behavior, and neural basis. Event memory differs from episodic memory in that it does not conflate the independent dimensions of whether or not a memory is relived, is about the self, is recalled voluntarily, or is based on a single encoding with whether it is recalled as a single occurrence of a scene. Thus, we argue that event memory provides a clearer contrast to semantic memory, which also can be about the self, be recalled voluntarily, and be from a unique encoding; allows for a more comprehensive dimensional account of the structure of explicit memory; and better accounts for laboratory and real-world behavioral and neural results, including those from neuropsychology and neuroimaging, than does episodic memory.

Brain activity during episodic retrieval of autobiographical and laboratory events: an fMRI study using a novel photo paradigm.

Functional neuroimaging studies of episodic memory retrieval generally measure brain activity while participants remember items encountered in the laboratory ("controlled laboratory condition") or events from their own life ("open autobiographical condition"). Differences in activation between these conditions may reflect differences in retrieval processes, memory remoteness, emotional content, retrieval success, self-referential processing, visual/spatial memory, and recollection. To clarify the nature of these differences, a functional MRI study was conducted using a novel "photo paradigm," which allows greater control over the autobiographical condition, including a measure of retrieval accuracy. Undergraduate students took photos in specified campus locations ("controlled autobiographical condition"), viewed in the laboratory similar photos taken by other participants (controlled laboratory condition), and were then scanned while recognizing the two kinds of photos. Both conditions activated a common episodic memory network that included medial temporal and prefrontal regions. Compared with the controlled laboratory condition, the controlled autobiographical condition elicited greater activity in regions associated with self-referential processing (medial prefrontal cortex), visual/spatial memory (visual and parahippocampal regions), and recollection (hippocampus). The photo paradigm provides a way of investigating the functional neuroanatomy of real-life episodic memory under rigorous experimental control.

Visual memory-deficit amnesia: a distinct amnesic presentation and etiology.

We describe a form of amnesia, which we have called visual memory-deficit amnesia, that is caused by damage to areas of the visual system that store visual information. Because it is caused by a deficit in access to stored visual material and not by an impaired ability to encode or retrieve new material, it has the otherwise infrequent properties of a more severe retrograde than anterograde amnesia with no temporal gradient in the retrograde amnesia. Of the 11 cases of long-term visual memory loss found in the literature, all had amnesia extending beyond a loss of visual memory, often including a near total loss of pretraumatic episodic memory. Of the 6 cases in which both the severity of retrograde and anterograde amnesia and the temporal gradient of the retrograde amnesia were noted, 4 had a more severe retrograde amnesia with no temporal gradient and 2 had a less severe retrograde amnesia with a temporal gradient.

Contribution from neuropsychology to the study of semantic memory

Semantic memory has been studied from various fields. The first models emerged from cognitive psychology from the hand of the division proposed by Tulving between semantic and episodic memory. Over the past thirty years there have been parallel developments in the fields of psycholinguistics, cognitive psychology and cognitive neuropsychology. The present work is to review the contributions that have emerged within the neuropsychology to the study of semantic memory and to present an updated overview of the points of consensus. First, it is defined the term "semantics" conceptually within the field of neuropsychology. Then, there is a dichotomy that passes through both psychological and neuropsychological models on semantic memory: the existence of modals versus amodal representations. Third, there are  developed the main theoretical models in neuropsychology that emerged in an attempt to explain categoryspecific semantic deficits. Finally, more robust contributions and points that still generate some discussion are reviewed.

A preliminary investigation of the running digit span as a test of working memory

The objective of this study was to compare performance on different versions of the running span task, and to examine the relationship between task performance and tests of episodic memory and executive function. We found that the average capacity of the running span was approximately 4 digits, and at long sequence lengths, performance was no longer affected by varying the running span window. Both episodic and executive function measures correlated with short and long running spans. suggesting that a simple dissociation between immediate memory and executive processes in short and long running digit span tasks may not be warranted.

Autobiographical memory and the self in a case of transient epileptic amnesia

Transient epileptic amnesia (TEA) is characterized by deficits in autobiographical memory (AM). One of the functions of AM is to maintain the self, suggesting that the self may undergo changes as a result of memory loss in temporal lobe epilepsy. To examine this, we used a modification of a task used to assess the relationship between self and memory (the IAM task) in a single case, E.B. Despite complaints of AM loss, E.B. had no difficulty in producing a range of self-images (e.g., I am a husband) and collections of self-defining AMs in support of these statements. E.B. produced fewer episodic memories at times of self-formation, but this did not seem to impact on the maintenance of self. The results support recent work suggesting the self may be maintained in the absence of episodic memory. The application of tasks such as that used here will further elucidate AM impairment in temporal lobe epilepsy. (C) 2011 Elsevier Inc. All rights reserved.

Autobiographical memory and amnesia: using conceptual knowledge to ground the self

A case of retrograde amnesia, PJM, elucidated the relationship between self, episodic memory and autobiographical knowledge. Results from a variety of measures including the I Am Memory Task (IAM Task), where memories are cued by self-generated self concepts, demonstrate that PJM has a coherent, continuous sense of self, despite having lost episodic memories for an 18-month period. Her use of conceptual autobiographical knowledge, in episodic tasks and to support aspects of identity, shows how autobiographical knowledge can support the self when episodic memories are inaccessible. These results are discussed with relation to current neuropsychological models of self and memory.

Type 2 diabetes and impaired glucose tolerance are associated with word memory source monitoring recollection deficits but not simple recognition familiarity deficits following water, low glycaemic load, and high glycaemic load breakfasts.

Isolated source monitoring recollection deficits indicate that abnormalities in glucose metabolism are not detrimental for global episodic memory processes. This enhances our understanding of how metabolic disorders are associated with memory impairments.

Retrieval of episodic versus generic information : does the order of recall affect the amount and accuracy of details reported by children about repeated events?

Children (N = 157) 4 to 8 years old participated 1 time (single) or 4 times (repeated) in an interactive event. Across each condition, half were questioned a week later about the only or a specific occurrence of the event (depth first) and then about what usually happens. Half were prompted in the reverse order (breadth first). Children with repeated experience who first were asked about what usually happens reported more eventrelated information overall than those asked about an occurrence first. All children used episodic language when describing an occurrence; however, children with repeated-event experience used episodic language less often when describing what usually happens than did those with a single experience. Accuracy rates did not differ between conditions. Implications for theories of repeated-event memory are discussed.

Glucose enhancement of recognition memory: differential effects on effortful processing but not aspects of 'remember-know' responses

The administration of a glucose drink has been shown to enhance cognitive performance with effect sizes comparable with those from pharmaceutical interventions in human trials. In the memory domain, it is currently debated whether glucose facilitation of performance is due to differential targeting of hippocampal memory or whether task effort is a more important determinant. Using a placebo-controlled, double-blind, crossover 2(Drink: glucose/placebo) × 2(Effort: ± secondary task) design, 20 healthy young adults' recognition memory performance was measured using the 'remember-know' procedure. Two high effort conditions (one for each drink) included secondary hand movements during word presentation. A 25 g glucose or 30 mg saccharine (placebo) drink was consumed 10 min prior to the task. The presence of a secondary task resulted in a global impairment of memory function. There were significant Drink × Effort interactions for overall memory accuracy but no differential effects for 'remember' or 'know' responses. These data suggest that, in some circumstances, task effort may be a more important determinant of the glucose facilitation of memory effect than hippocampal mediation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Sex Differences in Memory and Other Cognitive Abilities

The aim of the present thesis was to study sex differences in memory and other cognitive bilities in healthy adults. In Study I, participants performed a number of episodic memory tasks that were more or less verbal in nature. Results showed that women performed on a higher level than did men in the episodic memory tasks where it was possible to use verbal labels, whereas men performed on a higher level than did women in a visuospatial episodic memory task. In Study II, women’s advantage in face recognition was investigated.Results showed that women performed at a higher level than did men only in the recognition of other women’s faces. In Study III, sex differences in cognitive tasks as well as brain measures were investigated in healthy older adults. Results showed that only the sex differences in a motor task could, to some extent, be explained by sex differences in one of the brain measures. The findings, as well as possible explanations for these patterns of results, are discussed in a theoretical context.

Neuronal Correlates of Perception, Imagery, and Memory for Familiar Tunes

We used fMRI to investigate the neuronal correlates of encoding and recognizing heard and imagined melodies. Ten participants were shown lyrics of familiar verbal tunes; they either heard the tune along with the lyrics, or they had to imagine it. In a subsequent surprise recognition test, they had to identify the titles of tunes that they had heard or imagined earlier. The functional data showed substantial overlap during melody perception and imagery, including secondary auditory areas. During imagery compared with perception, an extended network including pFC, SMA, intraparietal sulcus, and cerebellum showed increased activity, in line with the increased processing demands of imagery. Functional connectivity of anterior right temporal cortex with frontal areas was increased during imagery compared with perception, indicating that these areas form an imagery-related network. Activity in right superior temporal gyrus and pFC was correlated with the subjective rating of imagery vividness. Similar to the encoding phase, the recognition task recruited overlapping areas, including inferior frontal cortex associated with memory retrieval, as well as left middle temporal gyrus. The results present new evidence for the cortical network underlying goal-directed auditory imagery, with a prominent role of the right pFC both for the subjective impression of imagery vividness and for on-line mental monitoring of imagery-related activity in auditory areas.