Episodic memory: insights from semantic dementia

Semantic dementia, also known as the temporal lobe variant of fronto-temporal dementia, results in a progressive yet relatively pure loss of semantic knowledge about words, objects and people, and is associated with asymmetric, focal atrophy of the antero-lateral temporal lobes. Semantic dementia provides a unique opportunity to study the organization of long-term memory particularly since initial observations suggested sparing of episodic memory. Recent studies reveal, however, a more complex but theoretically revealing pattern. On tests of autobiographical memory, patients with semantic dementia show a 'reverse step function' with sparing of recall of events from the most recent 2 to 5 years but impairment on more distant life periods. Anterograde recognition memory for visual materials is extremely well preserved, except in the most deteriorated cases, although performance is heavily reliant upon perceptual information about the studied stimuli, particularly for items that are no longer known by the subjects. On tests of verbal anterograde memory such as word learning, performance is typically poor even for words which are 'known' to the patients. A source discrimination experiment, designed to evaluate familiarity and recollection-based anterograde memory processes, found that patients with semantic dementia showed good item detection, although recollection of source was sometimes impaired. Semantic knowledge about studied items and measures of item detection and source discrimination were largely independent. The implications of these findings for models of long-term memory are discussed. The results support the concept that episodic memory, or at least the recall of temporally specific autobiographical experiences, draws upon a number of separable memory processes, some of which can function independently of semantic knowledge.     

Sensory-perceptual episodic memory and its context: autobiographical memory

Episodic memory is reconceived as a memory system that retains highly detailed sensory perceptual knowledge of recent experience over retention intervals measured in minutes and hours. Episodic knowledge has yet to be integrated with the autobiographical memory knowledge base and so takes as its context or referent the immediate past of the experiencing self (or the 'I'). When recalled it can be accessed independently of content and is recollectively experienced. Autobiographical memory, in contrast, retains knowledge over retention intervals measured in weeks, months, years, decades and across the life span. Autobiographical knowledge represents the experienced self (or the 'me'), is always accessed by its content and, when accessed, does not necessarily give rise to recollective experience. Instead, recollective experience occurs when autobiographical knowledge retains access to associated episodic memories. In this reworking of the 'episodic memory' concept autobiographical memory provides the instantiating context for sensory-perceptual episodic memory.     

Cophylogeny: insights from fish-parasite systems

Host-parasite cophylogeny is a topic that has grasped the attention of scientists since the end of the 19th century, but the development of dedicated analytical methods only arose in the last 30 years. Research on host-parasite systems and on the development of more and more sophisticated numerical methods to estimate the degree of cospeciation has thus progressed, permitting the elaboration of evolutionary scenarios. The main outcome of these studies is that the expected clear pattern of cospeciation between many hosts and parasites is often obscure. In practice, much attention has been devoted to few host-parasite systems. Particularly, aquatic host-parasite associations have not been so extensively studied, and, after briefly reviewing the main analytical methods, this paper focuses on host-monogenean systems, because this kind of interaction is expected to be an ideal model for cophylogeny studies. But is it? And what does it tell us about the evolutionary and ecological forces driving cospeciation in the open sea? Biogeography should also be considered when possible, and it has been useful for explaining some patterns of cospeciation. It should thus be more deeply exploited in the future. We need new methods and new biological models that better, if not fully, depict patterns and thereby permit deeper understanding of processes within cophylogenetic patterns.     

The neural basis of episodic memory: evidence from functional neuroimaging

We review some of our recent research using functional neuroimaging to investigate neural activity supporting the encoding and retrieval of episodic memories, that is, memories for unique events. Findings from studies of encoding indicate that, at the cortical level, the regions responsible for the effective encoding of a stimulus event as an episodic memory include some of the regions that are also engaged to process the event 'online'. Thus, it appears that there is no single cortical site or circuit responsible for episodic encoding. The results of retrieval studies indicate that successful recollection of episodic information is associated with activation of lateral parietal cortex, along with more variable patterns of activity in dorsolateral and anterior prefrontal cortex. Whereas parietal regions may play a part in the representation of retrieved information, prefrontal areas appear to support processes that act on the products of retrieval to align behaviour with the demands of the retrieval task.     

Neural mechanisms and computations underlying stress effects on learning and memory

Stress has complex effects on memory function that can vary depending on the type of information that is learned and in relation to inter-individual characteristics. Recent work has also shown that stress can switch performance between memory systems, biasing it toward habit in detriment of spatial or goal-directed strategies. In addition, novel synaptic mechanisms have been implicated in the effects of stress in plasticity and memory. Computational modeling is emerging as a useful approach to integrate and to ascertain neural and cognitive computations underlying different effects of stress in memory. Having provided novel explanations for the inverted-U-shaped relationship between stress and cognitive performance, model-based analysis studies can improve our understanding of diverse effects of stress in cognition and psychopathology.     

Iron homeostasis: insights from genetics and animal models

Disorders that perturb iron balance are among the most prevalent human diseases, but until recently iron transport remained poorly understood. Over the past five years, genetic studies of patients with inherited iron homeostasis disorders and the analysis of mutant mice, rats and zebrafish have helped to identify several important iron-transport proteins. With information being mined from the genomes of four species, the study of iron metabolism has benefited enormously from positional-cloning efforts. Complementing the genomic strategy, targeted mutagenesis in mice has produced new models of human iron diseases. The animal models described in this review offer valuable tools for investigating iron homeostasis in vivo.     

Understanding fragile X syndrome: insights from animal models

The fragile X mental retardation syndrome is caused by large methylated expansions of a CGG repeat in the FMR1 gene leading to the loss of expression of FMRP, an RNA-binding protein. FMRP is proposed to act as a regulator of mRNA transport or translation that plays a role in synaptic maturation and function. To study the physiological function of the FMR1 protein, mouse and Drosophila models have been developed. The loss-of-function mouse model shows slightly enlarged testes, a subtle behavioral phenotype, and discrete anomalies of dendrite spines similar to those observed in brains of patients. Studies in Drosophila indicate that FXMR plays an important role in synaptogenesis and axonal arborization, which may underlie the observed deficits in flight ability and circadian behavior of FXR mutant flies. The relevance of these studies to our understanding of fragile X syndrome is discussed.     

The hippocampus and memory: insights from spatial processing

The hippocampus appears to be crucial for long-term episodic memory, yet its precise role remains elusive. Electrophysiological studies in rodents offer a useful starting point for developing models of hippocampal processing in the spatial domain. Here we review one such model that points to an essential role for the hippocampus in the construction of mental images. We explain how this neural-level mechanistic account addresses some of the current controversies in the field, such as the role of the hippocampus in imagery and short-term memory, and discuss its broader implications for the neural bases of episodic memory.     

Mechanisms of cigarette smoke-induced COPD: insights from animal models

Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.     

Origin of animal epithelia: insights from the sponge genome

Epithelial tissues are a key metazoan cell type, providing a basic structural unit for the construction of diverse animal body plans. Historically, an epithelial grade of organization was considered to be restricted to the Eumetazoa, with the majority of cell layers described for Porifera lacking any of the conserved ultrastructural characteristics of epithelia. Now with the use of genomic information from the demosponge, Amphimedon queenslandica, we identify orthologs of bilaterian genes that determine epithelial cell polarity or encode components of specialized epithelial junctions and extracellular matrix structures. Amphimedon possesses orthologs of most bilaterian epithelial polarity and adherens junction genes but few or no tight junction, septate junction, or basal lamina genes. To place this information in an evolutionary context, we extended these analyses to the completed genomes of various fungi, the choanoflagellate, Monosiga brevicollis, the placozoan, Trichoplax adhaerens, and the cnidarian, Nematostella vectensis. The results indicate that the majority of epithelial genes originated in metazoan or eumetazoan lineages, with only two genes, Par-1 and Discs large, antedating the choanoflagellate-metazoan split. We further explored the mechanism of evolution for each of these genes by tracking the origin of constituent domains and domain combinations. In general, domain configurations found in contemporary bilaterians are inferred to have evolved early in metazoan evolution and are identical or similar to those present in representatives of modern cnidarians, placozoans, and demosponges.     

Bridging the regeneration gap: genetic insights from diverse animal models

Significant progress has recently been made in our understanding of animal regenerative biology, spurred on by the use of a wider range of model organisms and an increasing ability to use genetic tools in traditional models of regeneration. This progress has begun to delineate differences and similarities in the regenerative capabilities and mechanisms among diverse animal species, and to address some of the key questions about the molecular and cell biology of regeneration. Our expanding knowledge in these areas not only provides insights into animal biology in general, but also has important implications for regenerative medicine and stem-cell biology.     

动物细胞的基因转录调控:来自生化研究的启示

在真核细胞中,转录调控可以发生在多个层面,包括结构和功能迥异的RNA聚合酶、对应的广谱起始因子、基因特异性调控因子(DNA结合蛋白)以及各种共调节因子(coregulatory factors)。这些共调节因子可以通过染色质修饰,如组蛋白乙酰化和甲基化,或更直接地促进转录起始复合物的形成。通过一系列体外转录活性实验的研究,转录相关的酶、蛋白因子的性质和功能以及作用机制正逐步被揭示出来。该文将具体阐述近几十年科学家们在转录共调节因子方面取得的进展。     

Defective membrane remodeling in neuromuscular diseases: insights from animal models

Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1), and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1) a common molecular pathway underlying these different neuromuscular diseases, and (2) tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches.     

Lissencephaly: Mechanistic insights from animal models and potential therapeutic strategies

Lissencephaly is a severe human neuronal migration defect characterized by a smooth cerebral surface, mental retardation and seizures. The two most common genes mutated in patients with lissencephaly are LIS1 and DCX. LIS1 was the first gene cloned that was important for neuronal migration in any organism, and heterozygous mutations or deletions of LIS1 are found in the majority of patients with lissencephaly, while DCX mutations were found in males with X-linked lissencephaly. In this review, we will discuss how an understanding of the molecular and cellular pathways disrupted in model organisms with Lis1 and Dcx mutations or knock-down not only provide insights into the normal processes of neuronal migration, including neurogenesis, but they also may lead to potential novel therapeutic strategies for these severe cortical malformations.     

Neural substrates of memory: from synapse to system

One of the fundamental challenges of modern neuroscience is to understand how memories are acquired, stored, and retrieved by the brain. In the broadest terms, attempts to dissect memory can be broken down into four experimental disciplines: (1) identification of molecular components, (2) ex vivo and in vivo cellular analysis of neuronal function, (3) theoretical modeling approaches of neural systems, and (4) organismal-level behavioral analyses. Our objective here is to offer a conceptually unifying perspective and to discuss this perspective in relation to an experiment analysis of memory in Drosophila.