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Individuals with early Alzheimer's disease (AD) suffer from a selective and profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by neurologically active Aβ oligomers. We have named these oligomers "ADDLs" (for pathogenic Aβ-derived diffusible ligands). ADDLs constitute metastable alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. In AD brain, ADDLs accumulate primarily as Aβ 12-mers (∼54 kDa). The same size oligomers occur in tg-mouse AD models; in mice, these 12-mers appear concomitantly with memory failure, consistent with the ability of ADDLs to inhibit long-term potentiation (LTP) and block reversal of long-term depression (LTD). Mechanistically, ADDLs are gain-of-function ligands that bind with specificity to particular synapses, targeting synaptic spines. Binding leads to a rapid and ectopic expression of the memory-linked immediate early gene Arc. Such aberrant accumulation has been linked by others to memory dysfunction in tg-Arc mouse models. Consistent with the expected consequences of Arc overexpression, ADDLs promote loss of surface NMDA receptors and anomalous spine morphology, which are responses expected to contribute to plasticity failure and memory dysfunction. Importantly, the attack on synapses provides a putative mechanism that unifies AD memory dysfunction with major features of AD neuropathology. Recent findings show ADDL binding instigates synapse loss, AD-type tau hyperphosphorylation, and generation of reactive oxygen species (ROS). Binding sites for ADDLs are at or in the close vicinity of NMDA receptors. Antibodies against external domains of NMDA receptors reduce ADDL binding and inhibit ADDL-stimulated ROS formation. The ROS response also is inhibited by memantine, an open-channel blocker of NMDA receptors recently approved for AD therapeutics. The ability of memantine to contravene the impact of ADDLs offers a new mechanism to explain why an NMDA receptor antagonist should improve memory function in AD patients. Elimination of ADDLs by vaccines now under development could provide the first AD treatments that are truly disease-modifying. In addition to establishing a molecular mechanism of significant value for AD therapeutics and diagnostics, studies of ADDL interactions with synaptic pathways and control mechanisms ultimately may provide new insights into the extraordinary complexities of physiological synaptic information storage. [ABSTRACT FROM AUTHOR]

What controls your thoughts? How do you know how to act while dining in a restaurant? This is cognitive control, the ability to organize thought and action around goals. Results from our laboratory have shown that neurons in the prefrontal cortex and related brain areas have properties commensurate with a role in "executive" brain function. Perhaps most importantly, they transmit acquired know ledge. Here, I discuss how the prefrontal cortex and basal ganglia may help obtain our internal representations of rules and principles needed for goal-directed behavior, thereby providing the foundation for the complex behavior of primates, in whom the prefrontal cortex is most elaborate. [ABSTRACT FROM AUTHOR]

The ability to find one's way depends on the brain's ability to integrate information about location, direction and distance. The algorithms responsible for this integration are implemented in a large brain network that includes both hippocampal and parahip-pocampal cortices, as indicated by the existence of place cells in the hippocampus and head-direction cells in the dorsal presubiculum and a number of other regions. Recent results have pointed to the medial entorhinal cortex (MEC) as a possible site for the dynamic representation of position in animals that move through a two-dimensional environment. Layer II of the MEC contains position-sensitive neurons - grid cells - whose firing fields form a periodic triangular pattern that tiles the entire environment covered by the animal during exploration of an open surface. Grid cells are observed in all principal layers of MEC, but intermingle with head direction cells in layers III, V and VI. The two cell types form a continuous population in which a subset of the neurons, predominantly in layers III and V, have conjunctive grid and head-direction properties. The majority of the cells are modulated by velocity. These observations suggest that, despite the differential hippocampal and neocortical connections of different layers of the MEC, the area operates as an integrated unit, with significant interlaminar interaction between cells with different functional properties. As the animal moves across a surface, activity may be translated across the superficial sheet of grid cells by convergence of position, direction and velocity information in a neural subpopulation with conjunctive firing properties. [ABSTRACT FROM AUTHOR]

Recent identification of network-level coding units, termed neural cliques, in the hippocampus has allowed real-time patterns of memory traces to be mathematically described, directly visualized, and dynamically deciphered. Those memory coding units are functionally organized in a categorical and hierarchical manner, suggesting that internal representations of external events in the brain are achieved not by recording exact details of those events but rather by re-creating its own selective pictures based on cognitive importance. These neural clique-based, hierarchical-extraction and parallel-binding processes enable the brain to acquire not only large storage capacity but also abstraction and generalization capabilities. In addition, activation patterns of the neural clique assemblies can be converted to strings of binary codes that would permit universal categorizations of the brain's internal representations across individuals and species. [ABSTRACT FROM AUTHOR]

The groundbreaking description of the amnesic patient H.M. in the 1950s (Scoville and Milner 1957) demonstrated for the first time that the structures of the medial temporal lobe are critical for our ability to learn and retain new long-term memories for facts and events. This critical form of memory is referred to as declarative memory in humans (Squire et al. 2004) and relational memory in animals (Eichenbaum et al. 1999). The development of powerful animal models of human amnesia in monkeys (Zola-Morgan and Squire 1990; Mishkin 1978; Zola and Squire 2000; Suzuki et al. 1993) and in rodents (Bunsey and Eichenbaum 1993,1995, 1996; Fortin et al. 2002), together with detailed neuroanatomical studies (Suzuki and Amaral 1994a,b; Burwell and Amaral 1998a,b), demonstrated definitively that the key medial temporal lobe structures important for declarative/relational memory include the hippocampus together with the surrounding entorhinal, perirhinal and parahippocampal cortices. While this convergence of studies in humans and animals has provided detailed information about the pattern of memory impairment following a wide range of lesions to the medial temporal lobe, less information is known about how individual cells in the intact medial temporal lobe participate in the acquisition, consolidation or retrieval of various forms of declarative/relational memory. [ABSTRACT FROM AUTHOR]

The persistence of memories reflects a dynamic, rather than a stable, process. The reactivation of a previously learned memory, for example by re-exposure to a conditioned stimulus, renders it labile, such that the concomitant administration of a variety of amnestic agents results in a reduced ability subsequently to retrieve that memory. This reactivation-dependent amnesia suggests that memoriesmay undergo cycles of reactivation followed by a process of what has been called "reconsolidation". This review will discuss several of the central features of memory reconsolidation, taking a translational view of the potential of disrupting reconsolidation as a treatment strategy for maladaptive memory disorders such as post-traumatic stress and drug addiction. [ABSTRACT FROM AUTHOR]

Each memory item has a unique biography. The global outline of the narrative of this biography, however, is shared by different items. The textbook account charts the ontogeny of memory items as a universal linear process. First the new information is encoded. Then it enters a short-term persistence phase, during which it is prone to interference by various types of treatments, ranging from distracting sensory stimuli to physical agents and drugs, collectively termed "amnesic agents". The period during which the item becomes gradually immune to the effect of amnesic agents is termed "memory consolidation". Upon completion of consolidation, so goes the zeitgeist, the stabilized item enters into a long-term "store", from which it can be later retrieved for use. [ABSTRACT FROM AUTHOR]

While the molecular, cellular and systems mechanisms required for the initial processing of memory have been intensively investigated by the new field of molecular and cellular cognition, those underlying permanent storage remain elusive. Here, we review neuroanatomical, pharmacological and genetic results demonstrating that specific areas of the cortex play a critical role in the storage of remote memory. Imaging experiments in rodents show that specific areas of the cortex are activated by remote memory and that this activation is impaired by manipulations that block remote memory. Accordingly, reversible inactivation of specific cortical structures in rodents disrupts remote memory without affecting recent memory. These results open a new, exciting window into memory studies and suggest a number of interesting experiments that will address molecular, cellular, systems and cognitive aspects of this poorly understood phase of memory. [ABSTRACT FROM AUTHOR]

Despite the fact that the Drosophila brain has only 100 000 cells, it produces complex behaviors and sustains various forms of learning and memory. We show here how the power of Drosophila molecular genetics permits the interconnecting of the different levels of memory analyses: molecular, network and system. In particular new, tools allow a precise spatial and temporal control of network activity, as well as recording of brain activity. Recent results indicate that the Drosophila brain is the site of complex phenomena more frequently associated with mammalian species. [ABSTRACT FROM AUTHOR]

Both clinical studies and experiments in animals have provided evidence for the existence of a temporally graded retrograde amnesia following lesions of the medial temporal lobe, including the hippocampus. This form of amnesia, which is characterized by a loss of memory for recent events acquired prior to the onset of amnesia while more remote memories are preserved, is one of the major arguments for the existence of a consolidation process necessary for stable, long-term memory formation. It is now well established that the formation of declarative memory (memories for facts and events) involves changes in synaptic plasticity within the medial temporal lobe. However, our group and others have demonstrated that the hippocampus has only a time-limited role in long-term memory storage of certain types of information, such that extrahippocampal structures, namely cortical regions, eventually become capable of supporting the retrieval of remote memories independently. In other words, the hippocampus does not store remote memories, yet what happens beyond the hippocampus remains unclear. This issue has been the subject of intense investigation and debate in the field of cognitive neuroscience, but to date, no convincing evidence as to the identity, mechanisms and putative interactions between memory systems underlying remote memory storage and retrieval have clearly emerged. To address this issue, we have conducted brain imaging experiments using (14C)2-deoxyglucose mapping and analyses of changes in the expression of activity-dependent genes (c-fos and Zif268) in mice submitted to recent and remote spatial memory testing. Our findings show that memory processing and consolidation require a time-dependent hippocampal-cortical dialogue, ultimately enabling structured cortical networks to mediate recall and use of cortically stored remote memories independently. However, the cortex does not simply serve as a passive storage site but may also actively integrate new memories depending on the organization and status of pre-existing knowledge. The prefrontal cortex in particular appears to play a crucial role in integrating and binding information from distributed cortical networks and in modulating the level of hippocampal activation during memory recall. These findings are discussed in the context of current models of memory consolidation and in light of data from the recent literature in humans and animals. [ABSTRACT FROM AUTHOR]

The hippocampus and anatomically related structures in the medial temporal lobe support the capacity for declarative memory (Squire and Zola-Morgan 1991; Eichenbaum and Cohen 2001). Declarative memory refers to the capacity to recollect facts and events and has the defining features of being consciously accessible and flexible in its expression. Declarative memory can be contrasted to a collection of nondeclarative forms of memory that includes skills and habits, priming, and simple forms of conditioning. These forms of memory are supported by brain structures outside the medial temporal lobe. Nondeclarative memory is expressed through performance rather than recollection and what is learned is nonconscious and dependent on the original learning conditions for full expression. [ABSTRACT FROM AUTHOR]

What are the origins of mathematical truth? How can a finite and fallible human brain, created through the approximate tinkering of evolution rather than by an omnipotent designer, come to possess universal mathematical knowledge? Furthermore, “how is it possible that mathematics, a product of human thought that is independent of experience, fits so excellently the objects of physical reality?” (Einstein). Without pretending to address directly those difficult philosophical challenges, my research aims at understanding the cerebral origins of one of the foundations of mathematics, the concept of number. Both the human and the macaque parietal lobes contain neural representations of approximate number. Behavioral studies in the Mundurukú, an Amazonian people with very few number words, indicate that the concept of approximate number is independent of language and universally shared, but that exact calculation is not. These data lead to a mixed scenario for the origins of arithmetic. Evolution provides us with an approximate number sense, shared with our primate cousins. This representation then serves as the foundation for cultural constructions such as words, digits, and counting, which extend those abilities into the realm of exact arithmetic. [ABSTRACT FROM AUTHOR]

Humans are an exquisitely social species. Our survival and success depend critically on our ability to thrive in complex social situations. But how do we understand others? Which are the mechanisms underlying this capacity? In the present essay we discuss a general neural mechanism (“mirror mechanism”) that enables individuals to understand the meaning of actions done by others, their intentions, and their emotions, through activation of internal representations coding motorically the observed actions and emotions. In the first part of the essay we will show that the mirror mechanism for “cold” actions, those devoid of emotional content, is localized in the parieto-frontal cortical circuits. These circuits become active both when we do an action and when we observe another individual doing the same action. Their activity allows the observer to understand the “what” of an action. We will show, then, that a “chained” organization of motor acts plus the mirror mechanism enable the observer to understand the intention behind an action (the “why” of an action) by observing the first motor act of an action. Finally, we will discuss some recent data showing that the mirror mechanism localized in other centers, like the insula, enables the observer to understand the emotions of others. We will conclude briefly discussing whether these biological data allow inferences about moral behavior. [ABSTRACT FROM AUTHOR]

As stated by Jean-Pierre Changeux in his last book, “The Physiology of Truth,” objective knowledge does exist, and our brains are naturally equipped to recognize it. The results presented here provide the first insights into 1) the cerebral basis of reasoning errors, and 2) the neurocognitive dynamics that lead the human brain toward logical truth. [ABSTRACT FROM AUTHOR]

Traditional theories of moral psychology emphasize reasoning and “higher cognition,” while more recent work emphasizes the role of emotion. In this article, I discuss neuroimaging data that support a theory of moral judgment according to which both “cognitive” and emotional processes play crucial and sometimes mutually competitive roles. These data suggest that brain regions associated with cognitive control (anterior cingulate cortex and dorsolateral prefrontal cortex) are recruited to resolve difficult moral dilemmas in which utilitarian values require “personal” moral violations, violations associated with increased activity in brain regions associated with emotion and social cognition (medial prefrontal cortex, superior temporal sulcus, posterior cingulate cortex, temporal poles, and the amygdala). We have also found that brain regions including the anterior dorsolateral prefrontal cortices predict inter-trial differences in moral judgment behavior, exhibiting greater activity for utilitarian judgments. I speculate that our emerging psychological and neuroscientific understanding of moral judgment may influence our responses to real-world moral dilemmas. [ABSTRACT FROM AUTHOR]