Cold Spring Harbor symposia on quantitative biology最新文献

Parvalbumin (PV) basket cells are widespread local interneurons that inhibit principal neurons and each other through perisomatic boutons. They enhance network function and regulate local ensemble activities, particularly in the γ range. Organized network activity is critically important for long-term memory consolidation during a late time window 11-15 h after acquisition. Here, we discuss the role of learning-related plasticity in PV neurons for long-term memory consolidation. The plasticity can lead to enhanced (high-PV) or reduced (low-PV) expression of PV/GAD67. High-PV plasticity is induced upon definite reinforced learning in early-born PV basket cells, whereas low-PV plasticity is induced upon provisional reinforced learning in late-born PV basket cells. The plasticity is first detectable 6 h after acquisition, at the end of a time window for memory specification through experience, and is critically important 11-15 h after acquisition for enhanced network activity and long-term memory consolidation. High- and low-PV plasticity appear to regulate activity in distinct local networks of principal neurons and PV basket cells. These findings suggest how flexibility and stability in learning and memory might be implemented through parallel circuits and networks.

The ability to predict future outcomes increases the fitness of the animal. Decades of research have shown that dopamine neurons broadcast reward prediction error (RPE) signals-the discrepancy between actual and predicted reward-to drive learning to predict future outcomes. Recent studies have begun to show, however, that dopamine neurons are more diverse than previously thought. In this review, we will summarize a series of our studies that have shown unique properties of dopamine neurons projecting to the posterior "tail" of the striatum (TS) in terms of anatomy, activity, and function. Specifically, TS-projecting dopamine neurons are activated by a subset of negative events including threats from a novel object, send prediction errors for external threats, and reinforce avoidance behaviors. These results indicate that there are at least two axes of dopamine-mediated reinforcement learning in the brain-one learning from canonical RPEs and another learning from threat prediction errors. We argue that the existence of multiple learning systems is an adaptive strategy that makes possible each system optimized for its own needs. The compartmental organization in the mammalian striatum resembles that of a dopamine-recipient area in insects (mushroom body), pointing to a principle of dopamine function conserved across phyla.

Mouse models of Alzheimer's disease have commonly used transgenic overexpression of genes involved in production of amyloid β (APP and/or PSEN1/2) or Tau (MAPT) with mutations that result in familial forms of dementia. We discuss possible improvements that may create full models while avoiding the problems of overexpression and report synaptic results in APPKI models. We stress use of inappropriate controls without overexpression of the normal human protein and the mismatch between the learning deficits reported in mice with plaques but no tangles and the human condition. We focus on Tau overexpression, including new data that support previous reports of the grossly nonlinear relationship between Tau overexpression and neurofibrillary tangle load, with a twofold increase in Tau protein, resulting in a 100-fold increase in tangle density. These data also support the hypothesis that a high concentration of soluble Tau, in overexpression models, plays an important direct role in neurodegeneration, rather than only via aggregation. Finally, we hypothesize that there is an optimal concentration range over which Tau can bind to microtubules and a threshold beyond which much of the overexpressed protein is unable to bind. The excess thus causes toxicity in ways not necessarily related to the process in human dementias.

The purpose of this article is to outline a new molecular and synaptic theory of behavior called the "synaptomic theory," named because it is centered on the synaptome-the complement of synapses in the brain. Synaptomic theory posits that synapses are structures of high molecular complexity and vast diversity that are observable in maps of the brain and that these synaptome maps are fundamental to behavior. Synaptome maps are a means of writing or storing information that can be retrieved by the patterns of activity that stimulate synapses. Synaptome maps have the capacity to store large amounts of information, including multiple representations within the same map. The dynamic properties of synapses allow synaptome maps to store dynamic sequences of representations that could serve to program behavioral sequences. Synaptome maps are genetically programmed and experience-dependent, thereby storing innate and learned behaviors, respectively. Although learning occurs by modification of the synapse proteome, it does not require long-term potentiation (LTP) of synaptic weight or growth of new synapses, and the theory predicts that LTP modulates information recall. The spatial architecture of synaptome maps arise from an underlying molecular hierarchy linking the genome to the supramolecular assembly of proteins into complexes and supercomplexes. This molecular hierarchy can explain how genome evolution results in the behavioral repertoire of the organism. Mutations disrupting this molecular hierarchy change the architecture of synaptome maps, potentially accounting for the behavioral phenotypes associated with neurological and psychiatric disorders.

Tau filaments with distinct morphologies and/or isoform compositions underlie a large number of human neurodegenerative diseases. In conjunction with experimental studies, this has led to the suggestion that conformers of aggregated tau exist. Electron cryo-microscopy can be used to determine high-resolution structures of amyloid filaments from human brain. Paired helical and straight tau filaments of Alzheimer's disease (AD) are ultrastructural polymorphs. Each filament core is composed of two identical protofilaments extending from G273/304-E380 (in the numbering of the 441-amino acid isoform of human tau), which adopt a combined cross-β/β-helix structure. They comprise the ends of the first or second microtubule-binding repeat (R1 or R2), the whole of R3 and R4, and 12 amino acids after R4. In contrast, the core of the narrow filaments of Pick's disease (PiD) consists of a single protofilament extending from K254-F378 of 3R tau, which adopts a cross-β structure. It comprises the last 21 amino acids of R1, all of R3 and R4, and 10 amino acids after R4. Wide tau filaments of PiD, which are in the minority, consist of two narrow filaments packed against each other. The tau filament folds of AD and PiD appear to be conserved between different cases of disease. These findings show that filamentous tau adopts one fold in AD and a different fold in PiD, establishing the existence of distinct conformers.

Prolonged periods of social isolation can generate an internal state that exerts profound effects on the brain and behavior. However, the neurobiological underpinnings of protracted social isolation have been relatively understudied. Here, we review recent literature implicating peptide neuromodulators in the establishment and maintenance of such internal states. More specifically, we describe an evolutionarily conserved role for the neuropeptide tachykinin in the control of social isolation-induced aggression and review recent data that elucidate the manner by which Tac2 controls the widespread effects of social isolation on behavior in mice. Last, we discuss potential roles for additional neuromodulators in controlling social isolation and a more general role for Tac2 in the response to other forms of stress.