Gregory Lynch

Positive allosteric modulators of α-amino-3-hydroxyl-5-methyl-4-isoxazole- propionate –type glutamate receptors constitute a relatively new class of psychoactive drugs that enhance fast, excitatory transmission in the brain. Because of this effect, ampakines reduce the threshold for inducing memoryrelated changes to synapses and improve learning in animals across species and paradigms. While most CNS drugs target neurons that project in a onestep, parallel fashion to a multitude of sites, ampakine-type agents act on the multiple connections found in serial brain networks. This results in a multiplier effect for the drug, likely to be most pronounced in the elaborate circuits found in the cortex, thereby intensifying cortical regulation of lower brain areas. Evidence that the compounds are effective in animal models of psychiatric disorders associated with abnormal brainstem activity is in agreement with this hypothesis. The possibility that expanding cortical networks will lead to cognitive, as opposed to memory, enhancement in normal brains is largely unexplored. Finally, positive modulators increase the production of brain growth factors that promote plasticity and neuronal viability; upregulation is associated with neuroprotection, growth, and improved functional outcomes in different disease models.

Human performance approaches that of an ideal observer and optimal actor in some perceptual and motor tasks. These optimal abilities depend on the capacity of the cerebral cortex to store an immense amount of information and to flexibly make rapid decisions. However, behavior only approaches these limits after a long period of learning while the cerebral cortex interacts with the basal ganglia, an ancient part of the vertebrate brain that is responsible for learning sequences of actions directed toward achieving goals. Progress has been made in understanding the algorithms used by the brain during reinforcement learning, which is an online approximation of dynamic programming. Humans also make plans that depend on past experience by simulating different scenarios, which is called prospective optimization. The same brain structures in the cortex and basal ganglia that are active online during optimal behavior are also active offline during prospective optimization. The emergence of general principles and algorithms for goal-directed behavior has consequences for the development of autonomous devices in engineering applications. © 2014 IEEE.

© 2015 The Physiological Society. The present study evaluated learning-related synaptic operations across the serial stages of the olfactory cortex-hippocampus network. Theta frequency stimulation produced very different time-varying responses in the Schaffer-commissural projections than in the lateral perforant path, an effect associated with distinctions in transmitter mobilization. Long-term potentiation had a higher threshold in LPP field potential studies but not in voltage clamped neurons; coupled with input/output relationships, these results suggest that LTP threshold differences reflect the degree of input divergence. Theta pulse stimulation erased LTP in CA1 but not in the dentate gyrus, although adenosine eliminated potentiation in both areas, suggesting that theta increases extracellular adenosine to a greater degree in CA1. Moreover, adenosine A1 receptor antagonism had larger effects on theta responses in CA1 than in the DG, and concentrations of ecto-5'-nucleotidase were much higher in CA1. Input/output curves for two connections in the piriform cortex were similar to those for the LPP, whereas adenosine modulation again correlated with levels of CD73. In sum, multiple relays in a network extending from the piriform cortex through the hippocampus can be differentiated along three dimensions that potently influence throughput and plasticity. A model that incorporates the regional differences, supplemented with data for three additional links, suggests that network output goes through three transitions during the processing of theta input. It is proposed that individuated relays allow the circuit to deal with different types of behavioural problems.

Gadamer claims that human beings are capable of understanding only ‘aspects’ of reality, yet he also holds that, through these aspects, we understand reality itself. In this sense he is an ‘aspectival realist.’ This paper considers two attempts to explain Gadamer’s aspectival realism: the ‘schematization’ reading defended by Charles Taylor, and the ‘holist’ reading of Brice Wachterhauser. I criticize these views on two fronts: that they are at odds with Gadamer’s texts, and that they fail to reconcile aspectivalism and realism into a consistent philosophical position. I articulate an alternative reading that I call the ‘presentational’ account. At the heart of this account is the claim that, on Gadamer’s view, the ‘occasionality’ that characterizes language also characterizes being itself. I argue both that this interpretation fits Gadamer’s texts better than the views currently on offer in the literature and that it avoids the philosophical difficulties those views encounter.

Stabilization of long-term potentiation depends on reorganization of the dendritic spine actin cytoskeleton. The present study tested whether this involves activity-driven effects on the actin-regulatory protein cortactin, and whether such effects are disturbed in the Fmr1 knock-out model of fragile X syndrome, in which stabilization of both actin filaments and LTP is impaired. LTP induced by theta burst stimulation in hippocampal slices from wild-type mice was associated with rapid, broadly distributed, and NMDA receptor-dependent decreases in synapse-associated cortactin. The reduction in cortactin content was blocked by blebbistatin, while basal levels were reduced by nocodazole, indicating that cortactin's movements into and away from synapses are regulated by microtubule and actomyosin motors, respectively. These results further suggest that synapse-specific LTP influences cytoskeletal elements at distant connections. The rapid effects of TBS on synaptic cortactin content were absent in Fmr1 KOs as was evidence for activity-driven phosphorylation of the protein or its upstream kinase, ERK1/2. Phosphorylation regulates cortactin's interactions with actin, and coprecipitation of the two proteins was reduced in the KOs. We propose that, in the KOs, excessive basal phosphorylation of ERK1/2 disrupts its interactions with cortactin, thereby blocking the latter protein's use of actomyosin transport systems. These impairments are predicted to compromise the response of the subsynaptic cytoskeleton to learning-related afferent activity, both locally and at distant sites. © 2012 the authors.