Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H-Ras/ ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2-7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG-CA3-CA1 circuit.long-term potentiation | hippocampus | G protein signaling | RGS proteins | ERK

Componential theories of lexical semantics assume that concepts can be represented by sets of features or attributes that are in some sense primitive or basic components of meaning. The binary features used in classical category and prototype theories are problematic in that these features are themselves complex concepts, leaving open the question of what constitutes a primitive feature. The present availability of brain imaging tools has enhanced interest in how concepts are represented in brains, and accumulating evidence supports the claim that these representations are at least partly "embodied" in the perception, action, and other modal neural systems through which concepts are experienced. In this study we explore the possibility of devising a componential model of semantic representation based entirely on such functional divisions in the human brain. We propose a basic set of approximately 65 experiential attributes based on neurobiological considerations, comprising sensory, motor, spatial, temporal, affective, social, and cognitive experiences. We provide normative data on the salience of each attribute for a large set of English nouns, verbs, and adjectives, and show how these attribute vectors distinguish a priori conceptual categories and capture semantic similarity. Robust quantitative differences between concrete object categories were observed across a large number of attribute dimensions. A within- versus between-category similarity metric showed much greater separation between categories than representations derived from distributional (latent semantic) analysis of text. Cluster analyses were used to explore the similarity structure in the data independent of a priori labels, revealing several novel category distinctions. We discuss how such a representation might deal with various longstanding problems in semantic theory, such as feature selection and weighting, representation of abstract concepts, effects of context on semantic retrieval, and conceptual combination. In contrast to componential models based on verbal features, the proposed representation systematically relates semantic content to large-scale brain networks and biologically plausible accounts of concept acquisition.

Although much is known about the mechanisms underlying synaptic plasticity, the cellular mechanisms that negatively regulate plasticity in some brain regions are considerably less studied. One region where neurons do not reliably express long-term potentiation (LTP) is the CA2 subfield of the hippocampus. Given the connection between synaptic plasticity and increases in postsynaptic [Ca 2؉ ], and that CA2 neurons express a large number of calcium-regulating proteins, we tested the hypothesis that the relative lack of LTP in CA2 results from differences in the calcium dynamics of these neurons. By measuring calcium-dependent fluorescence transients in dendritic spines, we show that CA2 neurons have smaller action potential-evoked intracellular Ca 2؉ transients because of a higher endogenous Ca 2؉ -buffering capacity and significantly higher rates of Ca 2؉ extrusion when compared with CA1 and CA3 neurons. CA2 ͉ hippocampus ͉ synaptic plasticity

The capacity of 20 healthy adult subjects for detecting differences in the amplitude of two simultaneously delivered 25 Hz vibrotactile stimuli was assessed both in the absence and presence of prior exposure to different conditions of adapting stimulation. Results obtained from this study demonstrate that increasing durations of adapting stimulation at one of the two skin sites, in the range of 0.2 to 2.0 seconds, leads to a systematic and progressive decrease in a subject's ability to accurately discriminate between the two different amplitudes. Delivery of adapting stimuli to both of the sites of skin stimulation prior to simultaneous delivery of the test and standard stimuli, however, leads to an improvement in amplitude discrimination performance -a finding which is consistent with prior published psychophysical studies that demonstrate improvements in discriminatory capacity with much longer durations of adaptation. Striking parallels between the results obtained in this study and those reported in a prior study of the effects of vibrotactile adaptation on the optical response of squirrel monkey contralateral SI cortex to vibrotactile stimulation (Simons et al., 2007;Simons et al., 2005) suggest that the perceptual effects detected in this study could be attributable to adaptationinduced alterations of SI response.

Caffeine enhances cognition, but even high non-physiological doses have modest effects on synapses. A1 adenosine receptors (A1Rs) are antagonized by caffeine and are most highly enriched in hippocampal CA2, which has not been studied in this context. Here we show that physiological doses of caffeine in vivo or A1R antagonists in vitro induce robust, long-lasting potentiation of synaptic transmission in rat CA2 without effect in other regions of the hippocampus.

In previous studies, we showed that the spatial and intensive aspects of the SI response to skin flutter stimulation are modified systematically as stimulus amplitude is increased. In this study, we examined the effects of duration of skin flutter stimulation on the spatiotemporal characteristics of the response of SI cortex. Optical intrinsic signal (OIS) imaging was used to study the evoked response in SI of anesthetized squirrel monkeys to 25-Hz sinusoidal vertical skin displacement stimulation. Four stimulus durations were tested (0.5, 1.0, 2.0, and 5.0 s); all stimuli were delivered to a discrete site on the glabrous skin of the contralateral forelimb. Skin stimulation evoked a prominent increase in absorbance within the forelimb regions in SI of the contralateral hemisphere. Responses to brief (0.5 s) stimuli were weaker and spatially more extensive than responses to longer duration stimuli (1.0, 2.0, and 5.0 s). Stimuli >or=1 s in duration suppressed responses to below background levels (decreased absorbance) in regions that surrounded the maximally activated region. The magnitude of the suppression in the surrounding regions was nonuniform and usually was strongest medial and posterior to the maximally activated region. The results show that sustained (>or=1.0 s) stimulation decreases the spatial extent of the responding SI cortical population. Registration of the optical responses with the previously documented SI topographical organization strongly suggests that the cortical regions that undergo the strongest suppression represent skin sites that are normally co-stimulated during tactile exploration.

Abstract-Fiber organization is important for myocardial excitation and contraction. It can be a major factor in arrhythmogenesis and current distribution during defibrillation shocks. In this study, we report the discovery of a previously undetected thin epicardial layer in swine right ventricle (RV) with distinctly different fiber orientation, which significantly affects epicardial propagation. Experiments were conducted in isolated coronary-perfused right ventricular free wall preparations (nϭ8) stained with the voltage-sensitive dye di-4-ANEPPS. Optical signals were recorded from the epicardium with a CCD video camera at 800 fps. Preparations were sectioned parallel to the epicardial surface with a resolution of 50 m or better. To link the histological data with the observed activation patterns, resulting fiber angles were introduced into a 3D computer model to simulate the electrical activation and voltage-dependent optical signals.In all preparations, we detected a thin epicardial layer with almost no depth-dependent fiber rotation. The thickness of this layer (z 0 ) varied from 110 to 930 m. At the boundary of this layer, we observed an abrupt change in fiber angle by 64Ϯ13°followed by a gradual fiber rotation in the underlying layers. In preparations with z 0 Ͻ700 m, optical mapping during epicardial stimulation revealed unusual diamond-and rectangular-shaped activation fronts with two axes of fast conduction. Computer simulations accurately predicted the features of the experimentally recorded activation fronts. The free wall of swine RV has a thin epicardial layer with distinctly different fiber orientation, which can significantly affect propagation and give rise to unusually shaped activation fronts. This is important for understanding electrical propagation in the heart, and further refines the existing knowledge of myocardial fiber architecture. Key Words: myofiber organization Ⅲ optical mapping Ⅲ propagation T he fiber organization of ventricular myocardium is a significant determinant of both its mechanical function and its electrical propagation [1][2][3] Myocardial fiber organization has been implicated in the mechanisms of ventricular arrhythmias as one of the important factors responsible for the stability of 3D reentrant activity. 4 -8 It is also thought to affect current distribution during defibrillation shocks 9,10 and thus affect their odds of failure and success. All this explains the persistent interest in structural aspects of myocardial organization 11,12 and motivates further refining the existing knowledge of myocardial fiber architecture.The characteristic feature of myocardial fiber organization is the gradual counterclockwise rotation of fibers throughout the heart wall 1,13-16 with the total rotation angle from endocardium to epicardium across species ranging from 120°( dog) to 180°(pig). 17,18 Although in general the dependence of fiber rotation on depth is considered well established, information about fiber organization near the epicardial surface remains scarce.There are in...

We recorded the optical intrinsic signal response of squirrel monkey primary somatosensory cortex (SI) to 25 Hz vibrotactile ("flutter") stimulation applied independently to the thenar eminence on each hand and also to bilateral (simultaneous) stimulation of both thenars. The following observations were obtained in every subject (n ϭ 5). (1) Ipsilateral stimulation was accompanied by an increase in absorbance within the SI hand region substantially smaller than the absorbance increase evoked by contralateral stimulation. (2) The absorbance increase evoked by simultaneous bilateral stimulation was smaller (by ϳ30%) than that evoked by contralateral stimulation. (3) The spatiointensive pattern of the SI response to bilateral flutter was distinctly different than the pattern that accompanied contralateral flutter stimulation: with contralateral flutter, the center of the responding region of SI underwent a large increase in absorbance, whereas absorbance decreased in the surrounding region; in contrast, during bilateral flutter, absorbance decreased (relative to that evoked by contralateral flutter) in the central region of SI but increased in the surround. The results raise the possibility that somatosensory perceptual experiences specific to bimanual tactile object exploration derive, at least in part, from the unique spatiointensive activity pattern evoked in SI when the stimulus makes contact with both hands. It is suggested that modulatory influences evoked by ipsilateral thenar flutter stimulation reach SI via a two-stage pathway involving interhemispheric (callosal) connections between information processing levels higher than SI and subsequently via intrahemispheric (corticocortical) projections to the SI hand region.