Surprisingly, we observed neurons that encode an axis of motion m

Surprisingly, we observed neurons that encode an axis of motion matching the opposing preferences of DS neurons in the same dLGN region. We see two main possibilities for how this overlap in selectivity arises—either ASLGNs integrate opposing

direction-selective retinal ganglion cell-type inputs to form a new response class or ASLGNs receive direct input from an undiscovered axis-selective retinal ganglion cell type and relay that information. The latter hypothesis is most consistent with the view of the dLGN as a simple relay from retina to cortex. Interestingly, selleck screening library if this pathway exists, it may suggest further specificity of RGC projections based on motion axis preference, for example, if vertical axis cells are found in deeper dLGN. However, while axis-selective retinal ganglion cells have been found in the rabbit’s visual streak, they are nearly absent in the rabbit’s peripheral retina (Oyster, 1968) and have Small molecule library cost not been described previously in the rodent retina, which has no visual streak. Moreover, while the persistent view has been that the dLGN only relays retinal information and does not generate novel feature selectivity, the

current results present overlapping and opposing information channels in a single dLGN region, and thus the potential for direct integration of retinal pathways, for example, as evaluated by our random wiring model. Interestingly, one previous study suggested potential for rare mixing of RGC-type inputs in dLGN to yield intermediate tuning properties of X and Y cells in the cat (Mastronarde, 1992), suggesting that similar mechanisms may be involved in other species and cell types. However, the present results indicate that dLGN may integrate retinal

information to form a novel feature selectivity. Regardless of whether axis selectivity first arises in retina or dLGN, the importance of this pathway may be further pronounced if axis-selective inputs influence orientation selectivity in some neurons in the cortex. Integration of opposing direction preferences Levetiracetam by ASLGNs either could result from selective connectivity between DSRGCs and ASLGNs, for example, favored by developmental mechanisms, or could occur by chance if connections are nonspecific between retina and thalamus, given that incoming axonal arbors of opposing DSRGC types probably overlap spatially within superficial dLGN, as predicted by our results. Future studies are necessary to determine how axis selectivity develops in dLGN. In order to test whether our results are consistent with the generation of ASLGNs by chance integration of DSRGC afferents with opposing direction preferences, we generated a simple model based on random retinogeniculate wiring. In this model, dLGN neurons receive one to three driving retinal inputs (Chen and Regehr, 2000) randomly distributed according to the fraction of DS inputs from the retina.

Given this duplication of object representations along the ventra

Given this duplication of object representations along the ventral and lateral surface, the different response properties discovered for lateral and ventral category-selective

regions in general may also apply to Big-PHC, Small-OTS, and Small-LO. Object-responsive Obeticholic Acid molecular weight cortex anterior to early visual areas was originally thought to be nonretinotopic; however, there are now many well-documented retinotopic maps extending along dorsal and ventral streams (e.g., for reviews, see Wandell et al., 2007 and Silver and Kastner, 2009). Comparing object responses with retinotopic organization in this cortex may prove to be valuable for understanding the consistent spatial arrangement of category-selective regions (e.g., Levy et al., 2001, Malach et al., 2002, Hasson et al., 2002, Hasson et al., 2003 and Sayres and Grill-Spector, 2008), as well as the big/small object regions. Here we discuss how the big and small object responses relate to the retinotopic biases in occipitotemporal cortex. TGF-beta inhibitor The medial ventral surface has peripheral field biases while the lateral temporal surface has central

field biases, which extend directly from early visual areas V1-V4 (Levy et al., 2001, Malach et al., 2002 and Hasson et al., 2003; but see Brewer et al., 2005 and Arcaro et al., 2009, which suggest that there are separate foveal representations in these regions). Face- and scene-selective areas are found in cortex with foveal and peripheral biases, respectively (e.g., Levy et al., 2001 and Hasson et al., 2002). Similarly, given the positions of the big/small object regions relative to the scene/face regions, there is a striking convergence between big and small object information and the eccentricity biases of high-level object areas. For example, Figure 6 illustrates that Big-PHC region is near to peripheral early visual cortex, while the Small-OTS and Small-LO preferences are closer

to foveal early visual cortex, and both organizations are mirrored along the lateral surface. This convergence raises the possibility that big/small preferences may derive the in part from eccentricity biases. In their eccentricity-bias proposal of the organization of object representation, Malach and colleagues proposed a processing-based organization of cortex, positing that areas with foveal or peripheral biases carry out fine-detailed or integrative processing, respectively. On this account, any object will be represented along this cortex based on its processing-resolution needs (e.g., Malach et al., 2002). This account has met with some criticisms, however, as the concept of processing-resolution was not clearly operationalized (see also Tyler et al., 2005). For example, it is not obvious that faces require fine-detail processing and not integrative processing.

If Kr is acting in the control of NB fate as in the Hb/Kr/Pdm/Cas

If Kr is acting in the control of NB fate as in the Hb/Kr/Pdm/Cas cascade, Kr mutant NB clones should simply skip the Kr-dependent VA7l fate, resulting in the loss

of a single progeny neuron. In other words, VA7l-lacking Kr mutant NB clones should not carry any ectopic VA2 neurons, as observed in mutant www.selleckchem.com/products/bmn-673.html GMC clones. In support of this scenario, we confirmed that Kr mutant NB clones contain one lone VA2 adPN through visualizing specific adPN types using a sparse GAL4 driver ( Pfeiffer et al., 2008) ( Figure 4A). This is very different from the chinmo mutant NB clones in which loss of Chinmo-dependent adPNs was accompanied by an equivalent increase in the cell count of the next Chinmo-independent adPN type, leaving the lineage length unchanged VX-770 cell line ( Figure 4B). These observations indicate that Kr governs temporal fate transitions in the NB, whereas Chinmo acts in the offspring to refine neuronal temporal identity. We next examined how ectopic Chinmo or Kr might affect adPN development to assess their role as master genes for specifying temporal fate. Such gain-of-function experiments provide clues of their endogenous expression pattern, which is challenging to visualize in real time. In chinmo mutant NB

clones generated in first-instar larvae, expression of transgenic chinmo during neurogenesis effectively restored all the missing glomerular targets ( Figures S3C and S3D). Analogous induction also fully rescued chinmo mutant GMC clones ( Figure S3B). No gain-of-function

phenotype was observed, as ectopic Chinmo failed to elicit any late-to-early Adenylyl cyclase temporal fate changes in wild-type clones, even among those that normally acquire the D fate, the default fate for all the neurons born within the second Chinmo-required window ( Figures S3E and S3F). Use of various chinmo transgenes, including those expressed uniformly due to lack of the endogenous 5′ UTR, yielded identical outcomes ( Zhu et al., 2006). These results suggest that Chinmo promotes neuron diversity through collaborating with other temporal factors governed by NB temporal identity. By contrast, a transient induction of transgenic Kr severely perturbed adPN development. Single-cell clones, as well as the drastically reduced NB clones, no longer targeted dendrites to specific glomeruli; and their axons barely reached the LH (data not shown). Such rudimentary morphologies prevented any meaningful assessment of neuron types or temporal identity. To determine whether ectopic Kr can specify additional VA7l adPNs may require more sophisticated control over when, where, and at what level the Kr transgene should be induced.

Here, we explored the latter issue by recording the responses of

Here, we explored the latter issue by recording the responses of dlPFC neurons of two macaque monkeys during a task that yielded measurable changes in the animals’ behavioral performance at

filtering out a target from a distracter. The experimental design was based on the previous observation that when comparing the ranks of two stimuli within an ordinal scale (e.g., numbers or quantities), humans and monkeys respond faster and more accurately the greater the interstimulus ordinal distance (distance effect; Buckley and Gillman, 1974, Dehaene et al., 1998, Jou and Aldridge, 1999, Moyer and Landauer, 1967 and Nieder et al., 2002). We hypothesized that when monkeys select and sustain attention on a target stimulus that differs

in ordinal rank from a nearby distracter, changes in the animals’ ability to do so would be accompanied by corresponding changes in the cancer metabolism inhibitor activity of dlPFC neurons. We found that animals better detected changes in the target as the ordinal distance to the distracter increased (distance effect). More importantly, neurons in the dlPFC better filtered out the target from the distracter through their response rate as ordinal distance between the two stimuli increased. The latter effect was due to a gradual suppression of responses to distracters as a selleck kinase inhibitor function of ordinal distance to the target. We trained two adult monkeys (Macaca mulatta, Se and Ra) to hold gaze on a fixation spot at the center of a projection screen, and to attend to one of two moving random dot patterns (RDPs) appearing to the left and right of the spot. The dots in the two RDPs moved in the same direction

but differed in their color ( Figure 1). The attended mafosfamide (target) and ignored (distracter) RDPs were defined according to a color/rank-order selection rule (gray < pink < green < blue < red < turquoise). The animals were rewarded for releasing a button after a change in the target’s direction of motion while ignoring similar changes in the distracter (see Figure 1 inset and Experimental Procedures). Within 3–5 months of training, both animals reached stable performances in the task. First, we tested the hypothesis that they did so by learning, from the pattern of hits and errors, the position of the different colors in the ordinal scale according to our color/rank-order selection rule. As an alternative hypothesis, the animals may have learned, for each color pair, which RDP was the target and which one the distracter. The former hypothesis predicts a distance effect in the pattern of reaction times and proportion of correct button releases (hits). The latter predicts no systematic relationship between reaction time and proportion of hits, and rank/ordinal distance between the colors. In animal Se, we found that the hit rate ((number of hits − number of false alarms)/number of trials) increased (p < 0.

Log10 transformed frequency of each word was used to scale the er

Log10 transformed frequency of each word was used to scale the error derivatives. This level of frequency compression was employed to reduce the training time in this large model (Plaut et al., 1996). The error (difference between the target and the output patterns) was estimated with the cross-entropy method (Hinton, 1989). No error was backpropagated from a unit if the difference between

the output and the target was <0.1 (i.e., zero-error radius parameter was set to 0.1). Momentum was not used in this study. All the units in the hidden and output layers had a trainable bias link, except for the copy and Elman layers. Weights were initialized to random values between −1 and 1 (0.5 for recurrent connections). Weights Ruxolitinib nmr from the bias unit to hidden units were initialized at −1, so as to avoid strong hidden unit activation early in training (Botvinick and Plaut, 2006). A sigmoid activation function was used for each unit with activation ranging from 0 to 1. At the beginning of each trial, activations for all units in the hidden layer (including vATL-output layer) were set to 0.5, and for all units in the insular-motor output layer to zero. This work was supported selleckchem by an

MRC programme grant to M.A.L.R. (G0501632), a Royal Society travel grant to M.A.L.R. and S.S., and a Study Visit grant from the Experimental Psychology Society to T.U. T.U. was supported by an Overseas Research Scholarship (UK) and an Overseas Study Fellowship from the Nakajima Foundation (Japan). “
“Language processing depends not only on cortical regions, but also on the

white matter fiber bundles that connect them (Geschwind, PD184352 (CI-1040) 1965, Wernicke, 1874 and Friederici, 2009). Traditionally the arcuate fasciculus was considered to be the main pathway connecting frontal and temporal language areas (Geschwind, 1965). However, recent studies using diffusion tensor imaging (DTI) have revealed that frontal and temporal language regions are connected by multiple dorsal and ventral tracts. Dorsal tracts include not just the arcuate fasciculus, but also other branches of the superior longitudinal fasciculus (SLF) (Catani et al., 2005, Frey et al., 2008, Glasser and Rilling, 2008, Makris et al., 2005 and Makris and Pandya, 2009). Ventral tracts include the extreme capsule fiber system (ECFS), which connects the frontal operculum to mid-posterior temporal cortex, and the uncinate fasciculus (UF), which connects the orbitofrontal region to anterior temporal cortex (Anwander et al., 2007, Croxson et al., 2005, Frey et al., 2008, Friederici et al., 2006, Makris and Pandya, 2009, Parker et al., 2005 and Saur et al., 2008). Syntax is one important component of language and has been shown in functional imaging studies to depend on both frontal and temporal language regions (Bornkessel et al., 2005, Wilson et al., 2010a and Pallier et al., 2011).

In some experiments, the pipette solution included ∼0 1%–0 3% bio

In some experiments, the pipette solution included ∼0.1%–0.3% biocytin (Sigma). Alexa Fluor 488 or 594 fluorescence or biocytin labeling with immunoperoxidase reaction was used for post hoc verification of the localization of neurons along the proximodistal axis of CA3. Series resistance was <30 MΩ. CA3 neurons had resting membrane potentials between −60 and −76 mV (average: −68.0 ± 0.2 mV, n = 381). CA3PCs were usually kept at −68

to −72 mV, unless otherwise indicated. GSK1349572 molecular weight CA1 PCs were held at ∼−65 mV unless otherwise indicated. A dual galvanometer-based two-photon scanning system (Prairie Technologies) was used to image Alexa Fluor 488-loaded neurons and to uncage glutamate at individual dendritic spines (Losonczy and Magee, 2006, Losonczy et al., 2008 and Makara et al., 2009). Two ultrafast pulsed laser beams (Chameleon Ultra II; Coherent) were used, one at 920 nm for imaging Alexa Fluor 488 and the Fasudil price other at 720 nm to photolyze MNI-caged-L-glutamate (Tocris; 10 mM) that was applied through a puffer pipette with an ∼20- to 30-μm-diameter, downward-tilted aperture above the slice using a pneumatic ejection system (Picospritzer III [Parker Hannifin] or PDES-02TX [NPI]). Laser beam intensity was independently controlled with electro-optical modulators (Model

350-50, Conoptics). Local dendritic spikes were evoked by uncaging of MNI-glutamate at a spatially clustered set of visually identified spines (see also Supplemental Experimental

Procedures) with the highest synchrony our system allows, using 0.2 ms uncaging duration with 0.1 ms intervals between synapses (termed synchronous stimulation), unless otherwise indicated. For clarity, throughout the paper the term “Na+ spike” refers to local Na+ channel-mediated dendritic spikes, whereas the axosomatically generated spike is termed action potential or AP. Dendritic Na+ spikes were usually evoked using 5–20 synapses. NMDAR-mediated nonlinearity was measured in dendritic segments 61–193 μm (basal dendrites) or 152–315 μm (apical dendrites) from the soma. NMDA spikes were generated using 20–40 synapses activated synchronously (0.2 ms out uncaging duration and 0.1 ms intervals between synapses), except in some experiments (Figures 4G and 4H) in which longer intervals (1–5 ms) were used. To avoid variability in kinetic parameters of NMDA spikes due to distance-dependent distortion of voltage responses, we performed pharmacological experiments, spatiotemporal distribution experiments, and paired-pulse experiments exclusively on basal dendrites. For determining input-output function, the expected amplitude was calculated as the arithmetic sum of the physiologically sized unitary gluEPSPs at the given temporal input pattern. Unitary gluEPSPs were measured repeatedly (usually two to five times) interleaved with synchronous stimulations, using 205–420 ms intervals between the individual synapses (see also Supplemental Experimental Procedures).

1 varies substantially between different parts of the brain (Hoop

1 varies substantially between different parts of the brain (Hoopengardner et al., 2003). A recent study showed that the frequency of the I400V edit in the entorhinal cortex was four times higher in a rat model for chronic epilepsy, suggesting this site’s importance on brain function (Streit et al., 2011). Specifically how this edit affects neuronal

excitability, learn more and behavior, are the clear next questions. Many mRNAs besides GluA2 and Kv1.1 are edited in mammals, most of nervous tissue origin, prominently including functionally relevant sites in most AMPA and kainate receptor subunit transcripts. A functionally intriguing example centers on a second editing site in AMPA receptor subunit GluA2, termed the R/G site (Lomeli et al., 1994), which immediately precedes the alternatively spliced flip and flop modules within S2 of the bipartite

ligand binding PD-0332991 in vivo domain (Figure 1). The edit is also found in subunits GluA3 and 4. AMPA receptors containing subunits with edited R/G site (“G-form” subunits) possess faster recovery rates from desensitization than receptors containing unedited “R-form” subunits. This physiologically relevant functional distinction can be interpreted with the help of high-resolution structural data for the edited (Armstrong and Gouaux, 2000) and unedited (Greger et al., 2006) forms. It appears that the arginines at the unedited R/G site stabilize a subunit interphase, thus facilitating GluA2 receptor assembly and slowing entry into desensitization. Curiously, the enzyme ADAR2 edits its own primary transcripts, thereby producing an alternative splicing event (Rueter et al., 1999), which regulates ADAR2 levels (Feng

et al., 2006). A survey of the human brain transcriptome uncovered 38 recoding events (Li et al., 2009), many of which have been previously reported, and more recent screens suggest the number may be even higher (Li et al., 2011). For some of these targets, the effects of editing on protein function have been explored. For example, editing of the serotonin 5-HT2c receptor reduces the receptor’s affinity for its G protein (Burns et al., 1997), and editing Thiamine-diphosphate kinase of the GABA-gated Cl− channel subunit α3 affects gating kinetics, rectification, and trafficking (Daniel et al., 2011, Ohlson et al., 2007 and Rula et al., 2008). At present, the mechanistic details behind these effects are largely unknown and certainly provide fertile ground for further studies, as do the many yet to be explored editing sites. Unlike the case for mammals, where relatively few edited codons have been uncovered, recoding by RNA editing appears to be a surprisingly common event in higher invertebrates. As will be described in the upcoming sections, this assertion is based on two groups: fruit flies and squid. It should be noted that editing has been examined in detail in the relatively primitive C. elegans and, as far as we know, no recoding events have been found.

These abnormal firing patterns across the CxFn were effectively e

These abnormal firing patterns across the CxFn were effectively eliminated by STN-DBS. The simultaneous recording of spikes and LFP by the same recording channel also allowed us to study the coherence between them. The results showed that there was increased coherence level between spikes and local field potentials at beta band only in the 6-OHDA-lesioned hemisphere.

The significance of the increased coherence is unclear, but may contribute to bradykinesia and other movement suppression (Brown and Williams, 2005). Beta-band spike-field coherence may also represent excessive “stop” signals that underlie akinesia in PD (Swann et al., 2011). In this study, we also provided direct evidence of the occurrence of antidromic spikes in MI during the DBS paradigm. This finding Wnt antagonist supports previous studies using electroencephalogram (EEG) recordings

that STN-DBS results in the antidromic activation of motor cortex (Dejean et al., 2009; Li et al., 2007). In these studies, evoked wave in the EEG was correlated to the positive behavioral effects. In a recent study (Gradinaru et al., 2009), it was found that, while optogenetic stimulation of excitatory nerve terminals within STN was beneficial in improving Parkinsonian motor symptoms, optical inhibition or excitation confined to STN neurons was ineffective, learn more raising the possibility that antidromic activation of the cortico-STN pathway underlies the therapeutic

Phosphoprotein phosphatase mechanism. Our finding that the peak antidromic frequency generated coincided with the optimal effect of STN-DBS also supports this hypothesis. More importantly, we showed that an antidromic spike had a strong effect on the firing probability of the neuron immediately following it, and the increased mean firing rate during DBS was primarily the effect of antidromic spikes. Our results therefore provide the neurobiological basis of the recent findings that highlight the importance of cortex in mediating beneficial effect of STN-DBS. For example, by using the recorded activity to drive the stimulation, Rosin et al. (2011) showed that short trains of stimulation pulses were effective only if they were triggered from cortical activity, but not from the basal ganglia. Mure et al. (2012) showed that, in PD patients, the improved sequence learning with STN-DBS, but not with L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, was associated with increases in activity in supplementary and premotor cortices. In human PD patients, DBS of the internal globus pallidus (GPi) is also effective in alleviating Parkinsonian symptoms (Weaver et al., 2012). Whether a similar antidromic activation of the known cortex-GPi projection (Naito and Kita, 1994) contributes to the therapeutic effect of GPi-DBS remains to be studied.

However, funding for basic research is getting more difficult to

However, funding for basic research is getting more difficult to procure, discouraging young scientists from entering the field (Rohn, 2011). Also, given that academic success is measured largely by publications and scholarly awards, there is no easy path nor career incentives for researchers to accomplish translation. Furthermore, BTK inhibitor in vitro translational research by its nature entails

a high degree of risk (Figure 2) and requires milestone-based go/no-go decisions that can mean relinquishing exciting ideas, which is particularly difficult for basic researchers for whom ideas are often career identifiers. At the same time, lack of institutional funding for intellectual property (IP) investment and large lag times to generate IP, which delays publications, take a toll. When IP is generated, tech transfer is often inefficient, leaving IP to languish. Because of these inefficiencies, the number of products generated from promising basic research is disappointingly low, and researchers and academic institutions are not sharing in the CP-690550 supplier benefits of productive translation. Bold solutions are needed—for example, integrating interested researchers into translational teams so that they would spend a percentage of their time on a designated translational project, with commensurate (for time spent) funding for “blue

sky” research. This team-based DNA ligase model could work for government-led funding or within the context of private/public partnerships. Indeed, as pharmaceutical companies and biotech firms divest of in-house R&D arms, they are forming strategic academic partnerships to both capture IP and support research, and there is a growing list of companies in the stem cell space with CNS interests. Progress in such team approaches are exemplified by the NIH

U-funding mechanisms and the CIRM disease-team approach (Table 4). Stem cell research is one of the most rapidly developing areas of science and medicine. The explosive rise in discoveries and technologies that we see in the basic research labs has yet to enter the pipeline, and there is an enormous gap between what we can do at the bench and what we see in the current trials. While this is a constant source of frustration, the fact is that it means there is a lot to look forward to, as long as we can make the process of translation more efficient and affordable. Currently, the production of specific cell types from stem cells is conducted differently in individual labs, and in some cases protocols—typically complex, multistep, and lab-idiosyncratic—can be difficult to repeat. Furthermore, cell output is measured with relatively rudimentary characterization, raising concerns that cells produced for clinical trials might not be bona fide, or stable, or as pure as reported.

5 for a synapse activated at 47 μm in the dendrite, or 1 4 with d

5 for a synapse activated at 47 μm in the dendrite, or 1.4 with dendritic synaptic scaling (Figure 3F), a value closer to experimental results (Figure 6D). The simulated qEPSC PPR for dendritic synapses at 47 μm was 1.9 without dendritic scaling and 1.8 with scaling, showing that the conductance ratio (2.25) was underestimated even for quantal transmission (Figures 6B and 6D), and consistent with the observed 10% sublinearity for 2 quanta (Figure 5). The PPR was independent click here of Rm (data not shown), little affected by Ri and the number of branches (Figure 6D), but strongly dependent on dendrite diameter (Figure 6C). Moreover,

the distance dependence of simulated EPSP and qEPSP PPR (Figures S6E–S6G) was similar to experimental results (Figures 1K–1M). These findings indicate that the sublinear behavior of thin, passive selleck chemicals dendrites is sufficient to transform a spatially uniform

short-term plasticity of conductances into a gradient of short-term plasticity of synaptic potentials. In order to confirm the postsynaptic origin of PPR gradients along the somatodendritic axis, we compared somatic and dendritic AMPAR activation using glutamate uncaging. For all pEPSCs elicited in the soma, we adjusted the laser spot location in order to minimize the rise time and PPR (Figures S7A–S7E), thereby centering it on an AMPAR cluster (DiGregorio et al., 2007). A 30 μs laser pulse produced a mean somatic pEPSC amplitude similar to somatic qEPSCs (42 ± 2 pA; n = 12 cells; Figure 7A) but when delivered on their dendrites

produced pEPSCs that were twice the dendritic qEPSC amplitude (43 ± 5 pA; from n = 12). This difference is likely due to the higher density of synapses in dendrites (Figure 3E). As a final calibration, we increased the second laser pulse duration by 1.75 in order to mimic the average EPSC PPR for somatic synapses (Figure 1J). This produced a pEPSC PPR of 2.21 ± 0.08 at somatic locations that decreased to 1.35 ± 0.08 for dendritic locations (n = 12, p = 0.0005; Figure 7B). This PPR difference was observed for all laser pulse durations tested, consistent with a nearly linear increase in somatic pEPSC amplitude and a sublinear increase in dendritic pEPSCs (Figure 7C). This difference was not due to receptor desensitization or high receptor occupancy (Figures S7F–S7I). Taken together, the pharmacological experiments, numerical simulations, and direct AMPAR activation support the conclusion that sublinear postsynaptic properties are responsible for the apparent distance-dependent gradient in short-term plasticity. We next examined the spatial and temporal dependence of sublinear dendritic integration in order to determine how SCs might filter different spatial and temporal patterns of GC activity. pEPSPs elicited at 0.5 ms intervals by identical uncaging pulses produced a maximal sublinear summation of 15% ± 4% for uncaging spots 5 μm apart (n = 10 cells; observed versus expected, p = 0.004), 15% ± 3% when 10 μm apart (n = 9, p = 0.