The proposed activities are broadly interdisciplinary and will lead to the training of a new generation of scientists and the opening up of new strategies for evaluating pedagogical effectiveness. To succeed, the BAM Project needs two critical components: strong leadership from funding agencies and scientific administrators, and the recruitment of a large coalition of interdisciplinary scientists. We believe that neuroscience is ready for a large-scale functional mapping www.selleckchem.com/products/MDV3100.html of the entire brain circuitry, and that such mapping will directly address the emergent level of function, shining much-needed light into the “impenetrable jungles”

of the brain. This collaboration arose from a workshop held at Chicheley Hall, the Kavli Royal Society International Centre, supported by The Kavli Foundation, the Gatsby Charitable Foundation, and the Allen Institute for Brain Science. We also thank A.S. Chiang, K. Deisseroth, S. Fraser, C. Koch, E. Marder, O. Painter, H. Park, D. Peterka, S. Seung, A. Siapas, A. Tolias, and X. Zhuang—participants at a smaller, subsequent Kavli Futures Symposium, where initial ideas were jointly refined. We acknowledge support from Selleckchem Cabozantinib the DOE (A.P.A.), NHGRI (G.M.C.), NIH and the Mathers Foundation (R.J.G.), NIH

and Fondation pour la Recherche et l’Enseignement Superieur, Paris (M.L.R.), and the Keck Foundation and NEI (R.Y.). A more extensive version of this paper and additional documents about the BAM can be found at http://hdl.handle.net/10022/AC:P:13501. “
“Movement is generated by the activity of neuronal circuits collecting and integrating information, ultimately leading to precisely timed skeletal muscle contractions.

Work over many years has demonstrated that the most motor control system exhibits a multitude of interleaved layers of organization. It produces an enormous repertoire of behaviors including routine actions such as walking, as well as sophisticated movements like playing a violin or dancing. Independent of the action type performed, the interplay of three main components is important and adds modularity and flexibility to the system. First, neurons with projections confined to the spinal cord are essential to produce rhythmic and patterned motor activity as well as to support many other activities (Jankowska, 2001, Kiehn, 2011 and Orlovsky et al., 1999). These include highly diverse neuronal populations globally referred to as spinal interneurons. Second, spinal circuits are dependent on interactions with supraspinal centers in brainstem and higher brain areas (Grillner et al., 2005 and Orlovsky et al., 1999). Communication is bidirectional and includes many descending and ascending channels intersecting with local spinal circuits. Third, sensory feedback systems constantly monitor consequences of motor action (Brown, 1981, Rossignol et al., 2006 and Windhorst, 2007).

Altogether, one begins to appreciate that, although the combinatorial possibilities for circuit modulation are vast, our ability to map circuits involved in neuromodulation in the context of behavior is rapidly leading

to a functional understanding of the brain. Although refinement of the electrical this website properties of individual neuronal cell types and their modulation by small molecules must contribute substantially to the number of distinct types of neurons in any animal, the amazing histological diversity of the mammalian brain discovered more than a century ago (Ramon y Cajal, 1899), remains unsettling. Expression profiling experiments of specific cell types has established that cell-surface proteins that generate or modulate neuronal activity and the transcription factors that regulate their expression are among the most important determinants of neuronal identity (Toledo-Rodriguez and Markram, 2007, Okaty et al., 2009 and Doyle et al., 2008). However, the profile of cell-specific genes expressed by any given neuron type also includes a wide variety of proteins of unknown function and others that fine tune the biochemistry of that cell type (Heiman et al., 2008 and Doyle et al., 2008). For example, among the most specifically expressed genes in cerebellar Purkinje cells are two

carbonic anhydrases (Car7 click here and Car8), two centrosomal proteins (Cep76 and Cep72), a glucosyltransferase (b3gnt5), a ceramide kinase (Cerk), a subtilisin-like preprotein converstase (Pcsk6), and a whole host of encoding mRNAS of unknown function (1190004E09Rik, 2410124H12Rik, etc.). Although simple hypotheses can be formulated for many of the individually expressed

proteins, we do not understand the properties conferred upon Purkinje cells (or any other neuron type) by the unique ensemble of genes whose expression is enriched in them. Nevertheless, we suspect that the evolution of such a rich variety whatever of specialized neuronal cell types must be driven in part by the requirement for unique biochemical functions that we have yet to understand. The past 20 years have seen broad inroads made in our understanding of the development of neurons in all regions of the nervous system of both invertebrates and vertebrates. The invariant lineages that give rise to the 302 neurons in nematodes (Hobert, 2010) and the stereotyped iterative production of Drosophila neurons derived from sensory organ precursors, the ventral nerve cord, and the ommatidia during embryonic development have been particularly informative ( Jukam and Desplan 2010). Studies in these systems have provided a context for understanding how the broad classes of intrinsic and local determinants such as proneural genes and homeodomain proteins direct cell fate. Vertebrate studies have complemented this, most notably, those of the spinal cord, retina, and cerebral cortex of mammals.

, 2009). From sequencing adjacent linked polymorphisms in children and parents, we infer that on the order of 3/4 of new point mutations (50 of 67) derive from the father’s germline. Although we have less data, this conclusion holds as well for de novo small indels (6 of 7). These data confirm the paternal line is the main source for these types of new human variation. The data also indicate that the majority of the de novo calls in this study are not somatic in origin, but occur prior to conception. We infer this by assuming that after zygote formation, the mother’s and father’s genomes are equally vulnerable to subsequent somatic

mutation. selleck inhibitor By contrast, a previous study indicated that for de novo copy number variation both parents contribute almost

equally (Sanders et al., 2011). We observe very few cases where two siblings share the same de novo mutation, about one for every fifty occurrences, suggesting BMS-354825 concentration that the parent is rarely a broad mosaic. However, this conclusion could be an ascertainment bias, because our operational identification of “de novo” precludes observing the mutation in the parent at levels higher than expected from sequencing error. As presented, we do observe some evidence of parental mosaicism, and this is a subject of ongoing scrutiny using enhanced statistical modeling and validation. Finding the correct contribution from each genetic mechanism is critical for understanding the nature of the factors causing autistic spectrum disorders. Adding the 6% differential for large-scale

de novo copy number mutation previously observed (Levy et al., 2011 and Sanders et al., 2011) to the 10% differential for LGDs, we reach a total differential of 16% between affected children and siblings. This is far less than our predictions, based on modeling the AGRE population (Zhao et al., 2007), that causal de novo mutations would occur in about 50% of the SSC. This gap could be attributable to having modeled a more severely affected population. The SSC is skewed to higher functioning cases with a male to female ratio of 6:1 (Fischbach and Lord, 2010), so there may be more borderline cases in that collection than in the AGRE collection (male to female ratio of 3:1), from which we built our model (Zhao et al., 2007). But our Adenosine differential must underestimate the contribution from de novo events. First, we use extremely stringent criteria meant to eliminate false positives, and we fail to detect many true positives as a consequence. Second, even among the de novo events we do observe, we may be missing gene-disruptive events, for example, mutations outside the consensus that disrupt splicing and in-frame indels that disrupt the spacing of the peptide backbone. It would not be unlikely to miss even a 5% differential from de novo missense mutation in a study of this size, given the high background rate of neutral missense mutation. Third, our coverage of the genome is incomplete.

One barrel column in vS1 projects to a band of vM1, with its long axis in the anterior/posterior (A/P) direction (Aronoff et al., 2010). vM1 projects diffusely to vS1, covering most of the barrel field and adjacent areas (Veinante and Deschênes, 2003). Reciprocal cortical connections have also been detected in neurophysiological recordings in vivo. Following the deflection of a whisker, excitation first ascends into vS1 and then rapidly propagates to vM1 (Farkas et al., 1999, Ferezou et al., 2007 and Kleinfeld et al., 2002). Neuronal activity in vS1 is modulated

by whisking (Curtis and Kleinfeld, 2009, de Kock and Sakmann, 2009, Fee et al., 1997 and O’Connor et al., 2010b), mediated in Selleckchem BTK inhibitor part by an efference copy-like signal originating in vM1 (Ahrens and Kleinfeld, 2004 and O’Connor et al., 2002). Integrating signals related to whisking and whisker deflection might underlie object localization (Curtis and Kleinfeld, 2009 and Diamond et al., 2008). The detailed neural circuits underlying the vS1 ←→ vM1 loop are poorly understood. A circuit

diagram, based on functional connections between defined cell types, might reveal the primary loci where sensorimotor associations are formed. In addition to the connectivity between cell types, the interactions between neurons in vS1 and vM1 depend on the locations of synapses within the dendritic arbors of the postsynaptic neurons (Larkum et al., 2004 and London and Häusser, 2005). Anatomical methods, relying on visualizing axons and dendrites with light microscopy, have often been used to predict circuits (Binzegger et al., BIBF 1120 mouse 2004, Meyer et al., 2010a and Shepherd et al., 2005). However, axodendritic overlap is not necessarily a good predictor of functional connection strength (Callaway, 2002, Dantzker and Callaway, 2000, Petreanu et al.,

DNA ligase 2009, Shepherd et al., 2005 and White, 2002). Alternatively, electrophysiological methods that detect functional synapses, including paired recordings and glutamate uncaging-based methods, have been applied to map local circuits within vS1 (Bureau et al., 2006, Hooks et al., 2011, Lefort et al., 2009, Lübke and Feldmeyer, 2007, Schubert et al., 2003, Schubert et al., 2006, Shepherd et al., 2003, Shepherd et al., 2005 and Shepherd and Svoboda, 2005) and vM1 (Hooks et al., 2011). These techniques require the preservation of pre- and postsynaptic neurons and their axonal processes within a brain slice and are thus mostly limited to local circuits (Luo et al., 2008). Although a subset of long-range connections between vS1 and vM1 can be preserved in brain slices (Rocco and Brumberg, 2007), it is unclear how complete the preserved circuit is. We previously applied subcellular Channelrhodopsin-2-assisted circuit mapping (sCRACM) to chart the connections made by long-range projections onto vS1 neurons (Petreanu et al., 2009).

, 1999), further confirmed by the lack of Oxs/Hcrts this website in several individuals afflicted with narcolepsy ( Nishino et al., 2000). The mode of action of Ox/Hcrt system on sleep an arousal has been investigated (Figure 2). From the afferent side, it is known that the preoptic area, especially the ventrolateral

preoptic nucleus (VLPO), plays a critical role in the initiation of nonrapid eye movement (NREM) sleep and maintenance of both NREM and rapid eye movement (REM) sleep (Sherin et al., 1998). Neurons in the VLPO fire at a rapid rate during sleep and slow down during the waking period. These neurons contain GABA and/or galanin and promote sleep. GABAergic neurons originating in the preoptic area densely innervate Ox/Hcrt neurons (Sakurai et al., 2005; Yoshida et al., 2006). The orexin neurons are inhibited by activation of the GABA system (Xie et al., 2006; Yamanaka et al., 2003). These observations therefore suggest that VLPO neurons send GABAergic projections to orexin neurons to turn off orexin neurons during sleep. From the efferent side, it has been shown that Ox/Hcrt neurons innervate wake promoting centers such as the noradrenergic neurons of the locus coerulues (LC), the serotonergic neurons of the dorsal raphe (DR) and the histaminergic Sirolimus neurons of the tuberomammilary nucleus of the hypothalamus (TMN) (Saper et al., 2005; Figure 2). These monoaminergic neurons are synchronized and modulate sleep/wake

states. They fire tonically during the awake state, less during NREM sleep, and not at all during REM sleep

(Lee et al., 2005; Vanni-Mercier et al., 1984). Ox/Hcrt neurons discharge during active waking and virtually cease firing during sleep, including the NREM and REM periods (Lee et al., 2005) and thus should exert an excitatory influence on the wake-active neurons and help them sustain their activity. In addition, Methisazone Ox/Hcrt neurons project to laterodorsal tegmental nucleus/pedunculopontine nucleus (LDT/PPT) cholinergic neurons and affect the activity of these neurons in wakefulness and REM sleep. Finally, the Oxs/Hcrts neurons project and excite the cholinergic neurons of the basal forebrain (BF), which also regulate arousal. All together these data point at the Ox/Hcrt system as a central modulator for the maintenance of wakefulness. When dysfunctional it is a primary cause of the narcolepsy-catalepsy syndrome. At the onset of puberty, neurons in the medial preoptic area of the hypothalamus initiate the pulsatile secretion of gonadotropin releasing hormone (GnRH), which reaches the pituitary gland where it stimulates the release of the gonadotopic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones in turn act on the gonads to stimulate synthesis of the sex steroids, which are required for spermatogenesis and oogenesis. The mechanism that initiates the pulsatile secretion of GnRH at puberty was unknown.

, 2010 and McDonald and Rosbash, 2001). Taken together with the data showing that Mef2 is a direct target of the CLK/CYC complex ( Figure 5A), the mRNA enrichment and restricted cycling suggest that CLK binding to the Mef2 promoter is spatially limited and includes PDF neurons. Mef2 is also important for the activity-dependent plasticity of s-LNv neuron morphology (Figure 2A). It is notable that the effect of firing on s-LNv morphology fits with the reported increase of s-LNv electrical activity around lights-on (Cao and Nitabach, 2008); this is when the open

conformation of the s-LNv dorsal projections is normally observed. click here Although neuronal firing may affect core circadian oscillator function to influence these circadian morphological changes, we prefer the interpretation that it acts primarily downstream to influence Mef2 transcriptional activity and possibly Mef2 levels as shown in mammalian and amphibian experiments (Chen et al., 2012 and Cole et al., 2012). Alternatively, firing may modulate Mef2 activity via posttranslational modification

(Flavell et al., 2006 and Shalizi et al., 2006). To identify Mef2 target genes, we performed check details ChIP-Chip analysis on fly head chromatin. Mef2 binding undergoes circadian cycling, and among its top targets are genes relevant to neuronal function, axonal fasciculation, and cell adhesion. These include the gene encoding the NCAM homolog Fas2 as well as genes implicated in various aspects of axonal cytoskeleton dynamics, which influence both actin (e.g., Ptp61F, fray, sif, Sema-1A, and the Profilin homolog chickadee)

and microtubules of (Fmr1 and tau). Like Mef2, Fas2 and some other genes involved in cytoskeletal dynamics have cycling mRNAs in purified Drosophila PDF neuron RNA but not in whole-head RNA ( Kula-Eversole et al., 2010 and Nagoshi et al., 2010). The contribution of axonal fasciculation to circadian changes in s-LNv morphology was originally proposed (Fernández et al., 2008) based in part on the circadian regulation of cell adhesion molecules in adult Drosophila ( Ceriani et al., 2002 and McDonald and Rosbash, 2001). However, it is possible that the circadian morphological changes of PDF axons reflect additional mechanisms, including changes in axonal sprouting and retraction as well as fasciculation. The extreme truncated phenotype of Fas2 overexpression makes some contribution from sprouting retraction likely. In any case, Fas2 overexpression clearly rescues the Mef2 overexpression phenotype ( Figure 3). We interpret the failure of Fas2 overexpression to allow circadian morphological changes in an otherwise wild-type background to be due to excess Fas2. Mef2 overexpression should reduce endogenous Fas2 levels, which may bring overall Fas2 into a biologically acceptable range.

In the current study, the efficacy of three major by-products of ISM synthesis was compared to purified ISM, as well as the commercial products, Veridium® and Samorin®.

For the first time, the red and blue isomers and the disubstituted compound were synthesised, purified by HPLC and tested individually for trypanocidal activity against T. congolense and T. b. brucei in vitro, in addition to analysis of trypanocidal and prophylactic activity against T. congolense in vivo. Analysis of trypanocidal activity in Tanespimycin supplier vitro necessitated the development of a 96-well sensitivity test to determine IC50 values of the individual compounds. T. congolense IL1180, T. congolense IL3000 (kindly provided by the International Livestock Research Institute, Nairobi, Kenya)

and T. b. brucei Antat 1.1 strains were used for this study. T. congolense IL3000 and T. b. brucei Antat 1.1 bloodstream forms were used since the cultures of these strains are standardised ( Baltz et al., 1985 and Coustou et al., 2010). T. congolense Selleckchem EGFR inhibitor IL1180 was used for in vivo sensitivity tests since it causes a chronic infection in mice ( Coustou et al., 2010) and was previously used as a reference drug-sensitive strain for Samorin® uptake studies ( Peregrine et al., 1988) since it is ISM sensitive ( Hirumi, 1993). Isometamidium (M&B 4180A), the blue isomer (M&B almost 4250), red isomer (M&B 38897) and disubstituted compound (M&B 4596) were synthesised and purified by Provence Technologies SAS (Hôtel Technologique-BP100, Technopôle de Château-Gombert, 13382 Marseille Cedex 13-France). The compounds were analysed, and structures confirmed by LC/MS (M+) and NMR (1H and 13C). Respective purities were 99.7%, 97.6%, 95.4% and 97.9% for ISM, the blue isomer, red isomer and disubstituted compound. Veridium®, Samorin® and the compounds were dissolved in distilled water (10 mg/ml)

and stored at −20 °C. For in vitro drug sensitivity tests, drugs were subsequently diluted in the trypanosome culture medium. Prior to the drug sensitivity tests, observation of the general growth patterns of T. congolense IL3000 and T. b. brucei Antat 1.1 in 96-well plates for 72 h established that an inoculum of 4000 cells was optimal for exponential growth for 48 h. Parasites, counted using a haemocytometer (4000/well, 100 μl), were added to 96-well plates and incubated at 34 °C (T. congolense) or 37 °C (T. b. brucei) with 4% CO2 for ∼4 h before addition of drugs. The drugs were initially dissolved in water (10 mg/ml) and serial dilutions made in culture media (1:10). Each dilution of drug (100 μl) was added to 100 μl of culture in wells (duplicates were made for each dilution from 1 mg/ml until 1.10−19 mg/ml). Subsequently, parasites were cultivated under the aforementioned conditions for 24 and 48 h.

Other important factors have been the exploitation HTS assay of approaches derived from economic decision-making theory that have proven useful in guiding investigation of the ways in which reward value is represented in the

brain (Plassmann et al., 2007 and Glimcher et al., 2009) and other formal and computational descriptions of reward-guided learning and decision-making (Doya, 2008, Lee, 2008, Platt and Huettel, 2008 and Rangel et al., 2008). Rather than attempting another survey of these recent trends the aim of the current review is to focus more specifically on the role of frontal cortex in reward-guided behavior. It is proposed that current evidence suggests at least four frontal cortex regions can be identified with distinct roles in reward-guided behavior: ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex (vmPFC/mOFC), lateral orbitofrontal cortex (lOFC), anterior cingulate

cortex (ACC), and a lateral anterior prefrontal cortex (aPFC) region in, or at least adjacent to, the lateral part of the frontal pole (Figure 1). In reviewing the functions of these areas we draw on work conducted not only with human subjects but also with animal models for which more precise details of neuroanatomical connections and neurophysiological mechanisms are available. In addition to highlighting points of convergence between the studies of various researchers we also note outstanding debates and points of controversy. The human vmPFC/mOFC has perhaps been the most intensively studied frontal cortical area in investigations of reward-guided decision-making. Functional magnetic resonance imaging (fMRI) measures http://www.selleckchem.com/products/PD-0332991.html ADAMTS5 a blood oxygen level-dependent (BOLD) signal that reflects aspects of underlying neural activity. The correlation between the BOLD signal and behavior or between the BOLD signal and internal states of subjects that can be inferred from behavior

is examined. A widely replicated finding is that the vmPFC/mOFC BOLD signal is correlated with the reward value of a choice. There is agreement about some aspects of the location of the vmPFC/mOFC area that represents reward value but uncertainty about others. On the one hand, studies from many laboratories have identified reward-related signal changes at similar positions in the standard coordinate systems used for reporting fMRI results. The focus lies in the vicinity of the rostral sulcus, ventral and anterior to the rostrum of the corpus callosum on the medial surface of the frontal lobe. The activations extend onto the medial orbital gyrus and sulcus (Beckmann et al., 2009). On the other hand, exactly what name the area should be given has been less clear. Beckmann et al. (2009) used diffusion-weighted magnetic resonance imaging (DW-MRI) to estimate the anatomical connectivity of medial frontal cortex and then used these estimates to parcellate the cortex into regions, each with different connectivity patterns.

91 showed that sacroiliac joint dysfunction may also be a risk factor. However, similar to many previously discussed risk factors, the scientific basis of these proposed risk factors is not clear. Hamstring strain injury is one of the most common sports injuries that have significant effects on patients’ quality of life and sports career. The high recurrence rate and serious consequences of this injury have not been fully recognized. Basic science studies have demonstrated that the excessive strain during an eccentric contraction is the general

mechanism of muscle strain injury, and that the severity of the injury is affected by the eccentric contraction speed when the muscle strain find protocol is large and by the duration of activation before the eccentric contraction. In vivo studies CHIR-99021 datasheet demonstrated that hamstring injury is likely to occur during the late swing phase of sprinting when the knee is extending and the hip is flexed and during the late stance phase before takeoff when knee is extending and the trunk is

leaning forward. Many risk factors including poor flexibility, strength imbalance, insufficient warm-up, and fatigue have been proposed as risk factors for hamstring strain injury. Basic science studies have established the connections between muscle strain and strain injury, muscle optimum length and muscle strain, and flexibility and muscle optimum length, which support poor flexibility and insufficient warm-up as risk factors for hamstring strain injury. However, the theoretical basis of hamstring strength imbalance however and other proposed risk factors for hamstring strain injury is lacking. Many clinical studies have been conducted in attempts to provide clinical evidence

to support the proposed risk factors. However, the results of those clinical studies are descriptive and controversial. Clinical evidence for current prevention and rehabilitation programs for hamstring injury is lacking. Future studies are needed to improve the prevention and rehabilitation of hamstring strain injury, particularly randomized controlled trials, in order to establish the cause-and-effect relationships between those proposed risk factors and hamstring strain injury. Future clinical research should consider the interaction effects of multiple risk factors on the risk of hamstring strain injury. Clinical studies on risk factors and prevention and rehabilitation programs should be based on the injury mechanisms established in basic science studies. Evidence-based prevention and rehabilitation programs for hamstring strain injuries can be developed only after risk factors of the injury have been scientifically identified, confirmed, and understood through well-designed basic science and clinical studies. “
“Ankle sprains are common injuries that occur during physical activity, and this pathology has been linked to health impairments.

, 2010b). Indeed, it has been observed that CXCR7 is normally localized intracellularly and that it rapidly shuttles between the cell surface and intracellular compartments (Luker et al., 2010). Over the years the group of investigators represented

by Wang et al. (2011) have carefully defined the mechanisms by which the different populations of cortical GABAergic interneurons develop from their germinal zones. For example, progenitor cells localized in the medial ganglionic eminence (MGE) express a variety selleck products of transcription factors that can be used to trace their migration and development. Deletion of the transcription factor Lhx6 from the pool of MGE progenitors substantially disrupts their normal path of migration into the cortex. An important question therefore is what are the genes downstream of such transcription factors that mediate the actual mechanics of interneuron migration? Previous SCH 900776 datasheet publications have demonstrated that Lhx6 helps to control the expression of CXCR4 by migrating progenitors and that CXCR4 and Lhx6 knockout mice show similar defects in interneuron migration (Zhao et al., 2008). At the time when interneuron progenitors migrate from the

MGE, CXCL12 is expressed in two locales in the developing cortex .The chemokine is strongly expressed in the meninges and also in a deeper location that corresponds to the subventricular zone (SVZ)/intermediate zone (IZ).CXCR4-expressing progenitors in the MGE form migratory streams attracted by these sources of CXCL12 and normally populate the marginal zone (MZ) and SVZ (Tiveron et al., 2006). Disruption of CXCR4 signaling causes a failure of migrating interneurons to populate their normal destinations and results in overpopulation of the cortical plate (CP) region from which they are normally excluded. Early studies on the phenotypes of CXCR7 knockout mice did not report any abnormalities in nervous Thymidine kinase system development. However, the abundant expression of CXCR7 in the developing brain suggested that phenotypes might well be observed on closer inspection (Schönemeier et al., 2008). Indeed, the papers by Wang

et al. (2011) and Sánchez-Alcañiz et al. (2011) both demonstrate that not only is CXCR7 coexpressed with CXCR4 in migrating MGE progenitors but also that deletion of CXCR7 produces a phenotype that appears virtually identical to that observed in CXCR4 deficient mice. In both CXCR4 and CXCR7 mutants, migrating Lhx6-expressing progenitors exhibit reduced tangential and increased radial migration resulting in their enhanced positioning in the CP at the expense of the MZ or SVZ. Such observations suggest that CXCR4/CXCR7 may cooperate in regulating interneuron migration—but how? Wang et al. (2011) make several important observations that help in answering this question. In one experiment, they ectopically expressed CXCL12 in the cortex of control or mutant mice.