Copulation typically lasts ∼20 min (Jagadeeshan and Singh, 2006). For the first several minutes of this period, wild-type pairs may move forward or adjust positions, but for the remainder of this time the flies remain essentially motionless. Copulation in prt1 mutants differs dramatically. Similar to wild-type flies, prt1 males mount the female and curl their abdomen to begin copulation. However, after coupling, the

prt1 male continuously struggles to maintain his orientation and can be seen in a variety of different positions relative to the female ( Figure 6B, bottom pictures; Movie S2). We quantified the amount of time that prt1 http://www.selleckchem.com/products/GDC-0449.html males spent in a position distinct from that usually seen in wild-type flies as a percentage of the total copulation duration ( Figure 6C). Whereas CS flies primarily remain centered on the dorsal abdomen of the female, prt1 flies spent nearly half of copulation severely misaligned. Although the genitalia of the male and female remain in contact, the male can be positioned perpendicular AZD8055 to the normal

axis or rotated nearly 180° from horizontal. Moreover, during copulation, prt1 mating pairs move about the observation chamber, with the female dragging the male behind. In cross-genotype mating experiments, prt1 males mated to CS females showed defective copulation, whereas CS males mated to prt1 females did not ( Figure 6C). Thus, the prt1 males were primarily, if not exclusively, responsible for the defect in copulation. To determine whether the change in the males’ position was due to a defect in genital morphology, we examined both the prt1 male and female genitalia using scanning electron microscopy. We found that the external genitalia of prt1 males and females were indistinguishable from wild-type ( Figures S3D and S3E). We also examined the prt1 males’ sex combs, specialized foreleg structures used to grasp the female

during copulation ( Ahuja and Singh, 2008 and Ng and Kopp, and 2008). The morphology of prt1 sex combs was intact in scanning electron micrographs ( Figure S3F), without obvious gaps between bristles, although the number of bristles in the prt1 sex combs was slightly lower than controls ( Figure S3G; Ahuja and Singh, 2008 and Tokunaga, 1961). We employed deficiency analysis to help determine the severity of the prt1 sexual phenotype ( Figure 6D). Two deficiency lines that uncover the prt locus were used, and the extent of their chromosomal deletions is represented in Figure 4A. The copulatory phenotype seen in the prt1 homozygote was replicated in both the prt1/Df(3R)mbc-30 and prt1/Df(3R)Exel6195 transheterozygotes ( Figure 6D). It is possible that the prt1 copulation phenotype cannot get measurably worse, and further deficiency analysis using other aspects of the prt1 phenotype will be necessary to more precisely assess the severity of the prt1 allele.

As expected, the average NMDAR-EPSC decay times (τw) recorded from Cre-expressing cells from ΔGluN2A mice were significantly slower than cells from ΔGluN2B mice and control cells. Importantly, decay rate was not affected by the amplitude of the NMDAR-EPSC, indicating effective space clamp (Figure S1B). Normalizing and aligning the traces at the stimulus onset (Figure 1D) shows that NMDAR-EPSCs from ΔGluN2B cells have a significantly www.selleckchem.com/products/BAY-73-4506.html faster

rise than ΔGluN2A cells, with control cells intermediate. These results are consistent with rise times and decays previously described for diheteromeric GluN1/GluN2A and GluN1/GluN2B receptors in heterologous systems (Vicini et al., 1998) and suggest that the Cre-expressing cells have pure diheteromeric populations of synaptic NMDARs. Since GluN2C and GluN2D subunits have lower sensitivity to Mg2+ blockade compared with GluN2A and GluN2B subunits (Monyer et al., 1992), we examined the voltage-dependent Mg2+ sensitivity of the NMDAR-EPSCs in Cre-expressing ΔGluN2A and ΔGluN2B cells. As shown in Figure 1E, there is a high level of voltage-dependent Mg2+ block in Cre-expressing ΔGluN2A and ΔGluN2B cells that was indistinguishable from control

cells, further excluding a measurable contribution of diheteromeric GluN2C- or GluN2D-containing NMDARs. Previous studies have shown that the decay rate of NMDAR-EPSCs is voltage-dependent in the absence of Mg2+ (Hestrin, 1992 and Konnerth et al., 1990) and that early in development (<5 weeks) the decay is slower at positive potentials while CHIR-99021 chemical structure in older mice the decay is faster at positive potentials (Kirson and Yaari, 1996). This developmental switch in the direction of voltage-dependent decay rate may be related

to GluN2 subunit composition. However, as shown in Figure 1F, NMDAR-EPSC decay kinetics are slower at positive holding potentials regardless of subunit composition. Studies in heterologous systems have suggested that the probability of NMDAR opening in response to glutamate is dependent on the GluN2 subunit composition, with GluN2A imparting a higher open probability (PO) than GluN2B (Chen et al., 1999 and Erreger et al., 2005). However, the differential effect of GluN2 subunits on NMDAR open probability has been challenged by previous work in neurons (Chavis and Westbrook, 2001 and Prybylowski whatever et al., 2002). Using the pure diheteromeric GluN1/GluN2A and GluN1/GluN2B synaptic populations, we assessed NMDAR open probability using MK801, an open channel blocker that is effectively irreversible and has been used to estimate PO (Huettner and Bean, 1988 and Jahr, 1992). For each recording, a stable NMDAR-EPSC was obtained, stimulation was stopped for 10 min as 40 μM MK801 was perfused onto the slice, and then stimulation was restarted (Figure 2A). A greater rate of MK801 block was seen with ΔGluN2B than with ΔGluN2A (Figure 2B), suggesting a higher PO in the absence of differences in the presynaptic release probability (see Figure 5D).

A positive d′ in both conditions indicates units/sites that retained their preference in the BFS, while a negative d′ in the BFS condition indicates units/sites that fired more when their preferred stimulus was perceptually suppressed. Statistically significant modulations for each unit/site were identified by using a Wilcoxon rank-sum test to compare the two response distributions (consisting of the total number

of spike counts from t = 1,001–2,000 for the preferred and the nonpreferred stimuli, across all trials). Where appropriate, p values were corrected (and converted to q values) using the FDR method ( Benjamini & Hochberg (1995)). The PSD of the raw LFP signals from t = 1,001 to t = 2,000 ms was estimated using the multitaper method (Thomson, 1982). This method uses linear or nonlinear combinations of modified periodograms to estimate the Autophagy inhibitor datasheet PSD. These periodograms

are computed using a sequence of orthogonal tapers (windows in the frequency domain) specified from the discrete prolate spheroidal sequences. Selectivity of spectral power was computed using the d′ for narrow frequency bins of 1 Hz (d′sensory LFP and d′perceptual LFP) for sites where MUA exhibited significant sensory selectivity. Time frequency analysis was carried out by computing a spectrogram in each trial using overlapping (94%) 256 ms windows and then averaged across all trials. This study was supported by the Max Planck Society. Dabrafenib mouse We thank Drs. Andreas Tolias, Christoph Kayser, Kevin Whittingstall, and Michel Besserve for helpful discussions and comments on a previous version of the manuscript. Joachim Werner and Axel Oeltermann

provided excellent technical support. “
“Motor-sequence learning refers to the process by which temporally ordered movements are prepared and executed with increasing speed and accuracy (Willingham, 1998). For this type of learning to occur, the processing demands associated with the rapid planning of multiple serial movements within a sequence must be reconciled. The traditional notion is that the individual motor commands that constitute new sequences SPTLC1 become temporally integrated into elementary memory structures or “chunks” (Gallistel, 1980, Lashley, 1951 and Book, 1908). Chunking in motor sequencing allows groups of individual movements to be prepared and executed as a single motor program facilitating the performance of complex and extended sets of sequences at lower cost (Halford et al., 1998). The grouping of distinct elements into a single unit is a general performance strategy that is also observed in nonmotor tasks (Gobet and Simon, 1998 and Ericsson et al., 1980).

The initial contacts between axons and dendrites are mediated by specific adhesion-related proteins, such as neurexin and neuroligin (e.g., NRXN1 and NLGN3, genes perturbed by rare de novo CNVs associated with ASD are underlined here and below) ( Südhof, 2008). On the postsynaptic side of an excitatory synapse, the initial axon-dendrite contacts ultimately develop into a complex and dense structure, the postsynaptic density (PSD), dominated by several types of glutamate receptors (such as AMPA and NMDA), various scaffolding proteins (DLG4/PSD95, DLG2, SHANK2/3,

SynGAP1, DLGAP2) and trafficking/signaling proteins (CTNND2). In total, the PSD contains many hundreds of distinct Alisertib clinical trial proteins ( Bayés et al., 2011 and Sheng and Hoogenraad, 2007). Information for activity-dependent regulation of spine morphology is passed through an intermediate level of signaling protein, such as Rho family ( Linseman and Loucks, 2008) of small GTPases (RhoA/B, Cdc42, Rac1) to downstream targets (LIMK1 and PAK1/2/3) connected to proteins modifying morphology of the actin network (cofilin and Arp2/3) ( Blanchoin et al., 2000). The activity of the GTPases is regulated pre-

or postsynaptically by many guanine exchange factors (GEFs), GDP dissociation inhibitors (GDIs, such as GDI1) and GTP-activating PF-01367338 cell line proteins (GAPs). Many other proteins shown in Figure 3, such as FLNA, CTNNA3, DOCK8, SPTAN1, CYFIP1, either bind directly to the actin network or mediate interaction of actin filaments with other proteins. The WNT signaling pathway plays a crucial role in diverse processes associated with formation of neural circuits (Salinas and Zou, 2008). This pathway is also known to be directly involved in the regulation of dendrite morphogenesis (Rosso et al., 2005 and Salinas et al., 1994). WNT signaling Megestrol Acetate is accomplished through the canonical branch (DVL, AXIN1, beta-catenin) and the noncanonical branch (DVL1/2/3, Rac1, and JNK); both of these pathway branches converge on regulation of actin network morphogenesis.

Similar to WNT, the reelin signaling also plays a prominent role in the context of autism phenotype and specifically dendritic spine morphogenesis ( Fatemi et al., 2005 and Niu et al., 2008). Signaling by secreted extracellular RELN protein acts though VLDR and Apoer2 receptors and the PI3K/Akt pathway ( Jossin and Goffinet, 2007) regulating the mammalian target of rapamycin (mTOR) pathway ( Kumar et al., 2005 and Shaw and Cantley, 2006). Another important pathway converging on mTOR involves MAPK3/ERK, which can be activated by Ras and NF1. mTOR integrates various inputs from upstream growth-related pathways, and is also known to regulate dendrite morphogenesis ( Tavazoie et al., 2005).

A second subtype of glia, referred

to as Drosophila astrocytes, extends cellular processes deeply into the neuropil and associates closely with axons, dendrites, and synapses ( Awasaki et al., 2008 and Doherty et al., 2009). Selleckchem HIF inhibitor One might not think so, but fly CNS glia have evolved a complex association with the vasculature (containing hemolymph), likely to maintain neuronal health. Gas exchange in Drosophila occurs through a series of trachea, gas filled tubules that penetrate most tissues in the fly, including the CNS. Within the cell cortex, trachea are tightly surrounded by glial membranes, likely from cortex glia, and within the neuropil tracheal elements are in close proximity to astrocyte membranes ( Pereanu et al., MAPK inhibitor 2007). These glia-trachea contacts provide an obvious potential route of gas exchange between CNS neuronal cell bodies and the environment. And what about nutrient delivery? The Drosophila nervous system is surrounded by a multilayered BBB, which is composed of an outermost neural lamella (a carbohydrate-based extracellular matrix), a layer of glial cells termed perineurial glia, and then subperineurial glia (SPGs) ( DeSalvo et al., 2011). SPGs are flattened, surround the entire CNS, and form pleated septate junctions with one another that act as a BBB. The

entire BBB structure can be thought of as an inside-out blood vessel—hemolymph is on the outside and, to get in, the CNS molecules must pass through the neural lamella (a charge and size exclusion barrier). The PGs and SPGs (the latter sealed with tight junctions) are probably the site of exchange of ions, metabolites, growth factors, and other molecules that travel into and out of the CNS. The final subtype of CNS Mephenoxalone glia is ensheathing cells, which form a layer between the neuropil and cell cortex but also penetrate the neuropil to compartmentalize different regions of the brain. Rhombomeres of the vertebrate CNS are an example where compartmentalization of brain structures is important for segregating function;

whether this is also the case for Drosophila glial brain segregation remains for the moment speculative. Certainly these cells are critical to maintain brain health—after injury, ensheathing glia become “reactive” and extend membranes to sites of injury, where they phagocytose degenerating neuronal material ( MacDonald et al., 2006). Certain functional roles for glial cells in the fly are analogous to those defined in mammals. Drosophila CNS glia express glutamate transporters, glutamine synthetase, and GABA transporters presumably to aid in neurotransmitter recycling ( Rival et al., 2004 and Soustelle et al., 2002). They guide axon outgrowth, dendrite morphogenesis, and provide trophic support required for neuronal survival ( Edenfeld et al., 2005 and Freeman and Doherty, 2006). Peripheral glial cells are important for maintaining nerve health, NMJ integrity, and growth.

, 1999). Owing to the fact that only few inhibitory neurons carry spines, studies of structural plasticity in cortical inhibitory neurons thus far have primarily focused on changes to the branch tips of dendrites (Chen et al., 2011, Lee et al., 2006 and Lee et al., 2008). The potential plasticity of dendritic spines on cortical inhibitory neurons in both the naive brain and following sensory deprivation is still unexplored.

Similarly, axonal boutons can serve as a structural marker for presynaptic components in chronic in vivo imaging experiments (De Paola et al., 2006 and Stettler et al., 2006). These studies have shown that axonal boutons of excitatory Talazoparib clinical trial cells display a baseline turnover in the unperturbed cortex (De Paola et al., 2006 and Stettler et al., 2006) and that, like spines, bouton dynamics increase following sensory deprivation in both excitatory (Yamahachi et al., 2009) and inhibitory (Chen et al., 2011 and Marik et al., 2010) neurons.

While the importance of inhibitory circuits in cortical plasticity is well established in juvenile animals during the critical period (Hensch, 2005), the role of inhibition is less understood in adult animals. In both functional (Froemke et al., 2007) and anatomical (Chen et al., 2011, Hendry and Jones, 1988 and Rosier et al., 1995) studies in adult animals, changes in inhibition seem to occur prior to changes in excitatory connections, over time courses Tryptophan synthase ranging from seconds (Froemke et al., 2007) to days (Chen et al., 2011 and Rosier et al., 1995) to months (Hendry and Jones, 1988), suggesting a possible role of reduced inhibition find more in enhancing plasticity of excitatory connections. In previous work, we have introduced a retinal lesion paradigm in mice (Keck et al., 2008), which leads to functional alterations in the visual cortex. Permanent ablation of a small part of the retina leaves a region of the monocular

visual cortex temporarily unresponsive. As had been described previously (Calford et al., 2003, Giannikopoulos and Eysel, 2006, Gilbert and Wiesel, 1992, Heinen and Skavenski, 1991 and Kaas et al., 1990), in the weeks and months following the retinal lesion, the cortical “lesion projection zone” (LPZ) reorganizes functionally and regains responsiveness to visual stimuli. The functional reorganization is believed to occur largely within the cortex (Gilbert and Wiesel, 1992), as there is only very restricted recovery in the lateral geniculate nucleus (LGN, Eysel, 1982). Reorganization is accompanied by cortical structural plasticity, such as increased spine dynamics in layer 5 pyramidal neurons in the LPZ (Keck et al., 2008) and axonal sprouting of layer 2/3 pyramidal cells into the LPZ from adjacent regions of cortex (Darian-Smith and Gilbert, 1994 and Yamahachi et al., 2009). Here, we use chronic two-photon imaging to examine the structural plasticity of inhibitory neurons following retinal lesions.

Unlike prototypic GP-TI cells, none of the GP-TA neurons (n = 5) gave rise to a descending projection axon that targeted downstream BG nuclei. Instead, all reconstructed GP-TA neurons emitted local axon collaterals (although somewhat restricted; see below) and at least one ascending projection axon collateral that targeted striatum (Figure 4). Reconstructing the full axonal arborizations of every labeled GP-TA neuron was beyond the scope of this study, but we visually Dolutegravir ic50 confirmed the extrinsic axonal projections of another nine GP-TA neurons (revealed with Ni-DAB). All but one of these neurons gave rise to only ascending axonal projections that

entered and ramified in striatum; one unusual neuron innervated striatum and EPN. GP-TA neurons thus challenge the widely-held assumption that all GPe neurons innervate STN (Baufreton et al., 2009, Bevan et al., 1998, Smith et al., 1998 and Wichmann and DeLong, 1996). The specific striatal innervation of the two fully-reconstructed GP-TA neurons (cells #6 and #7) was massive; the main axon split to form up to five ascending collaterals that established dense clusters of boutons over large striatal territories (Figures 4A and 4B). Remarkably, each GP-TA neuron gave rise to thousands of axonal boutons in striatum (9,085 and 13,789 boutons for cells #6 and #7). This extensive striatal innervation meant that total axon lengths of GP-TA neurons

(126.2 and 164.2 mm for cells #6 and #7) were considerably longer than those of TCL GP-TI neurons (37.8 and 59.4 mm for cells #1 and #2). Electrophysiological and molecular diversity in GPe is thus mirrored Akt inhibitor drugs by a profound structural diversity. While GP-TI neurons innervate STN and other downstream BG nuclei, GP-TA neurons do not conform to this prototypic connectivity but instead provide a massive innervation of striatum. Our discovery

of a novel GPe cell type that only projects to striatum raises the issue of which types of striatal neuron are innervated. We first tested whether identified GP-TA neurons target the three major classes of aspiny interneuron (two GABAergic, one cholinergic) by revealing immunoreactivity for PV, nitric oxide synthase (NOS), or ChAT (Tepper and Bolam, 2004), respectively, with a light-brown DAB precipitate. The axons of single neurobiotin-labeled GP-TA neurons (n = 3) were revealed with a black Ni-DAB precipitate. Axonal boutons were found in close apposition to the somata and proximal dendrites of all three classes of interneuron, some of which were targeted by clusters of apposed boutons arranged in a “basket-like” manner (Figures 5A–C). Such specialized arrangements are indicative of synaptic contacts established by GPe cells (Bevan et al., 1998 and Sadek et al., 2007). This analysis thus suggests that different classes of striatal interneurons are targeted by GP-TA neurons.

Recent detailed comparisons of human and chimpanzee DNA differences have identified important differences related to gene expression including human accelerated regions (HARs) (Pollard et al., 2006a, 2006b) or conserved noncoding sequences (CNSs) (Prabhakar et al., 2006), genomic neighborhood differences (De et al., 2009), copy number variations (CNVs) (Gazave et al., 2011; Perry et al., 2008), and promoter and enhancer variations (Haygood et al., 2007; Planas

and Serrat, 2010) that could contribute substantially to differences in phenotype. In addition to these DNA studies, several previous studies have directly examined human-chimpanzee differences Ribociclib solubility dmso in gene expression in the brain using microarrays to measure RNA transcript levels (Cáceres et al., 2003; Enard et al., 2002a; Khaitovich et al., 2004a). While these studies were an important first step in uncovering human-specific patterns of gene expression in the brain, microarray technology has several limitations that are especially germane to evolutionary comparisons. First, BYL719 solubility dmso microarray analysis

relies on a priori knowledge of the sequence of the sample being measured, which precludes identifying unannotated transcripts. The dynamic range of microarrays is also narrow compared to that of new sequencing technologies (Asmann et al., 2009; Feng et al., 2010). Perhaps most importantly, with respect to cross-species comparisons, is the tremendous loss of usable probes due to sequence divergence (Preuss et al., 2004). To avoid these limitations, we utilized Bumetanide next-generation

sequencing (NGS) (Metzker, 2010) to compare gene expression in the brains of three primates: humans, chimpanzees, and rhesus macaques, employing 3′ digital gene expression (DGE) tag-based profiling to assess levels of mRNA expression. DGE has been shown to be both highly sensitive and reproducible when assessing gene expression from human brain (Asmann et al., 2009). Importantly, the present study included rhesus macaques as an outgroup, which provides a basis for inferring whether differences between humans and chimpanzees occurred in the human lineage or the chimpanzee lineage. With a few exceptions (Brawand et al., 2011; Cáceres et al., 2003; Liu et al., 2012; Somel et al., 2009, 2011), previous microarray or NGS studies have not included an outgroup or only investigated one brain region (Babbitt et al., 2010; Cáceres et al., 2003; Enard et al., 2002a; Khaitovich et al., 2004a, 2005; Liu et al., 2011; Marvanová et al., 2003; Somel et al., 2009; Uddin et al., 2004; Xu et al., 2010a). We examine three brain regions representing different developmental origins within the telencephalon: subpallial (caudate), allocortical (hippocampus), and neocortical (frontal pole). Frontal pole is of particular interest because it was enlarged and structurally modified in human evolution (Semendeferi et al.

(2012) exist in the reward circuit, it would provide not only a potential mechanism for the “ghrelinergic” effects on reward but also a new paradigm for the rational development of therapeutic interventions for abnormal reward-seeking behaviors. “
“A major goal of neuroscience is to elucidate the molecular mechanisms mediating the different forms and phases of long-term synaptic plasticity that are thought to underlie learning and memory. Although many forms of synaptic plasticity have been described, four have been the most widely studied: (1) NMDA receptor (NMDAR)-dependent, transient early long-term potentiation (LTP), (2) NMDAR-dependent, persistent late LTP that requires Onalespib clinical trial new protein synthesis, (3) mGluR-dependent

long-term depression (LTD) that also requires new synthesis, and (4) NMDAR-dependent LTD. A current challenge to the field is to determine how these four forms of plasticity might mediate different aspects of behavior in the hopes of finding simple rules that may reframe the psychology of memory in neurophysiological and molecular terms. This requires understanding the core molecular mechanisms of these long-term synaptic modifications

in detail. The molecular mechanisms for any long-term form of synaptic plasticity can be divided into three phases: induction, triggering the plasticity; maintenance, sustaining it over time; and expression, transducing the mechanism of maintenance into a change PD0325901 solubility dmso in synaptic transmission. From the point of view of the search for the physical substrates of memory, the heart of the matter is maintenance. In recent years, significant progress has been made toward understanding the maintenance

of the two protein synthesis-dependent forms of synaptic plasticity. Whereas induction involves scores of signaling molecules, the critical requirement for new protein synthesis in the transition to maintenance constrains the complexity of the signaling network involved in sustaining modified synaptic Phosphoprotein phosphatase transmission in the maintenance phase. For example, in late LTP, PKMζ, a protein kinase C isoform that is uniquely synthesized as an autonomously active kinase by strong afferent stimulation, is the only kinase that has been found to maintain increases in synaptic transmission from hours to days after induction ( Sacktor, 2011). Because PKMζ is not involved in the maintenance of LTD, pharmacological and genetic tools that inhibit the kinase and block or reverse late LTP have been used to demonstrate a role for late-LTP maintenance in several forms of long-term memory ( Sacktor, 2011). Analogously, researchers are hot on the trail of a few suspects that are newly synthesized in mGluR-LTD, including arc, STEP, and MAP1b, which may maintain this form of synaptic depression ( Lüscher and Huber, 2010). In contrast, the core mechanisms that maintain the forms of synaptic plasticity that rely entirely on posttranslational modifications have been harder to pin down.

In sum, our results demonstrate that the reading problems experienced by children with dyslexia are not a consequence of visual magnocellular dysfunction. While visual magnocellular weakness does manifest in dyslexia, it is not the cause of the reading problem. Second, the weaknesses in the magnocellular visual system, indexed in this

study by the amount of activity in area V5/MT during the perception of visual motion, do not represent a symptom of dyslexia. They are not, Tariquidar manufacturer as previous models assumed, part of a common etiology with different behavioral manifestations and thereby an integral part of the pathophysiology of dyslexia. Rather, they are a secondary consequence of reading experience itself. We suggest that phonological deficits, by restricting the amount and quality of reading in dyslexics, limit the opportunity for reading to induce changes in the visual magnocellular system (by mechanisms that remain to be determined). As such, reading itself can be thought of as an environmental influence that bears on functional and anatomical aspects of the brain and, in the case of reading disability, these changes are not invoked to the same degree as they are in typical Bortezomib concentration readers. In the context of the observed differences at the level of the LGN, larger neurons in the controls relative to the dyslexic at postmortem could be due to extensive versus limited experience with reading over

a lifetime. The same explanation holds to account for the differences between dyslexics and age-matched controls in behavioral studies

of magnocellular function and brain imaging studies of V5/MT. Together, our results represent not only an important advancement in understanding the etiology of developmental dyslexia, but also offer a reinterpretation of the existing data on visual magnocellular dysfunction in dyslexia. They also contribute to an important growing body of work that explains how experience, in this case for reading, alters the functional organization of the brain. Subjects participating in all three experiments were native English speakers with no history of neurological or psychiatric disorder, and all Chlormezanone had normal or corrected-to-normal visual acuity. Written informed consent was obtained from the subjects themselves or from the subjects’ parents (in the case of pediatric participants), and all procedures were approved by the Georgetown University Institutional Review Board. All subjects completed a battery of behavioral tests to evaluate intelligence and proficiency on reading and reading-related skills, including the Wechsler Abbreviated Scale of Intelligence Verbal and Performance tests (IQ), Woodcock-Johnson III (WJ-III) Word Identification (WID, single real word reading), and Woodcock-Johnson Word Attack (WA, single pseudoword reading). Subjects in Experiment 3 also completed the Lindamood Auditory Conceptualization Test (LAC-3, phonemic awareness).