(2011). Briefly, neurons were KRX 0401 represented as a compartmental, conductance-based model using reconstructed morphologies from rat S1. The compartments were separated in four zones: axon initial segment (AIS), soma, basal dendrites, and apical dendrites (Figure 1). The

full axon was not simulated; only the AIS was simulated (Figure 1, bottom row). Synapses at the postsynaptic cells were activated after spike detection in AIS in the control case and prerecorded spike trains otherwise. A conduction delay based on axonal path distance to the soma (assuming spike conduction velocity was 300 μm/ms; Stuart et al., 1997) was accounted for. Passive membrane capacitance was 1 μF/cm2 for the soma, AIS, and dendrites, whereas for pyramids it was 2 μF/cm2 for basal and apical dendrites to correct for dendritic spine area. Axial resistance was 100 Ω cm for all compartments. Input resistance Rin was 225 ± 41 MΩ for L4 pyramids and 74 ± 35 MΩ for L5 pyramids. For basket cells, Rin = 379 ± 210 MΩ. The resting potential was −74.1 ± 0.1 mV for L4 pyramids, −73.8 ± 0.1 mV for L5 pyramids, and −71.6 ± 1.4 mV for basket cells. Up to ten active membrane conductance types were accounted for with kinetics taken from the published ion channel models or from published experimental

data (Hay et al., 2011). The reversal potentials for sodium and potassium were 50 and −85 mV, respectively, and −45 mV was used for the Ih current. Ion currents were modeled using the Hodgkin-Huxley formalism. Connectivity patterns were implemented as presented in Hill et al. (2012). Briefly, reconstructed cells from L4 and L5 were placed in a hexagonal volume with a radius of 320 μm, matching biological PD0332991 solubility dmso densities

of approx. 240,000 per mm3 in L4 and 90,000 per mm3 in L5 (J. Gonzalez-Soriano, J. DeFelipe, L. Alonso-Nanclares, personal communication). Every axonal part closer than 3 μm to a dendrite is detected, and synapses are placed at a 5% subset of these appositions. The subset is chosen such that the number of synapses per connection and synaptic bouton densities match biological values. Spatial distributions of synapses placed in such manner are known to match biological distribution for Endonuclease a number of intracortical pathways with a mean error <8%. All 15,137,757 synapses were modeled using conductance changes. AMPA- and NMDA-type synapses accounted for excitation. For AMPA receptor (AMPAR) kinetics, the synaptic conductance was 0.3 ± 0.2 nS. The rise and decay time constants were 0.2 ± 0.05 ms and 1.7 ± 0.18 ms, respectively. For NMDAR kinetics, conductance was 0.2 ± 0.1 nS with rise and decay times, 0.29 ± 0.23 ms and 43 ± 1.2 ms, respectively. The reversal potential of AMPAR and NMDAR was 0 mV. For inhibitory GABAA synapses, the mean conductance was 0.66 ± 0.2 nS with the rise and decay time constants, 0.2 ± 0.05 ms and 8.3 ± 2.2 ms. Time constant for recovery from depression and time constant for recovery from facilitation were adopted (Angulo et al.

Alfaro et al. 28 showed that Cd34 (−/−) mice displayed a defect in muscle regeneration after acute or chronic muscle injury, and that this defect was caused by impaired entry into proliferation and delayed myogenic progression of satellite cells. Thus, CD34 plays an important function in modulating satellite cell activity. However, it is not known whether circulating CD34 cells are involved in the muscle regeneration process in humans. It cannot be denied that the effect of local muscle damage on CD34+ cells was not

detected. It is possible that if the magnitude of muscle damage had been greater and/or the amount of damaged muscle had been greater than in the present study, then significant changes in KPT-330 chemical structure circulating CD34 cells could have been observed, and thus this warrants further study. Rehman et al.24 stated that exercise-induced endothelial progenitor cells could promote angiogenesis and vascular regeneration. Laufs et al.25 demonstrated that nitric oxide played an important see more role in the vascular endothelial growth factor (VEGF)-mediated regulation of circulating progenitor cells. Möbius-Winkler et al.14 also reported that increases in hematologic and endothelial progenitor cells (CD34+, CD133+) were related to VEGF and IL-6. Eccentric exercise affects not only muscle fibers, but also

the capillary structure such that the capillary luminal area was increased by more than 20% at 1 and 3 days after 300 eccentric contractions of the gastrocnemius muscles in rats, although the capillary endothelial cells retained their normal structure.17 It is not known whether the eccentric exercise in the present study affected the capillaries,

but it is reasonable to assume that endothelial repair was not required. Eccentric exercise of the elbow flexors has a minimal effect on the circulation, because it does not affect the heart rate or blood pressure during exercise.21 Together with the results from previous studies, the present data indicate that the changes in the number of circulating CD34+ cells are not necessarily Rolziracetam related to muscle damage, but that other factors such as increased shear stress may be involved in the larger increases in circulating CD34+ cells after endurance exercise reported in previous studies.10, 11, 12, 13 and 14 In the present study, we examined only one subfraction of leukocytes based on the presence or absence of the CD34 antigen. This is a definite limitation of this study. It is possible that certain subpopulations within the CD34+ cell fraction, for example, CD34+/VEGFR2(KDR)+, CD34+/CD133+, or CD34+/CD45+ EPCs, might have changed following eccentric exercise. It would have been better if other bone marrow-derived progenitor cells were also investigated.

, 2008). Different phases of adult neurogenesis are subject to regulation by pharmacological manipulations, mostly through various neurotransmitter systems (reviewed by Jang et al., 2008). Both the dentate gyrus and olfactory bulb are enriched with inputs from many brain regions that release different neurotransmitters and neuropeptides. Among classic neurotransmitters, glutamate, GABA, and probably acetylcholine directly regulate migration, maturation, integration, and survival of newborn

neurons. In most of other cases, it is not always clear whether pharmacological manipulations act by directly affecting neural precursors and newborn learn more neurons or through indirect modulation of the niche. Interestingly, antidepressants used in clinics, through changes in serotonin and nonrepinephrine levels, increase neural progenitor proliferation, accelerate dendritic development, and enhance survival of newborn neurons in the adult hippocampus (reviewed by Sahay and Hen, 2007 and Warner-Schmidt and Duman, 2006). Our understanding of extracellular cues that regulate targeted neuronal migration, axon/dendritic development, and synapse formation during adult neurogenesis is limited.

A number of adhesion molecules (e.g., β1-integrin, PSA-NCAM, Tenascin-R) and extracellular cues (e.g., GABA, NRGs and Slits) are known to regulate the stability, motility, or directionality of neuronal migration during adult SVZ neurogenesis (reviewed Selleckchem NVP-BKM120 by Lledo et al., 2006 and Ming and Song, 2005). In the dentate gyrus, reelin signaling prevents new neurons from migrating into the hilus region; loss of reelin expression from local interneurons after pilocarpine-induced seizures may explain the ectopic hilar localization of new granule cells (Gong et al., 2007). Cell-cycle regulators, transcription factors, and epigenetic

factors are major intracellular regulators of adult neurogenesis (Zhao et al., 2008). Cell-cycle inhibitors, including p16, p21, and p53, play major roles in maintaining the quiescence of adult neural precursors; deletion of these factors leads to transient activation and subsequent depletion of the precursor pool. Sequential Oxymatrine activation of different transcription factors ensures proper development of adult neural precursors. Sox2 is a major mediator of Notch signaling in maintaining the precursor pool in the adult SGZ (Ehm et al., 2010). Shh appears to be a direct target of Sox2 in neural precursors and deletion of Sox2 in adult mice results in a loss of hippocampal neurogenesis (Favaro et al., 2009). Orphan nuclear receptor TLX is also required for self-renewal and maintenance of neural precursors in the adult brain, probably through a canonical Wnt/β-catenin pathway (Qu et al., 2010).

Purkinje cells were loaded with Oregon Green BAPTA-2 and Alexa 633 by adding these dyes to the pipette solution. The experiments

were initiated after the dendrite was adequately loaded with the dyes and the fluorescence at the selected ROIs reached a steady-state level, which typically required ≥ 30min. The recordings were performed at room temperature. Resting calcium levels were calculated as [Ca2+]=KD(G/R)−(G/R)min(G/R)max−(G/R)where KD is the dissociation constant of Oregon Green BAPTA-2, and (G/R)max and (G/R)min are the fluorescence ratios at saturating and zero (external) calcium concentrations, respectively. For this calculation, we used the following values: KD = 485 nM (cuvette measurements), G/Rmax = 0.9440 (in situ measurement; injection of depolarizing currents in [Ca2+]o = 4mM), and G/Rmin = 0.0196 (in situ; no stimulation; [Ca2+]o = 0 mM). Selleck Y 27632 Data were analyzed using Fitmaster software (HEKA Electronics) and Igor Pro software (WaveMetrics). Linearity was assessed by

using Pearson’s correlation coefficient, and statistical significance was Ribociclib mw determined by using the paired Student’s t test (to test for significance of changes after an experimental manipulation in comparison to baseline) and the Mann-Whitney U test (between-group comparison), when appropriate. All data are shown as mean ± SEM. This study was supported by grants from the National Institute of Neurological Disorders and Stroke (NS-062771 to C.H. and NS-038880 to J.P.A.), the Netherlands Organization for Scientific Research (NWO-ALW 817.02.013 to C.H.), and the Japanese Society for the Promotion of Science (JSPS 02714 to G.O.). We would like to thank S.M. Sherman, N. Spruston, and J. Waters for invaluable comments on the manuscript and

laboratory members for helpful discussions. “
“Neural responses in primary sensory cortices encode the physical attributes of a stimulus with considerable precision. Additionally, these neural responses can reflect a large number of experience-dependent contextual attributes of a stimulus (Meyer et al., 2010, Shuler and Bear, 2006 and Zhou et al., 2010) including those that reflect its 4-Aminobutyrate aminotransferase behavioral significance (Polley et al., 2006, Recanzone et al., 1993, Rosselet et al., 2011, Siucinska and Kossut, 1996 and Weinberger, 2004). On the local network level, neuronal responses to a stimulus are both redundant and sparse (Houweling and Brecht, 2008, Kerr et al., 2007, O’Connor et al., 2010 and Olshausen and Field, 2004). Redundancy, in which the total number of spikes elicited by a sensory stimulus exceeds the number needed for sensory perception (Houweling and Brecht, 2008, Huber et al., 2008 and O’Connor et al., 2010), permits fault-tolerant coding in cortical networks, which have characteristically high response variability. However, redundant coding increases the metabolic load on the system.

By contrast, circuits

based upon neuronal thresholds are insensitive to loss of inputs from low-threshold inhibitory neurons but highly sensitive to loss of high-threshold inhibitory neurons. Thus, ablating high-threshold inhibitory neurons in such circuits would have a much larger effect on the drift patterns than ablating low-threshold inhibitory neurons (Figure 7B). For detailed analysis of the specific patterns of drift seen in Figure 7, we refer the reader to the simplified analytic model of the Supplemental Methods and Figure S2. A second prediction arises from analyzing the time constants of drift following inactivation. Both in the well-fit and poorly fit models, the rate of drift BI 6727 supplier following inactivation scaled approximately linearly with the inverse UMI-77 ic50 of the recurrent excitatory synaptic

time constant. To reproduce quantitatively the drift rates observed experimentally following inactivation, a recurrent excitatory synaptic time constant of ∼1 s was required. This finding predicts a role for a slow cellular component of persistence at excitatory synapses or dendrites (see Discussion). The results above show that there are multiple circuit structures, understandable by the tradeoff between two thresholding mechanisms, that could reproduce the experimental Calpain data. As shown next, however, these structural differences masked strong similarities in functional connectivity that were revealed only when the combined effects of the structural connectivity Wij, the synaptic nonlinearities s(rj), and the threshold nonlinearity of the tuning curves were considered.

To generate the functional connectivity, also known as “effective connectivity” (Sporns et al., 2004), between neurons at different eye positions, we calculated the amount of current provided by any given neuron to its postsynaptic targets at different eye positions. These currents then were normalized by the presynaptic firing rate to obtain a functional connectivity measure, current per presynaptic spike, that did not simply reflect the strength of presynaptic firing. Below-threshold neurons were assigned a functional connectivity strength of zero. The resulting functional connectivities for all circuits exhibited a striking pattern not evident in the anatomical structure: when the eyes were directed leftward, the left-side inhibitory neurons projected strong functional connections. However, the functional weights of inhibitory right-side neurons were almost zero (Figures 8D–8F). When the eyes were directed rightward, the opposite pattern emerged, with the right side inhibitory neurons dominating and those on the left side contributing little (Figures 8G–8I).

We RAD001 concentration found that endocytosis of APP is essential for the activity-dependent convergence of APP/BACE-1 in neurons (Figure 6). Specifically, experimental paradigms blocking clathrin-mediated

endocytosis (or APP endocytosis) also abrogated APP/BACE-1 convergence (Figures 6C and 6D), and such conditions led to expected stalling and clustering of APP and clathrin (Figure 6E), suggesting that a recycling-dependent pathway (as opposed to homotypic fusion) is responsible for this convergence. What is the relevance of our findings to human disease? Studies show that amyloid plaque deposition is most conspicuous in the “default mode network”—a circuit that is metabolically active during unidirected mentation (Buckner et al., 2009)—leading to the hypothesis that activity-dependent amyloidogenesis may play a role in AD (Bero et al., 2011). Though our experiments do not address this directly, our finding that APP/BACE-1 convergence is exaggerated in stimulated neurons as well as AD brains is consistent with this idea. However, other studies implicate defective Aβ clearance (and not increased Aβ production) as the primary pathologic event in AD (Mawuenyega et al., 2010), and further work is needed to clarify these issues. In summary, our studies uncover fundamental trafficking strategies

by which neurons largely restrict APP (substrate) and BACE-1 (enzyme) in distinct organelles—thus limiting Aβ biogenesis in physiologic states (Figures 1 and 2); define a trafficking MDV3100 ic50 pathway by which APP and BACE-1 converge upon induction of neuronal activity (Figures 3, 4, 5, and 6); and, finally, our data from human brains (Figure 7) suggest potential relevance of these mechanisms in human disease. Several constructs Methisazone were obtained from other laboratories, as mentioned in the Acknowledgments. The CFP/YFP tags in the BACE-1:CFP/APP:YFP constructs were replaced by GFP or mCherry, cloned in-frame, and confirmed by sequencing (see Figure S1).

The promoter in the NPYss construct (Banker laboratory) was swapped with CMV. The clathrin:GFP and Rab-5:mCherry constructs were obtained from Addgene. Antibodies used for biochemistry were the following: APP (1565-1; Epitomics), BACE1 (MAB931; R&D), TfR (clone H68.4; Invitrogen), Tubulin (clone DM1A, Sigma), anti-pan cadherin (ab22744, Abcam), KDEL (Ab12223, Abcam), Rab11 (71-5300, Invitrogen), GM130 (610822, BD Transduction), and Rab5 (108011, Synaptic Systems). D-AP5, dynasore, picrotoxin, and memantine were from Sigma and Alexa 488 Transferrin was from Molecular Probes. Beta-secretase Inhibitor II (Calbiochem) was prepared in DMSO and neurons were treated with final 0.5 μM inhibitors for 24 hr. Primary hippocampal neurons were obtained from postnatal (P0–P1) CD-1 mice and cells were transfected using Lipofectamine-2000 (Invitrogen) as described previously in Roy et al. (2012). Briefly, dissociated neurons were plated at a density of 50,000 cells/cm2 in poly-D-lysine-coated (1.

, 2002) were bred with an Olig1-Cre line, in which

Cre recombinase is produced in the oligodendrocyte lineage ( Xin et al., 2005 and Ye et al., 2009) ( Figure 2A). We observed that all resulting mutant Sip1flox/flox;Olig1Cre+/− mice (referred to as Sip1cKO), but not their control littermates, developed generalized tremors, hindlimb paralysis, and seizures from postnatal week 2 ( Figure 2B, upper panel), although they were born at a normal Mendelian ratio. Sip1cKO mice exhibited the phenotypes reminiscent of myelin-deficient mice ( Nave, 1994) and died around postnatal week 3, in contrast to the normal lifespan of wild-type (WT) and Sip1 conditional heterozygous FK228 clinical trial control (Sip1flox/+;Olig1Cre+/−) mice ( Figure 2C). The optic nerve, a well-characterized CNS white matter tract, from Sip1cKO mice was translucent compared to the control ( Figure 2B, lower panels), which is a sign of severe deficiency in myelin formation. To confirm the myelin-deficient phenotypes, we examined myelin gene expression in

Sip1cKO mice. In contrast to robust expression in control mice, expression of myelin genes such as Mbp (myelin basic protein) and Plp1 (proteolipid protein) is essentially undetectable in the forebrain, spinal cord, and cerebellum of mutant mice at P14 (Figures 2D and 2F). In light of our data demonstrating that expression of mature oligodendrocyte markers was absent in Sip1cKO mice, we further examined myelin sheath assembly in the CNS of these mutants by electron microscopy. In contrast to a large number of myelinated axons Z-VAD-FMK order that are observed in control mice at P14 (Figures 2G and 2H, upper panels), they were completely absent in the optic nerve

and spinal cord of Sip1cKO mutants (Figures 2G and 2H, lower panels), indicating that myelin ensheathment has not begun in these animals. These results suggest that Sip1 is required for myelinogenesis in the CNS. Despite the deficiency in myelin gene expression, the OPC marker PDGFRα was detected in the brain these and the spinal cord in the mutant mice (Figures 3A and 3B). The number of OPCs and their proliferation rate (percentage of Ki67+ proliferating OPCs) in Sip1 mutants were comparable to control mice ( Figures 3C and 3D). We did not detect any significant cell death in the brain and spinal cord of Sip1cKO mice at P7 and P14 based on TUNEL assay and staining for the active form of caspase-3 (n = 3; data not shown). In addition, oligodendrocyte lineage-specific Sip1 inactivation did not lead to obvious alterations of astrocytes and neurons marked by GFAP and NeuN, respectively, in the brain of Sip1cKO mice ( Figure S2). Our data indicate that OPCs are able to form in the CNS of Sip1cKO mice. To investigate whether the differentiation capacity of OPCs in the absence of Sip1 in vitro is blocked, we carried out Cre-mediated Sip1 excision in cultures of purified OPCs.

To address this possibility,

mice habituated to restricted feeding were left without food at the presumptive feeding time (Figure 7A; no food). In contrast to mice that ate food, those without food continued to show exploratory behavior, without resting, sleeping, or extended periods of grooming, during the initial 2 hr of the presumptive feeding time (data not shown). In this period, there was no increase in apoptotic GC number (Figure 7B; 2 hr—no food). In addition, mice with restricted feeding that were allowed to smell food odor but were prevented from eating (Figure 7A; food odor) also showed continual exploratory and sniffing behaviors during the presumptive feeding time, and also exhibited no enhancement of GC apoptosis (Figure 7B; 2 hr—food odor). The observation period of the food-deprived mice S3I201 was then prolonged beyond the presumptive feeding time (Figure 7C). After many hours, the mice showed various behaviors including grooming, resting, and sleeping. When examined after showing sleeping behavior (Figure 7C, arrows),

some showed a several-fold increase in GC apoptosis (Figure 7D). Pazopanib mw This observation indicates that actual food intake is not an absolute requirement for enhanced GC apoptosis in food-restricted mice and also suggests that the postprandial period is a typical but not the only period in which GC apoptosis can be enhanced (see Discussion). The enhanced GC apoptosis observed so far might largely depend on the specific paradigm of food restriction. Alterations in body status such as hormonal levels and energy metabolism in long-term food-restricted mice (Gao and Horvath, 2007) may be important to the enhancement of GC apoptosis during the postprandial period. To examine whether GC apoptosis during the postprandial period is enhanced in mice without long-term food restriction, we designed a one-time food restriction paradigm. In this paradigm, food was abruptly removed only for 4 hr and 20 min in ad libitum feeding mice

and then made available again to efficiently induce feeding and postprandial behaviors (Figure 7E, middle bar). Food was removed during the early dark phase of the circadian cycle, because this was the period in which ad libitum feeding mice ate most extensively (data not shown; Zucker, 1971). Following food redelivery, the mice successfully showed feeding and subsequent postprandial behaviors, including grooming, resting, and sleeping. Under this paradigm, GC apoptosis was enhanced in mice with feeding and postprandial behaviors compared to mice before food supply (Figure 7F). Because under this condition the time of eating and postprandial behaviors after food redelivery varied widely among mice, the redelivery period was limited to 1 hr only (Figure 7E, bottom bar), which efficiently induced postprandial behaviors and enhanced GC apoptosis within 2.

This occurs by a spread of the change in synaptic strength from activated to neighboring non-activated synapses, as opposed to changes in LTP which are usually restricted to a single dendritic spine coactivated by two inputs. Heterosynaptic facilitation after brief nociceptor triggering input can last for hours while homosynaptic LTP may last longer. Mechanistically, central sensitization includes pre- and postsynaptic changes as well as an increase in post synaptic membrane excitability (Latremoliere and Woolf, 2009). As for LTP, alterations in postsynaptic calcium levels are a major

driver in initiating change in synaptic strength: Calcium change can be caused by calcium flux through ionotropic receptors and voltage-gated calcium channels or by release from intracellular stores on activation of metabotropic receptors or receptor tyrosine kinases (Cheng et al., 2010 and Ohnami et al., Ku0059436 2011). Cav1.2 L-type see more calcium channels play important roles and can undergo bidirectional regulation by miR-103 to initiate some forms of central sensitization (Favereaux et al., 2011 and Fossat et al., 2010). Calcium-dependent intracellular signaling pathways produce posttranslational and transcriptional changes in many effector proteins, altering their levels,

distribution, and functional activity (Asiedu et al., 2011, Katano et al., 2011, Matsumura et al., 2010 and Miletic et al., 2011). The major players in the synaptic changes underlying activity-dependent central sensitization are the NMDA, AMPA, and mGluR glutamate receptors, the substance P NK1 receptor, BDNF and its TrkB receptor, ephrinB and EphBR, CaMKII, PKA, PKC, src, ERK and CREB,

and Kv4.2 (D’Mello et al., 2011, Hu and Gereau, 2011, Latremoliere and Woolf, 2009 and Nozaki et al., 2011). Central sensitization in normal individuals can only be initiated by a conditioning nociceptor input, because these afferents corelease glutamate and neuropeptides, mafosfamide providing greater opportunity for sufficient postsynaptic calcium increase. After nerve injury, however, Aβ fibers can undergo phenotypic changes including increased expression of neuropeptides (Nitzan-Luques et al., 2011) such that they may acquire the capacity to trigger or maintain central sensitization (Figure 4). More recently, changes in dendritic spines in dorsal horn neurons mediated by the monomeric G protein Rac1 have been detected after peripheral nerve injury, indicating that spinal circuitry may physically change after nerve injury (Tan et al., 2011). In addition, it appears that some individuals have a higher susceptibility, due to genotypic differences, in producing central sensitization, and therefore have a higher risk of neuropathic pain development or persistence (Campbell et al., 2009, Tegeder et al., 2006 and Tegeder et al., 2008).

The subtlety of these effects indicates that the motor system’s influence on perception is modulatory rather than comprising a necessary component of speech sound recognition. In sum, there is unequivocal neuropsychological evidence that a strong version of the motor theory of speech perception, one in which the motor system is necessary component, is untenable. However, there is suggestive evidence

that the motor system is capable of modulating the perceptual system to some degree. Models of speech perception will need to account for both sets of observations. During the last decade a great deal of progress has been made in mapping the neural organization of sensorimotor integration for speech. Early functional imaging Luminespib studies identified an Selleck OSI744 auditory-related area in the left planum temporale region that was also involved in speech production ( Hickok et al., 2000 and Wise et al., 2001). Subsequent studies showed that this left dominant region, dubbed Spt for its location in the Sylvian fissure at the parietal-temporal

boundary ( Figure 2A) ( Hickok et al., 2003), exhibited a number of properties characteristic of sensorimotor integration areas such as those found in macaque parietal cortex ( Andersen, 1997 and Colby and Goldberg, 1999). Most fundamentally, Spt exhibits sensorimotor response properties, activating both during the passive perception of speech and during covert (subvocal) speech articulation (covert speech was used to ensure that overt auditory feedback was not driving the activation) ( Buchsbaum et al., 2001, Buchsbaum et al., 2005 and Hickok et al., 2003). Further, different subregional patterns

of activity are apparent during the sensory and motor phases of the task ( Hickok et al., 2009), likely reflecting the activation of different neuronal subpopulations ( Dahl et al., 2009) some sensory- and others motor-weighted. Figures 2B–2D show examples of the sensory-motor response properties of Spt and the patchy new organization of this region for sensory- versus motor-weighted voxels ( Figure 2C, inset). Spt is not speech specific; its sensorimotor responses are equally robust when the sensory stimulus is tonal melodies and (covert) humming is the motor task (see the two curves in Figure 2B) ( Hickok et al., 2003). Activity in Spt is highly correlated with activity in the pars opercularis ( Buchsbaum et al., 2001 and Buchsbaum et al., 2005), which is the posterior sector of Broca’s region. White matter tracts identified via diffusion tensor imaging suggest that Spt and the pars opercularis are densely connected anatomically (for review see Friederici, 2009 and Rogalsky and Hickok, 2010).