, 2005), and neurobiological variables have only rarely been used as predictors of individual differences in altruism (de Quervain et al., 2004, Harbaugh et al., 2007, Hare et al., 2010, Moll et al., 2006 and Tricomi et al., 2010). Recent applications of brain morphometry indicate that individual differences in brain structure can be useful in understanding individual differences in traits and skills (Kanai and Rees,

2011). We therefore conjectured that variables reflecting relatively stable neuroanatomical Navitoclax individual differences—such as gray matter (GM) volume—may help predict individual differences in altruism. In humans, altruism is likely to be related to perspective taking, i.e., the ability to take other individuals’ perspectives

into account. In fact, developmental data suggest that preschoolers who have already acquired theory of mind skills behave more prosocially (Takagishi et al., 2010), and experiments with adults indicate that subjects with better skills in reading others’ mental states show more altruistic behavior (Underwood and Moore, 1982). One brain region that has been repeatedly and reliably found to be implicated in tasks requiring the ability find more to represent and understand others’ perspectives is the temporoparietal junction (TPJ) (Decety and Lamm, 2007, Frith and Frith, 2007, Ruby and Decety, 2001, Saxe and Kanwisher, 2003 and Young et al., 2010). We therefore hypothesized that GM volume in the TPJ may provide a neuroanatomical basis for individual differences in human altruism. Research on human social preferences provides behavioral (Bolton

and Ockenfels, 2000, Charness and Rabin, 2002 and Fehr and Schmidt, 1999) and neural (Tricomi et al., 2010) evidence that other-regarding behaviors and motives depend on the initial payoff allocation between the subject and the subject’s partner. In particular, if subjects have a lower initial payoff than their partner (“disadvantageous initial inequality”), they are much less willing to behave altruistically toward the partner compared to a situation with advantageous initial inequality (i.e., when the heptaminol subject has a higher initial payoff than the partner). In fact, some individuals even reduce the partner’s payoff if possible if the latter has a higher initial payoff. In view of the radically different propensities for behaving altruistically in the domain of advantageous and disadvantageous inequality, it may be possible that the neuroanatomical basis for human altruism is not identical across these domains. In the present study, subjects had to allocate money between themselves and anonymous partners (Figure 1; task description in Experimental Procedures) in a series of binary choice problems. In each trial, subjects faced a binary choice in which they could increase or decrease the partner’s monetary payoff.

, 2005, Dölen et al., 2007 and Osterweil et al., 2010). This phenotype was confirmed by measuring [35S]-methionine/cysteine incorporation in acute

hippocampal slices (Fmr1 KO: 115% ± 7% of wild-type [WT]; p < 0.05; Figures 1E and 1F). As previously shown with MPEP ( Osterweil et al., 2010), bath application of CTEP (10 μM) corrected the elevated protein synthesis rate in Fmr1 KO hippocampal slices (KO/CTEP: 104.9% ± 10% of WT/vehicle) with no significant effects in WT slices. Fmr1 KO mice show an elevated group 1 (Gp1) mGlu-dependent long-term depression ( Huber et al., 2002) which can be corrected by genetic reduction of mGlu5 expression levels ( Dölen et al., 2007), but not by bath application of MPEP ( Volk et al., 2006). We therefore determined

whether in vivo administration of CTEP could reduce Selleckchem Ruxolitinib the elevated LTD ex vivo in the Fmr1 KO hippocampus to WT levels. WT and KO animals (postnatal day 25–30) received a single dose of CTEP (2 mg/kg, subcutaneous [s.c.]) or vehicle 24 hr prior to euthanasia and hippocampal slice preparation. We found that Gp1 mGlu-mediated hippocampal LTD was elevated in vehicle-treated C646 Fmr1 KO mice compared to WT (WT/vehicle: 84.6% ± 2.4%; KO/vehicle: 76.1% ± 2.5%; p < 0.05; Figures 1G and 1H) and was normalized by a single dose of CTEP (KO/vehicle versus KO/CTEP: 86.9% ± 3.3%; p < 0.01). CTEP treatment also reduced the maximum transient depression (MTD) to DHPG, which represents an electrophysiological readout of Gp1 mGlu activation. After 4 weeks of chronic dosing, MTD was strongly suppressed by CTEP (KO/vehicle: 57.1% ± 2.2%; KO/CTEP: 33.2% ± 2.6%; p < 0.01; Figures 1I and 1J), even more so than after a single dose (KO/vehicle: 62.9% ± 3.0% versus KO/CTEP: 49.4% ± 4.6%; p < 0.05), showing that the drug efficacy is maintained throughout chronic treatment. Cognitive impairment is a core symptom in FXS. We confirmed not that

Fmr1 KO mice exhibit deficits in inhibitory avoidance (IA) ( Figure 2). Vehicle-treated Fmr1 KO mice showed significantly reduced latencies to enter the dark compartment compared to vehicle-treated WT littermates 6 hr after conditioning and during all extinction trials (6 hr, p = 0.0186; 24 hr, p = 0.0095; 48 hr, p = 0.0582; Figures 2B–2D). There was no difference in the pain threshold between Fmr1 KO and WT mice ( Figure 2E). Chronic treatment fully rescued the learning and memory deficit in the IA paradigm, with CTEP-treated Fmr1 KO mice exhibiting latencies to enter the dark compartment similar to vehicle-treated WT mice at all test sessions. Correspondingly, CTEP-treated Fmr1 KO mice exhibited significantly more avoidance than vehicle-treated Fmr1 KO mice (6 hr, p = 0.0817; 24 hr, p = 0.0016; 48 hr, p = 0.0007). FXS patients frequently present a hypersensitivity to sensory stimuli (Miller et al., 1999), mirrored in Fmr1 KO mice by a hypersensitivity to low-intensity auditory stimuli ( Nielsen et al., 2002).

Hence we scanned the participants while they performed the Study using a high-resolution EPI, resulting in 2∗2∗2 mm voxels, keeping the same TR (2 s). The scan did not cover the whole brain, but had our ROI—the amygdala—in the center of the field of view (FOV) (see Figure S3). Trials were first classified based only on the Study session behavior as follows: trials in which the camouflage was reported as spontaneously identified (i.e., when the click here participant pressed “Yes” at the QUERY stage) were labeled SPONT. The rest of the trials in which the camouflage was reported as not identified spontaneously were labeled NotIdentified. We then used the SOL versus

baseline contrast, as was done in Experiment 2, this website to delineate the subject-specific amygdala ROIs which we a priori set out to test. Subsequent memory information was not used at this stage to avoid circularity when choosing the voxels whose data is used for prediction. Next, we calculated the area under the curve for the peak time points of each NotIdentified

trial. The trials were sorted by this measure, and following the results of the previous experiments, the top 40% of the sorted trials list were predicted to be subsequently remembered, while the rest were predicted to be not remembered. When we compared the above described prediction with the actual performance of the participants at Test, the average hit rate of the prediction (i.e., the number of trials in which the image was predicted to be remembered, and was indeed recognized at the Grid task 1 week later, as a fraction of the total number of REM trials) was (0.548 ± 0.127). The average false alarm rate of the prediction (i.e., the number of trials in which the image was predicted to be remembered yet

was not recognized at the Grid task 1 week later, as a fraction of the total number of NotREM trials) was Tryptophan synthase (0.312 ± 0.052). The average d-prime for the prediction was (0.628 ± 0.445). The hit rate versus false alarm rate relation per subject is depicted in Figure 8. As in Experiment 2 the right amygdala also showed higher activity in REM trials than in NotREM ones. Yet again that difference was much smaller than in the left amygdala. The average hit rate, false alarm rate, and d-prime for the prediction based on the right amygdala ROI were (0.446 ± 0.102), (0.356 ± 0.073), and (0.237 ± 0.461), correspondingly. We developed a paradigm to study the behavioral and brain mechanisms that lead to long-term memory of a brief, unique experience: induced perceptual insight. We found that activity in several brain regions correlated with subsequent long-term memory of the insightful information encoded during a brief exposure to the original images (solutions) of degraded, unrecognized real-world pictures (camouflages). Most notably, activity in the amygdala during the moment of induced insight was linked to long-term memory retention of the solution.

This indicates that waking period can increase the excitability of callosal axons. (2) The frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) Autophagy inhibitor purchase are higher in slices collected from animals after prolonged waking as compared to sleep (Liu et al., 2010). This is likely due to a rebound over excitability in the absence of acetylcholine. Indeed, waking state is characterized by activities of the cholinergic system and acetylcholine reduces the amplitude of excitatory postsynaptic potentials (EPSPs) (Gil et al., 1997; Figure 5D). (3) In somatosensory cortical slices of juvenile rats, calcium-permeable

AMPA receptors were shown to be present at the synapse when animals were sacrificed after the wake period and they were absent after the sleep period (Lanté et al., 2011). Obviously, not all types of AMPA receptors are removed from synapses during sleep; thus, it does not preclude the insertion of other AMPA receptor types at synapses during sleep. A recent study in cats showed that intracortical inhibition of mTOR signaling abolished sleep-dependent plasticity, while no effects were observed in the plasticity induced during wake (Seibt et al., 2012). Therefore, it is very likely that plasticity CT99021 induced during wake or during sleep has different mechanisms. The stimulation of medial lemniscal

fibers is not a learning task per se; thus, it is difficult to affirm whether this experiment simulates a declarative or a nondeclarative learning task. However, most procedural learning tasks implicate the somatosensory system and procedural memory was shown to benefit from SWS (Huber et al., 2004; Rasch et al., 2009), which is also in agreement with our results. The enhancement

of responses was always present after the first SWS episode and often also after the second SWS episode, but then the response was saturated. Our results suggest that, once potentiated, the response cannot be further potentiated for a certain time window. next This is in agreement with studies on humans showing that mainly early sleep and naps, rich in slow waves, are important for memory improvement (Gais et al., 2000; Mednick et al., 2003; Nishida and Walker, 2007). Our results show a potentiation of cortical responsiveness after a period of SWS and that an imitation of sleep slow oscillation in vitro was sufficient to strengthen the cortical synapses, providing a physiological mechanism for sleep-dependent memory formation. Experiments were carried out in accordance with the guideline of the Canadian Council on Animal Care and approved by the Laval University Committee on Ethics and Animal Research. Experiments were conducted on four adult nonanesthetized cats. The cats were purchased from an established animal breeding supplier.

Deconvolution of EPSCs to calculate the rates of transmitter Autophagy inhibitor in vitro release was done as first described by Neher and Sakaba (2001), with routines written in IgorPro. The deconvolution analysis assumes that mEPSC with a double-exponential decay (Schneggenburger and Neher, 2000) add linearly to give rise to an evoked EPSC. The calculated release rates were corrected for a contribution

of a spillover glutamate current as described (Neher and Sakaba, 2001). Cumulative release traces were obtained by simple integration of the transmitter release traces without further correction for an assumed recovery process. Cumulative release traces were fitted with the following functions: single-exponential, exponential plus line, double-exponential, double-exponential Protein Tyrosine Kinase inhibitor plus line, and triple-exponential (Wölfel et al., 2007). The best-fit function was selected based on the Bayesian information criterion (BIC; Kochubey et al., 2009). Data are reported as average ± standard deviation (SD) values unless otherwise noted. Statistical significance was evaluated with Student’s t test, and accepted at p < 0.05. For the comparison of release rates, release delays, and fast release time constants between two data sets at various [Ca2+]i (Figures 4E–4H), the data sets were double-logarithmized and then assessed for statistical

significance by analysis of covariance (ANCOVA). The Ca2+-uncaging data were fitted by a five-site model of Ca2+ binding and vesicle fusion (Schneggenburger Oxymatrine and Neher, 2000). The following parameters were used for control/RIM1/2

cDKO synapses respectively: kon, 1.65 ∗ 108 / 1.05 ∗ 108 [M−1s−1]; koff, 7000/5000 [s−1]; pool size, 1390/315 vesicles. The remaining parameters were the same for both data sets (cooperativity factor b, 0.35; final fusion rate γ, 7000 s−1). Ca2+ uncaging was done with a DP-10 flash-lamp (Rapp Optoelektronik) according to standard procedures described before (Schneggenburger and Neher, 2000 and Wölfel et al., 2007); details are given in Supplemental Experimental Procedures. Transmission EM was performed in the MNTB area of a RIM1/2 cDKO mouse and its control Cre-negative littermate (both at P11) with standard fixation and resin embedding procedures (see Supplemental Experimental Procedures). Serial images were taken with a Philips CM10 TEM operated at 80 kV at a magnification of 16,000 times with 10–20 adjacent sections of 50 nm thickness. Only active zones that were completely contained in the series were analyzed. The image series were aligned and active zones, including vesicles and surrounding plasma membrane, were reconstructed in 3D with the Fiji software (http://pacific.mpi-cbg.de/wiki/index.php/Main_Page). The shortest distance from the vesicle membrane to the active zone membrane was then calculated in the 3D model, and all vesicles at distances of less than 300 nm were taken into account.

, 2002). A likely mechanism for presynaptic recruitment requiring the intracellular region of PTPσ (Figures 4D and 4E) is binding of the second phosphatase domain (D2) to α-liprins (Pulido et al., 1995). α-Liprins directly interact with

CASK, RIMs, and ERC/ELKS/CAST and are important for presynaptic differentiation in Drosophila and Caenorhabditis elegans ( Stryker and Johnson, 2007). The mechanism linking TrkCTK- and TrkCTK+ to glutamatergic postsynaptic proteins is not yet known but presumably occurs via the shared extracellular, transmembrane, and 75-aa membrane-proximal intracellular region. TrkCTK- (NC2) could further recruit the scaffold protein tamalin to activate Arf6-Rac signaling ( Esteban et al., 2006) and TrkCTK+ could recruit and activate PLCγ, Shc, and Frs2 leading to Ras and PI3-kinase ( Huang and Reichardt, 2003). The existence of eight alternatively spliced TrkC variants Akt tumor possessing different intracellular regions and a common extracellular region may contribute to diversity of glutamatergic postsynaptic composition. We show here that TrkC is required in cortical neurons in vivo for development of dendritic spines, a function that does not require TrkC kinase activity (Figures 8A–8D). These data indicate a noncatalytic function of TrkC in morphological excitatory synaptogenesis in vivo. Linkage Selleckchem Veliparib of NTRK3 to panic

disorder ( Armengol et al., 2002), obsessive-compulsive disorder Cediranib (AZD2171) ( Alonso et al., 2008), and childhood-onset mood disorders ( Feng et al., 2008) in patients supports the importance of TrkC for cognitive function.

Deletion of all TrkC isoforms in mice (NTRK3−/−) results in earlier postnatal lethality by several weeks compared with deletion of only the kinase-active isoforms (NTRK3TK−/−) ( Klein et al., 1994 and Tessarollo et al., 1997). The earlier lethality with additional loss of the noncatalytic isoforms may be in part because of a defect in synaptogenesis. Brain-specific transgenic overexpression of TrkC increases anxiety-related behaviors and markedly increases hippocampal CA1 field EPSPs in vivo after classical conditioning or LTP induction ( Dierssen et al., 2006 and Sahun et al., 2007). Such outcomes are consistent with enhanced glutamatergic synapse development, at the expense of inhibitory GABAergic synapses, upon TrkC overexpression. However, these global genetic manipulations clearly have multiple consequences. The in vivo knockdown of TrkC performed here also did not specifically assess the role of TrkC interaction with PTPσ. A more specific TrkC knockin will be needed to precisely define the role of its interaction with PTPσ in vivo without altering NT-3 and kinase-mediated functions. Consistent with the proposed dual function of PTPσ, Ptprs−/− mice also show multiple defects, including increased lethality, ataxia, and neuroendocrine dysplasia, as well as altered hippocampal and cortical development ( Elchebly et al., 1999, Meathrel et al.

Antagonist co-contraction is observed in humans during voluntary elbow rotations (Patton and Mortensen, 1971), isometric clasping of the hand (Long et al., 1970), and walking along a balance beam (Llewellyn et al., 1990). Co-contraction will stiffen and stabilize joints, which may aid in the performance of new motor tasks,

or those subject to unpredictable perturbations. Spinal pathways have been implicated in suppressing reciprocal inhibition mediated by inhibitory group Ia interneurons in order to promote co-contraction. During voluntary co-contraction of antagonist ankle muscles, this suppression has been shown to involve enhanced recurrent inhibition of Ia interneurons as well as an increase in presynaptic inhibition of group Ia afferents that excite Ia interneurons, though the mechanisms underlying co-contraction at the wrist appear distinct ISRIB concentration (Pierrot-Deseilligny and Burke, 2006). Cortical output during voluntary co-contraction is unlikely simply to reflect the combination of separate drives for activating two antagonist muscles. Recordings from motor cortex have detected units specifically active during co-contraction (Humphrey and Reed, 1983). Some CSMNs facilitate activation of certain wrist muscles but suppress their antagonists—and these have been shown to fire during flexion and extension movements Selleckchem ABT888 but can cease during isometric clasping (Fetz and Cheney, 1987). Moreover, the suppression of group Ia inhibition during the co-contraction

of ankle antagonists is far greater than that expected based on the inhibitory activity observed during activation of either muscle alone (Nielsen and Kagamihara, 1992). Lastly, measurements of cerebral blood flow (Johannsen et al., 2001) and EEG-EMG coherence (Hansen et al., 2002) suggest that distinct corticospinal pathways may be active during co-contraction of ankle antagonist muscles compared to the separate activation of either muscle alone. If parallel descending pathways exist, how do they engage

spinal circuits? A pathway involved in co-contraction could directly target interneurons mediating recurrent and presynaptic inhibition. Exploiting genetic access to measure and perturb activity in CSMNs targeting these interneurons could implicate the involvement of particular unless spinal targets in a co-contraction pathway. It is also possible that the generation of appropriate motor neuron drive during co-contraction involves indirect pathways through other spinal interneurons or descending relay systems. Intriguingly, measurements of forelimb EMG in rats during a reach-to-target task show distinct movement phases in which antagonist muscles either alternate activation or co-contract (Hyland and Jordan, 1997). Nevertheless, it is still possible that there is substantial overlap in the CSMNs active during co-contraction and flexion-extension movements and that temporal patterning of CSMN output is critical to differential recruitment of motor neurons.

Are the unimodal cells we identified with calcium imaging in RL functionally distinct from those of primary areas, or is RL a selleck chemical transition area where unimodal “primary” visual and tactile neurons, possibly left over during cortical area parcellation, coexist? The latter possibility seems unlikely for several reasons. First, many neurons that appear unimodal at suprathreshold level receive synaptic inputs from the other sensory modality, accounting for the fact that they also show ME (see Figure S3), as also described in

cats (Allman and Meredith, 2007). Second, in primary cortices heteromodal inputs mostly give rise to inhibitory responses (Iurilli et al., 2012), that we failed to observe in RL. Third, we failed to find consistent labeling of specific thalamic nuclei (such as LGN or VPM) in our retrograde tracing studies, suggesting that unimodal neurons

in RL have a distinct connectivity compared to unimodal neurons in primary cortices. The functional responses of RL neurons appear to obey the “empirical principles of multisensory integration” (Stein and Stanford, 2008) such as evidence of significant ME, topographic alignment of the modality maps, and also adherence to the so-called “inverse effectiveness principle,” in which a tactile stimulus preferentially enhances responses to weak rather than strong visual stimuli (e.g., non-preferred versus preferred Z-VAD-FMK clinical trial direction of motion). This is line with the idea that one of the advantages of multisensory integration is to preferentially enhance sensory processing of weak or ambiguous sensory stimuli. The multisensory character of RL has interesting implications with regard to its possible behavioral role. It has been recently proposed that the visual association areas that surround V1 might be involved in different types of visual processing. Area RL could belong to the more “dorsal” stream involved in visual motion coding, as suggested by the presence of many direction-selective neurons in RL (Marshel et al., 2011). Our data indicate that this view could be reconsidered, because

RL has a clear multisensory (visuotactile) character, and because the visual direction selectivity could be disrupted by the arrival of a tactile stimulus TCL (i.e., a given tactile stimulus preferentially enhances the visual response to the non-preferred direction compared to the preferred direction). In this view, area RL is part of a circuit within the posterior parietal cortex of rodents that integrates visuotactile inputs in a behaviorally-relevant manner (Pinto-Hamuy et al., 1987). Area RL sends projections to motor areas related to whisker and eye movements (Wang et al., 2012). Also, area RL projects to other posterior parietal areas that are involved in path integration and spatial navigation, as shown by lesion (Whitlock et al., 2008) and imaging (Harvey et al., 2012) studies.

, 2009). Moreover, the sigmoidal shape of the voltage/fluorescence response curve of ArcLight indicates that the process is associated with rearrangements arising from gating charge movements and that the

chromophore is not directly affected by changes in the voltage field (like a traditional small molecule organic voltage-sensitive dye). The nonlinearity and slow kinetics of ArcLight check details do not allow detailed studies of action potential shape and propagation within a single cells as is possible with small molecule organic voltage dyes (e.g., Popovic et al., 2011) but do allow action potential detection with lower bandwidth recording. Voltage sensors based on GFP-like fluorescent proteins offer the advantage of substantially greater brightness when compared to other spontaneously fluorescent proteins (Kralj et al., 2011, 2012). While sensors based on microbial rhodopsins have shown promise selleckchem in terms of far red-shifted spectrum and relative response magnitude, the brightness of these probes is dramatically lower than GFP-based probes. Arch D95N has a quantum yield of 0.0004 (Kralj et al., 2012) versus 0.54 for eGFP (Ilagan et al., 2010). In addition the on rate of the nonconducting rhodopsin-based probe (i.e., Arch D95N) is four times

slower than ArcLight probes (41 ms for Arch D94N (Kralj et al., 2012) versus ∼10 ms for the fast component of ArcLight). The large modulatory effect imparted by the D227 mutation introduces the concept of tuning the FP in FP-based voltage sensors as a way to improve them. Previous

studies have made changes to the types of FPs or locations CYTH4 of FPs but have not attempted to modify the FP as a way to improve a probe’s characteristics. In the present study, a small collection of mutations in the FP dramatically increases the change of its fluorescence intensity in response to voltage-induced movements in CiVS. However, these mutations do not alter obvious biophysical properties (i.e., the excitation and emission spectra, pH sensitivity) that would have allowed identification a priori using traditional mutagenesis and screening in E. coli. Mutated sensors still need to be screened in eukaryotic cells in which constructs traffic to the plasma membrane and the resting membrane potential can be set and altered. The ArcLight sensors do not utilize FRET between two fluorescent proteins to produce a signal and it functions at several different insertion sites within the CiVS. ArcLight and its derivatives represent a very substantial improvement in the signal size of a FP voltage sensor, providing a protein-based method to monitor action potentials and subthreshold depolarization in neurons and potentially other cells and organelles.

It will also aid in identifying new ways to stimulate endogenous stem and progenitor cells, e.g., with small-molecule mimics of instructive factors that can

lead to controlled in vivo cell expansion and differentiation. In terms of cell transplantation for replacement, in addition to achieving routine and standardized protocols for hundreds of specific CNS cell types, we anticipate further genetic manipulation of cells prior to transplantation to correct genetically based diseases or combat the disease process. As well as directed single-gene excision or supplementation, the ability to alter networks and pathways via targeting noncoding RNAs and RNA binding proteins is another exciting BIBW2992 molecular weight avenue with great potential. Combination therapies that take into account the specific cell-cell and cell-matrix

interactions that are crucial for CNS function are an active area of research. One promising option is to employ scaffolding along with stem cells to provide a substrate and functionalized artificial niche to direct stem cell behavior (Keung et al., 2010). Expanding on this idea, CNS repair may be better achieved by transplantation of functional units that take into account the interdependence of different CNS cell types, maintaining key interactions such as endothelial cells and neural GSK1349572 cells to improve graft vascularization, neurons, and glial cells or different neuron types to replace multiple elements of damaged circuits, perhaps in three-dimensional arrangements, as dramatically demonstrated by mouse ES-derived eye cup formation (Eiraku et al.,

2011). Medical advances require a permissive environment to reach patients, and Histamine H2 receptor progress in regulatory science will be critical to enable successful, efficient translation. Current regulatory paradigms are of variable stringency depending upon global region and continue to evolve with scientific progress. Failure to conduct trials under strict regulatory oversight can increase risk to patients and the stem cell field in general. Sobering examples of isolated reports of adverse events in patients exploring so-called “stem cell tourism” include a young patient with ataxia telangiectasia given multiple CNS injections of unpurified and uncharacterized mixtures of fetal-derived NSCs from multiple donors over several years that led to donor cell tumor growth (Amariglio et al., 2009). This emphasizes the need to conduct such trials under suitable regulatory and ethics oversight. One controversial issue is that regulatory clearance can be given in the absence of peer-reviewed publication of the relevant preclinical data, which precludes full scrutiny and replication of stem cell culture protocols and results by the broader research community. It should be underscored that the IND review process provides in-depth peer-review scrutiny through ad hoc consultants available to both regulatory and ethics bodies.