Based on these results, we chose the parameter values of the inhibitory-response function for subsequent simulations to be k = 10, S50 = 8, m = 5, and h = 15. The resulting switch-like CRP is shown in Figure 3C. Next, we tested whether this circuit model can produce adaptive shifts in the CRP switch value. We simulated two CRPs with RF stimulus strengths of 8°/s and 14°/s, respectively, and asked whether any combination of input and output divisive inhibition

(din and dout, respectively; (2) and (3)) could appropriately shift the CRP switch value. The ranges of din and dout tested, [0, 3] and [0, 0.24], respectively, were chosen such that the smallest value produced no modulation of the RF stimulus-response function, and the largest value produced 90% of the maximum possible modulation ( Figures S2A and S2B). All the parameters of the inhibitory-response function were maintained at the previous values, Selleck Cabozantinib chosen to yield buy 17-AAG switch-like CRPs. For each pair of din and dout values, we computed the switch values for the two CRPs and calculated them as the CRP shift ratio, the ratio of the shift in the switch value to the change in the RF stimulus speed; a ratio of 1 represents a perfectly adaptive shift. The plot of model CRP shift ratios as a function of din and dout demonstrated that

this circuit produced almost no shift in CRP switch values in response to an increase in the strength of the RF stimulus ( Figure 3D and Figure S2C). The maximum shift ratio produced was 0.03 (din = 1.5, dout = 0), and the two CRPs corresponding to this shift ratio are shown in Figure 3E. To understand why this circuit cannot produce adaptive shifts in the CRP switch value, we compared the patterns of inhibition in the two CRP measurement conditions. Because the activity of the inhibitory neuron (I) depended only on the strength of the competitor and not on the strength of the RF stimulus (I, sin and sout; Equation 4), the pattern of inhibition was identical in both cases ( Figure S2E; identical magenta and blue lines). Therefore, the

only difference between the two CRPs measured at the output unit was the upward (without a rightward) shift ( Figure 3E, blue curve relative to magenta Vasopressin Receptor curve), reflecting the increased excitatory drive caused by the stronger RF stimulus (l in Equation 3). The simulations for Figure 3 explored a large portion, but not the entire space, of parameter values. Nonetheless, it is clear from the above observation that no possible combination of parameters for this circuit can produce adaptive, rightward shifts in the CRP when the strength of the RF stimulus is changed. Thus, feedforward lateral inhibition, as modeled with widely used divisive normalization (Equation 5), although able to produce switch-like CRPs, is unable to produce adaptive shifts in the CRP switch value.

Individually ablating any other neurons did not affect turning rate in naive animals (Figure 5G). The AIB and AIY interneurons are postsynaptic to AWC, and regulate turns during odor sensation in crawling animals (Chalasani et al., 2007). RIM, which receive inputs from both AIY and AIB, synapse onto the four

SMD motor neurons. Taken together, these results indicate that these strongly connected interneurons and motor neurons regulate turning rates downstream of AWB and AWC (Figure 5H). When naive worms are subjected to alternating smells of OP50 and PA14, the smell of OP50 activates AWC neurons and raises turning rate, whereas the smell of PA14 inactivates AWC and lowers turning rates (Figures 5A and 5H).

Thus, the differential responses of AWC to the smells of PA14 and OP50 could regulate downstream neurons to generate stimulus-specific turning selleck chemical rates that are displayed as the olfactory preference for PA14 in naive animals (Figure 5H). Although the activity of the AWB neurons also reflects the naive olfactory preference for PA14 (Figure 5D), ablating AWB click here eliminated naive olfactory preference without significantly changing turning rates. It is possible that AWB might regulate AIZ directly and/or indirectly through ADF (Figure 5G). Ablating AIZ interneurons specifically lowered the turning rate on exposure to the smell of OP50 in both naive and trained SB-3CT animals, eliminating the naive olfactory preference for PA14 without affecting olfactory learning (Figures 3C–3E, 5G, and 6G). Although AIB or RIM or SMD also contribute to the generation of different turning rates on exposure to the smell of OP50 and PA14 in naive animals (Figure 5G), the ablation effects were not specific (RIM) or prominent enough (AIB or SMD) to significantly change the naive olfactory preference for PA14 (Figure 3C). Together, our results indicate that in naive animals AWB and AWC exhibit stimulus-specific patterns of activity. Differential response of AWC

to the smells of OP50 and PA14 regulates downstream circuit to display olfactory preference through the control of turning rate. AIZ contribute to naive olfactory preference by regulating the response to the smell of OP50 (Figure 5H). Finally, we investigated how this network is changed by training with PA14 to generate learned olfactory preference. First, we studied intracellular calcium responses in the AWB and AWC olfactory neurons on exposure to the smells of OP50 and PA14 after training. Surprisingly, although AWCON neuronal responses are strongly correlated with the behavioral preference for PA14 over OP50 in naive animals, AWCON neuronal responses in trained animals did not reflect the shift in olfactory preference away from the smell of PA14. As we did with naive animals, we subjected trained worms to alternating streams conditioned with either OP50 or PA14.

The use of zebrafish will also open new avenues for addressing these issues. Our tracing data of anatomical connections from the activated

area indicate that this area sends efferents to the Vd, the presumptive zebrafish striatum that expresses precursor genes for Substance P and Enkephalin, two markers of projection neurons in the mammalian striatum (Figures S4K and S4L). Moreover, our tracing data showed that the activated area receives afferents from the midbrain multimodal sensory relay nucleus, the preglomerular nucleus (PG) (Figure 4E, see Supplemental Information and Figures S4M–S4T). Thus, the visual stimulus (i.e., cue) and the somatosensory STI571 supplier PD-1/PD-L1 inhibitor 2 stimulus (i.e., electric shock) information from sensory organs probably enter the activated area of the telencephalon via the PG during learning. Based on its connectivity

and developmental origin, fish PG has been proposed to be part of the thalamus (Mueller and Wullimann, 2009). These results suggest that neurons in the activated area may be a part of the neural circuit homologous to the mammalian corticobasal ganglia circuit. Recently, it was anatomically shown that lamprey, the oldest phylogenetic group of vertebrates, possesses a well-conserved basal ganglia circuit (Stephenson-Jones et al., 2011). Zebrafish can be a good system to further test whether the canonical and functional circuit homologous to the corticobasal ganglia

circuit in mammals is conserved anatomically and functionally in evolution. All surgical and experimental procedures were reviewed and approved by the Animal Care and Use Committees of the RIKEN Brain Science Institute. See also full experimental procedures in the Supplemental Experimental Procedures for Ca2+ imaging, electrophysiological recordings, and other histological studies. Either transgenic HuC:IP or wild-type adult zebrafish were trained in a shuttle tank divided into two compartments of equal size by a hurdle ( Figure 1A). MycoClean Mycoplasma Removal Kit The fish had to cross a hurdle to avoid a mild electric shock delivered as a punishment upon presentation of a red LED lamp given as a cue (avoidance). When a fish achieved the learning criterion by making eight avoidance responses in ten trials, or when a maximum of 60 trials was reached, the training session was terminated. Fish that achieved the learning criterion within three consecutive sessions were considered learners. As control groups, we trained either HuC:IP or wild-type fish in three conditions: cue-alone group, shock-alone group, and cue-shock unpaired group. Cue-alone group fish were given only cue, and shock-alone group fish were given only shock for 35 trials for the first session and ten trials for each of the second and third sessions.

Sip1 is a multidomain zinc-finger E-box-binding homeobox transcription factor that may also interact with many distinct protein complexes other than p-Smads, such as CtBP ( Postigo et al., 2003) and the NuRD chromatin remodeling complex ( Verstappen et al., 2008), to regulate the oligodendrocyte differentiation program. Whether these effects converge or exist in parallel at different stages during oligodendrocyte development, and whether Sip1 also regulates other signaling pathways

as seen in different contexts ( Goossens et al., 2011, Miquelajauregui PI3K Inhibitor Library ic50 et al., 2007 and Seuntjens et al., 2009), are compelling new questions for future investigation.

We show here that during oligodendrocyte differentiation, Sip1 inhibits BMP-Smad signaling activity by interacting directly with the receptor-activated Smad complex while activating expression of Smad7, encoding a negative feedback regulator of TGF-β/BMP signaling. These two action modes via Sip1 work in concert to inhibit negative BMP-Smad signaling activity on expression of myelin genes and therefore indirectly promote myelination ( Figure 8C). Other potential Sip1 downstream components such as these encoded by MRF and Sox10 may coordinate with Smad7 to regulate myelin gene expression. Thus, Sip1 may act, even within the same cell, both as repressor and activator in a context-dependent GDC-0199 chemical structure manner, probably depending on the transcriptional coregulators with which it cooperates at a specific time during oligodendrocyte differentiation. In either case, our findings suggest that Sip1

exerts a dualistic function via controlling the activity of distinct Smad effectors and functionally coordinate the positive and negative regulatory cues to establish the program that promotes myelination ( Figure 8C). Although BMP-Smad signaling has been reported Tolmetin to block oligodendrocyte maturation (Cheng et al., 2007, Miller et al., 2004 and See et al., 2004), the function of negative feedback Smad effectors in the regulation of oligodendrocyte differentiation is not known. The identification of the Smad7 gene as a direct target of Sip1 suggests that Sip1 exerts its function in oligodendrocyte myelination at least in part by activating I-Smad gene expression. Of particular interest, Smad7 is found uniquely and highly elevated in oligodendrocytes both in vivo and in vitro, in contrast to the second I-Smad gene, Smad6, whose mRNA is hardly detectable in oligodendrocytes by in situ hybridization, although Smad6 overexpression in OPCs downregulates BMP signaling (data not shown).

Collectively, these observations highlight the importance of neurovascular factors in maintaining white matter health. The realization that most cases of dementia have mixed pathological features has raised the intriguing possibility that vascular factors play role in AD and other neurodegenerative diseases. As discussed in the section on “Mixed lesions,” AD brains have a wide variety of vascular lesions, suggesting

a potential pathogenic interaction between vascular factors and AD. However, since cerebrovascular diseases and AD are common in the aged, the coexistence of the two pathologies could simply be coincidental (Hachinski, 2011). The overall effect on cognition would results from the combined burden of vascular and neurodegenerative pathology, according to an additive model. Alternatively, vascular disease could promote AD and vice-versa, PI3K Inhibitor Library resulting in a reciprocal interaction amplifying their pathogenic effects. The DNA Damage inhibitor cognitive impact of vascular and AD neuropathology depends on the severity of the AD pathology and location of the vascular lesions (Gold et al., 2007). In advanced cases of AD, vascular lesions do not seem to have a major influence on the progression of the cognitive deficits, suggesting the AD pathology is the major driver of the cognitive dysfunction (Chui et al., 2006 and Jellinger,

2001). On the other hand, in older individuals with moderate AD pathology subcortical too vascular lesions are a major determinant of the expression of the dementia (Esiri et al., 1999, Schneider et al.,

2007b and Snowdon et al., 1997). Cerebrovascular function is reduced in patients with early AD or at risk for AD (Claassen et al., 2009, Gao et al., 2013, Luckhaus et al., 2008, Mentis et al., 1996, Niedermeyer, 2006, Ruitenberg et al., 2005, Sabayan et al., 2012 and Tanaka et al., 2002), implicating reduced cerebral perfusion in the pathobiology of the disease (Iadecola, 2004). Conversely, some studies (Jendroska et al., 1995 and Ly et al., 2012), but not others (Aho et al., 2006 and Mastaglia et al., 2003), have reported increased amyloid deposition in stroke patients, implicating that ischemia promotes AD pathology. Furthermore, AD and cerebrovascular diseases may have common risk factors, such as hypertension, insulin resistance, diabetes, obesity, hyperhomocystinemia, hyperlipidemia, etc. (Craft, 2009, Fillit et al., 2008, Honjo et al., 2012 and Purnell et al., 2009). However, the correlation was most evident when the risk factors were considered together and not individually (Chui et al., 2012). Furthermore, the correlation was strongest for vascular dementia and weakest for AD, suggesting that vascular risk factors may independently increase the likelihood of dementia without exacerbating AD pathology (Chui et al., 2012).

The histofluorescence method developed in the early 1960s allowed the visualization of these nuclei and their projection pathways in the rat brain and revealed a remarkably similar organization in that the cell bodies are found in rather compact nuclei with widespread axonal projections to distant forebrain regions (Dahlstrom and Fuxe, 1964). Cholinergic nuclei in the brainstem (lateral dorsal tegmental nucleus and pedunculopontine nucleus [LDT/PPN]) and basal forebrain area (nucleus basalis of Meynert [NBM]) have similar anatomical organization and are also implicated in the regulation of vigilance and cognitive function (Jones, 2008). In

addition to their distal forebrain projections, the neuromodulatory nuclei have multiple reciprocal connections. The LC has strong Regorafenib datasheet projections to all of the others and receives direct input from its neighbor LDT/PPN and

from DR. The DR also projects to VTA and NBM, thereby influencing both dopamine (DA) and cholinergic input to the cortex (Hervé et al., 1987). To add to the complexity of the situation, these systems interact at the level of axon terminals by reciprocal modulation of release of transmitters. For example, noradrenaline (NA), acting at alpha 2 adrenoceptors located on terminals of all four neuronal types, inhibits release of their transmitters. At the same time, there are mutual increases of release of DA and NA via alpha 1 and D1 receptors, respectively, in selleck chemicals llc the prefrontal cortex (PFC) (Pan et al., 2004) and acetylcholine provokes a calcium-dependent release of both DA and NA via a muscarinic receptor (Rao et al., 2003). Ultimately, an understanding of the concerted action of neuromodulatory systems will reveal how behavioral states influence, promote, or even permit cognitive activity (Briand et al., 2007). Nevertheless, TCL in our view, a great deal has yet to be understood about the relative contribution of each one of these systems in attention,

perception, reward and punishment, learning, and memory. Here, we address the specific role of the noradrenergic nucleus locus coeruleus in modulating forebrain networks mediating cognitive activity. In addition to strongly innervating all of the other neuromodulatory nuclei, the LC sends projections to all cortical regions, as well as to thalamic nuclei, septum, hippocampus, and basal lateral amygdala (Loughlin et al., 1986; Figure 1). Moreover, LC is the sole source of noradrenergic innervation to these structures (Jones and Moore, 1977; Moore and Bloom, 1979; Asan, 1998; Samuels and Szabadi, 2008; Figure 1). Multiple approaches using lesions, pharmacology, and transgenic technology combined with behavioral analysis and in vitro and in vivo electrophysiological recording in target regions have generated a large literature and contributed much to our knowledge of how NA acts in the brain. Noradrenergic action in thalamus and cortex strongly influences arousal and behavioral state (Berridge et al.

Because it is difficult to bridge this gap, few studies are able to provide a mechanism that plausibly explains how aberrant functioning of the identified gene could lead to the onset of schizophrenia. These pitfall was cleverly surmounted by two innovative studies in this issue of Neuron focusing on the biology of the schizophrenia candidate gene DISC1 ( Kang et al., 2011 and Singh et al., 2011). In 1968, a cytogenetic survey of Scottish juvenile delinquents detected a single boy who carried a balanced translocation from chromosome 11 into the long arm of chromosome 1. Later

MLN8237 concentration analysis revealed a major mental illness in roughly half of those family members carrying the t(1;11) translocation, whereas only 1 in 10 cytogenetically normal relatives were so afflicted (St Clair et al., 1990). Three decades after its initial discovery, it was recognized

that this insertion truncates the gene now known as disrupted in schizophrenia 1 (DISC1), a bit of misnomer given that schizophrenia was less prevalent than major mood disorders in the t(1:11) proband ( Millar et al., AG-14699 2000). This association with schizophrenia was first corroborated through linkages studies of the Finnish population and later by using SNP-haplotype (genome-wide) association studies of Caucasian and Asian cohorts. DISC1 is a large scaffolding protein (93 kDa) that is widely expressed throughout the fetal and adult brain, most prominently in the human hippocampus. Initially, yeast two-hybrid screens indentified a host of DISC1 binding partners, including MAP1a, GSK-3β, and PDE4, which bind the N-terminal domain; FEZ1, which binds in the region containing the original t(1,11) disruption; and NDEL1 and LIS1, which bind near the C terminus. Moreover, association studies have linked PDE4, FEZ1, and NDEL1 with disease onset, though none have been rigorously

validated (reviewed by Chubb et al., 2008). Given the wide variety of binding partners, it is not surprising that DISC1 mediates a plethora of different biological functions, both in vitro and in vivo. Some examples include regulating neuroblast migration (Duan et al., 2007 and Ishizuka Dipeptidyl peptidase et al., 2011) or the proliferation of neural progenitors via an interaction with GSK-3β (Mao et al., 2009 and Singh et al., 2010). Signaling through GSK-3β is a key step in the canonical Wnt pathway. This family of pathways is essential for proper development of the fetal forebrain-hippocampus and midbrain dopaminergic systems, the brain regions most frequently implicated in the etiology of schizophrenia and bipolar affective disorder. In fact, one of the first transgenic animal models of schizophrenia was the result of knocking out the Wnt transducing protein disheveled (Lijam et al., 1997). GSK-3β and Wnt signaling also play critical roles in the development and function of neuronal circuits in the adult brain.

Studies that examined cardiovascular outcomes in healthy individuals were not included (e.g., normal baseline blood pressure). Abstracts of all research studies were reviewed to determine if participants were assigned

to a Tai Ji Quan intervention or if a Tai Ji Quan exercise group was compared with another group. After eliminating editorials, reviews papers, and duplicate citations, studies were examined in-depth to determine if they met the inclusion criteria. A total of 20 studies comprising 11 randomized clinical trials, seven quasi-experimental studies and two cross-sectional studies, met the inclusion criteria (Table 1). There were a total of 1182 participants (44% women), who ranged in age from 51 to 77 years old. Study click here sample sizes ranged from 18 to 207 participants per study. Tai Ji Quan as an exercise modality to prevent and manage CVD was examined on a variety of study variables (i.e., more than 20) among persons with coronary artery disease (n = 5 studies), 19, 20, 21, 22 and 23 chronic heart failure (n = 5 studies), 11, 24, 25, 26 and 27 stroke (n = 4 studies), 28, 29, 30 and 31 and CVD risk factors (n = 6 studies). 32, 33, 34, 35, 36, 37, 38 and 39 These studies were conducted primarily in Asia (n = 9, 45%)

19, 20, 21, 22, 29, 30, 36, 38 and 39 or the United States (n = 8, 40%). 11, 23, 24, 26, 27, 31, 32, 33, 34 and 35 Across all studies there were a total of 587 persons enrolled in Tai Ji Quan exercise. The Yang style of Tai Ji Quan was the principal style used (75%, n = 15), followed by the Wu style (10%, n = 2), and combined selleck or unspecified styles (15%, n = 3). The Tai Ji Quan interventions ranged from 12 1-h sessions over 12 weeks 29 and 30 to 156 1-h sessions over

52 weeks 36 and 38 with participants learning between 5 and 108 postures. Oxygenase The main control condition was usual care (n = 8), 19, 20, 21, 22, 25, 27, 31 and 38 followed by other exercise classes, such as stretching, balance training, cardiac rehabilitation exercise, or resistance training (n = 5), 23, 28, 29, 30 and 36 sedentary comparisons or wait-list control groups (n = 4), 32, 36, 37 and 39 or group-based education (n = 3). 11, 24 and 26 Overall, attrition in these studies was low, and ranged from 0 to 27%: only two studies had attrition rates higher than 20%. 21 and 38 A total of four quasi-experimental studies and one cross-sectional study examined Tai Ji Quan among persons with coronary artery disease (Table 1).19, 20, 21, 22 and 23 Study participants ranged in age 60–70 years old, had coronary artery disease confirmed by coronary angiography and/or were attending cardiac rehabilitation. The effects of Tai Ji Quan on CVD risk factors, cardiac health behaviors, autonomic nervous system function, exercise capacity, and physical, cognitive, and psychosocial functioning compared to usual care/cardiac rehabilitation were examined.

After washes, 9EG7 antibody (2 μg/ml in Dulbecco’s modified Eagle’s medium [DMEM]) was applied, followed by incubation for 15 min at 37°C. After washes, the cells were lysed in SDS sample buffer. Bound 9EG7 antibodies were detected using biotin-conjugated donkey antirat IgG (1:2000, Jackson ImmunoResearch) followed by horseradish peroxidase-conjugated streptavidin (1:2000, Perkin Elmer). Detailed procedures are described in the Supplemental Experimental Procedures. Cell adhesion

assay was performed as described previously (Bourgin et al., 2007), with some modification. E16 embryonic cortices were dissociated, stimulated with Reelin-conditioned medium for 15 min at 37°C, and plated onto the coated wells (7 × 104 cells per well) filled with DMEM for 5 min at 37°C. Then, after three washes with warm DMEM, the attached cells were counted (nine microscopic selleck compound fields [20×] were counted in each well). Detailed procedures are described in the Supplemental Experimental Procedures. The fluorescence intensity of GFP and Dylight-549 was detected using FV1000. Detailed procedures are described in the Supplemental Experimental Procedures. For direct comparisons, selleck chemical the data were analyzed by Mann Whitney

U test (n < 10). For multiple comparisons, ANOVA was performed, followed by Tukey's posthoc test. All bar graphs were plotted as mean ± SEM. This project was supported by the Strategic Research Program for Brain Sciences (“Understanding of molecular and environmental bases for brain health”), Grant-in-Aid for Thiamine-diphosphate kinase Scientific Research, Global COE Program of the Ministry of Education, Culture, Sports, and Science and Technology of Japan, and Keio Gijuku Academic Development Funds. J.H. is supported by grants from the NIH, AHAF, the Consortium for Frontotemporal

Dementia Research, and SFB780. We thank Drs. T. Curran (reelin); J. Cooper (dab1); F. Miller (Tα1 vector); D. Turner (mU6-provector); M. Matsuda (c3g); H. Kitayama (rap1a); N. Minato (spa1); L. Huganir (n-cadherin); T. Tsuji (integrin α3); M. Ginsberg (talin1); J. Takagi (2A-reelin); C. Cepko (pCALNL vector); T. Miyata (Tα1-Cre vector); and J. Miyazaki (pCAGGS vector) for providing the plasmids, and all of the members of the Nakajima laboratory for discussion. K.S. is a research fellow of the Japan Society for the Promotion of Science. K.S. designed and performed all of the experiments, analyzed the data, and wrote the manuscript. T. Kawauchi designed the initial experiments, analyzed the data, and wrote the manuscript. K.K. supported the preparation of Reelin, performed some in utero electroporation, and analyzed the data. T.H. constructed a part of the Dab1 expression vectors and analyzed the data. J.H. and M.H. provided the mutant mice, and J.H. edited the paper. T. Kinashi designed the integrin experiments and analyzed the data. K.N. supervised the whole project, analyzed the data, and wrote the manuscript.

, 2009 and Mahncke et al., 2006a). Intuitively, an obvious target might be the ability to form and retrieve representations of episodes, which is

thought to depend on the medial temporal lobes (MTL) (Eichenbaum et al., 2007). However, it is generally believed GW786034 datasheet that memory formation and retrieval constantly engage the MTL, even when one is not attempting to do so. Thus, it is not clear whether repeated performance of episodic encoding and retrieval tasks would further tax MTL function and result in general improvements in memory. Instead, research has largely focused on processes that contribute to effective memory encoding and retrieval. For instance, one view is that memory impairments in aging and in many clinical disorders reflect a “downstream” consequence of primary sensory deficits. According to this view, the fidelity of sensory inputs degrades with age and may be affected by various neurological and psychiatric conditions. Peripheral sensory

deficits, in turn, could lead to degraded encoding of events and possibly impaired episodic memory performance (Mahncke et al., 2006a). Thus, if perceptual abilities can be improved through training tasks (e.g., phoneme discrimination with degraded stimuli), this could lead to improved memory encoding. Working from this premise, some companies have designed products aimed at improving perceptual abilities through Nintedanib cost cognitive training. For example, Posit Science (http://www.positscience.com/) has developed an intervention program using computerized tasks that place increasing demands on perceptual processing (as well as other modules which emphasize more high-level processing). This program is based in part on findings that, even in the adult brain, there to is substantial plasticity in primary sensory regions (Mahncke et al., 2006a). A strength of perceptual training approaches is that they target a potential cause of memory problems in the real world whose impact

may be underestimated in laboratory experiments. In laboratory or clinical settings, researchers typically try to ensure that stimuli to be learned are highly discriminable, but in the real world, the stimuli that we encounter are often embedded in noisy contexts (such as words spoken in a loud room, or a face that is seen under poor lighting conditions). That said, it is important to point out that perceptual degradation might not be a primary cause of memory impairments seen over the course of normal aging or in memory disorders (Murphy et al., 2000). Another approach to ability training is based on evidence showing that the prefrontal cortex (PFC) plays a critical role in successful episodic memory encoding and retrieval (see Ranganath and Blumenfeld, 2008, for review). Recent work has demonstrated that prefrontal functioning can be improved through behavioral training.