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Since the birth of cognitive science, researchers have used reaction time and accuracy to measure cognitive ability. Although recognition of these two measures is often based on empirical observations, the underlying consensus is that most cognitive behaviors may be along two fundamental dimensions: cognitive processing speed (CPS) and cognitive processing accuracy (CPA). In this study, we used genomic-wide association studies (GWAS) data from 14 cognitive traits to show the presence of those two factors and revealed the specific neurobiological basis underlying them. We identified that CPS and CPA had distinct brain phenotypes (e.g. white matter microstructure), neurobiological bases (e.g. postsynaptic membrane), and developmental periods (i.e. late infancy). Moreover, those two factors showed differential associations with other health-related traits such as screen exposure and sleep status, and a significant causal relationship with psychiatric disorders such as major depressive disorder and schizophrenia. Utilizing an independent cohort from the Adolescent Brain Cognitive Development (ABCD) study, we also uncovered the distinct contributions of those two factors on the cognitive development of young adolescents. These findings reveal two fundamental factors underlying various cognitive abilities, elucidate the distinct brain structural fingerprint and genetic architecture of CPS and CPA, and hint at the complex interrelationship between cognitive ability, lifestyle, and mental health., (© 2024. The Author(s).)

Studies of COMT Val 158 Met suggest that the neural circuitry subserving inhibitory control may be modulated by this functional polymorphism altering cortical dopamine availability, thus giving rise to heritable differences in behaviors. Using an anatomically-constrained magnetoencephalography method and stratifying the sample by COMT genotype, from a larger sample of 153 subjects, we examined the spatial and temporal dynamics of beta oscillations during motor execution and inhibition in 21 healthy Met 158 /Met 158 (high dopamine) or 21 Val 158 /Val 158 (low dopamine) genotype individuals during a Go/NoGo paradigm. While task performance was unaffected, Met 158 homozygotes demonstrated an overall increase in beta power across regions essential for inhibitory control during early motor preparation (∼100 ms latency), suggestive of a global motor "pause" on behavior. This increase was especially evident on Go trials with slow response speed and was absent during inhibition failures. Such a pause could underlie the tendency of Met 158 allele carriers to be more cautious and inhibited. In contrast, Val 158 homozygotes exhibited a beta drop during early motor preparation, indicative of high response readiness. This decrease was associated with measures of behavioral disinhibition and consistent with greater extraversion and impulsivity observed in Val homozygotes. These results provide mechanistic insight into genetically-determined interindividual differences of inhibitory control with higher cortical dopamine associated with momentary response hesitation, and lower dopamine leading to motor impulsivity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The causal relationship between thyroid function variations within the reference range and cognitive function remains unknown. We aimed to explore this causal relationship using a Mendelian randomization (MR) approach., Methods: Summary statistics of a thyroid function genome-wide association study (GWAS) were obtained from the ThyroidOmics consortium, including reference range thyroid stimulating hormone (TSH) (N = 54,288) and reference range free thyroxine (FT4) (N = 49,269). GWAS summary statistics on cognitive function were obtained from the Social Science Genetic Association Consortium (SSGAC) and the UK Biobank, including cognitive performance (N = 257,841), prospective memory (N = 152,605), reaction time (N = 459,523), and fluid intelligence (N = 149,051). The primary method used was inverse-variance weighted (IVW), supplemented with weighted median, Mr-Egger regression, and MR-Pleiotropy Residual Sum and Outlier. Several sensitivity analyses were conducted to identify heterogeneity and pleiotropy., Results: An increase in genetically associated TSH within the reference range was suggestively associated with a decline in cognitive performance (β = -0.019; 95%CI: -0.034 to -0.003; P = 0.017) and significantly associated with longer reaction time (β = 0.016; 95 % CI: 0.005 to 0.027; P = 0.004). Genetically associated FT4 levels within the reference range had a significant negative relationship with reaction time (β = -0.030; 95%CI:-0.044 to -0.015; P = 4.85 × 10 -5 ). These findings remained robust in the sensitivity analyses., Conclusions: Low thyroid function within the reference range may have a negative effect on cognitive function, but further research is needed to fully understand the nature of this relationship., Limitations: This study only used GWAS data from individuals of European descent, so the findings may not apply to other ethnic groups., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome-wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a GWAS of RTV in participants of white British ancestry (n = 404,302) as well as a trans-ancestry GWAS meta-analysis (n = 44,873) to assess replication. We found 161 genome-wide significant single nucleotide polymorphisms (SNPs) distributed across 7 genomic loci in our discovery GWAS. Functional annotation of the variants implicated genes involved in synaptic function and neural development. The SNP-based heritability (h 2 SNP ) estimate for RTV was 3%. We investigated genetic correlations between RTV and selected neuropsychological traits using linkage disequilibrium score regression, and found significant correlations with several traits, including a positive correlation with mean reaction time and schizophrenia. Despite the high genetic correlation between RTV and mean reaction time, we demonstrate distinctions in the genetic underpinnings of these traits. Lastly, we assessed the predictive ability of a polygenic score (PGS) for RTV, calculated using PRSice and PRS-CS, and found that the RTV-PGS significantly predicted RTV in independent cohorts, but that the generalisability to other ancestry groups was poor. These results identify genetic underpinnings of RTV, and support the use of RTV as an endophenotype for neurological and psychiatric disorders., (© 2023. The Author(s).)

Neuroimaging demonstrates that athletes of collision sports can suffer significant changes to their brain in the absence of concussion, attributable to head acceleration event (HAE) exposure. In a sample of 24 male Division I collegiate football players, we examine the relationships between tryptophan hydroxylase 2 ( TPH2 ), a gene involved in neurovascular function, regional cerebral blood flow (rCBF) measured by arterial spin labeling, and virtual reality (VR) motor performance, both pre-season and across a single football season. For the pre-season, TPH2 T-carriers showed lower rCBF in two left hemisphere foci (fusiform gyrus/thalamus/hippocampus and cerebellum) in association with higher (better performance) VR Reaction Time, a dynamic measure of sensory-motor reactivity and efficiency of visual-spatial processing. For TPH2 CC homozygotes, higher pre-season rCBF in these foci was associated with better performance on VR Reaction Time. A similar relationship was observed across the season, where TPH2 T-carriers showed improved VR Reaction Time associated with decreases in rCBF in the right hippocampus/amygdala, left middle temporal lobe, and left insula/putamen/pallidum. In contrast, TPH2 CC homozygotes showed improved VR Reaction Time associated with increases in rCBF in the same three clusters. These findings show that TPH2 T-carriers have an abnormal relationship between rCBF and the efficiency of visual-spatial processing that is exacerbated after a season of high-impact sports in the absence of diagnosable concussion. Such gene-environment interactions associated with behavioral changes after exposure to repetitive HAEs have been unrecognized with current clinical analytical tools and warrant further investigation. Our results demonstrate the importance of considering neurovascular factors along with traumatic axonal injury to study long-term effects of repetitive HAEs.

Background: The driving behavior of patients with mild Alzheimer's disease dementia (ADD) and patients with mild cognitive impairment (MCI) is frequently characterized by errors. A genetic factor affecting cognition is apolipoprotein E4 (APOE4), with carriers of APOE4 showing greater episodic memory impairment than non-carriers. However, differences in the driving performance of the two groups have not been investigated., Objective: To compare driving performance in APOE4 carriers and matched non-carriers., Methods: Fourteen APOE4 carriers and 14 non-carriers with amnestic MCI or mild ADD underwent detailed medical and neuropsychological assessment and participated in a driving simulation experiment, involving driving in moderate and high traffic volume in a rural environment. Driving measures were speed, lateral position, headway distance and their SDs, and reaction time. APOE was genotyped through plasma samples., Results: Mixed two-way ANOVAs examining traffic volume and APOE4 status showed a significant effect of traffic volume on all driving variables, but a significant effect of APOE4 on speed variability only. APOE4 carriers were less variable in their speed than non-carriers; this remained significant after a Bonferroni correction. To further examine variability in the driving performance, coefficients of variation (COV) were computed. Larger headway distance COV and smaller lateral position COV were observed in high compared to moderate traffic. APOE4 carriers had smaller speed COV compared to non-carriers., Conclusion: The lower speed variability of APOE4 carriers in the absence of neuropsychological test differences indicates reduced speed adaptations, possibly as a compensatory strategy. Simulated driving may be a sensitive method for detecting performance differences in the absence of cognitive differences.

Although the genetic influence on global stopping has been extensively investigated, little is known about the genetic contribution to other more complex forms of inhibitory control such as selective stopping. The selectivity of inhibitory control can be assessed by using the stimulus-selective stop-signal task. Notably, recent behavioural and neural evidence indicates that individuals can adopt selective but also non-selective stopping strategies to solve it. This study aimed to investigate for the first time the influence of two relevant dopaminergic polymorphisms (in COMT and DRD2 genes) on stimulus-selective stopping in a sample of 529 adults. Results showed that although none of these polymorphisms (neither individually nor in combination) modulate the latency of the stop process in each strategy (the stop-signal reaction time), the choice of strategy was influenced by their interaction. These results suggest that dopaminergic polymorphisms might influence strategy adoption in selective stopping paradigms, which constitutes a novel finding., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Investigating the contribution of biology to human cognition has assumed a bottom-up causal cascade where genes influence brain systems that activate, communicate, and ultimately drive behavior. Yet few studies have directly tested whether cognitive traits with overlapping genetic underpinnings also rely on overlapping brain systems. Here, we report a step-wise exploratory analysis of genetic and functional imaging overlaps among cognitive traits. We used twin-based genetic analyses in the human connectome project (HCP) dataset (N ​= ​486), in which we quantified the heritability of measures of cognitive functions, and tested whether they were driven by common genetic factors using pairwise genetic correlations. Subsequently, we derived activation maps associated with cognitive tasks via functional imaging meta-analysis in BrainMap (N ​= ​4484), and tested whether cognitive traits that shared genetic variation also exhibited overlapping brain activation. Our genetic analysis determined that six cognitive measures (cognitive flexibility, no-go continuous performance, fluid intelligence, processing speed, reading decoding and vocabulary comprehension) were heritable (0.3 ​< ​h 2  ​< ​0.5), and genetically correlated with at least one other heritable cognitive measure (0.2 ​< ​ρ g  ​< ​0.35). The meta-analysis showed that two genetically-correlated traits, cognitive flexibility and fluid intelligence (ρ g  ​= ​0.24), also had a significant brain activation overlap (ρ perm  ​= ​0.29). These findings indicate that fluid intelligence and cognitive flexibility rely on overlapping biological features, both at the neural systems level and at the molecular level. The cross-disciplinary approach we introduce provides a concrete framework for data-driven quantification of biological convergence between genetics, brain function, and behavior in health and disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Reaction time variability (RTV) is a ubiquitous phenomenon in Attention-Deficit/Hyperactivity Disorder (ADHD). Few studies have examined RTV in relation to functional outcomes such as social impairment in children with ADHD. In this exploratory study, we investigated whether RTV is associated with social functioning in children at risk for ADHD. Specifically, we explored the association between RTV (tau derived from correct go trials of a Stop-Signal task) and social functioning in 198 children ages 7-12 years referred for an ADHD evaluation. Social functioning measures included child and/or parent ratings of social competence, aggression, social problems, and impairment in relationships. In regression analyses that also included Oppositional Defiant Disorder symptoms and sex, higher RTV was significantly associated with lower ratings of social competence, and higher proactive/reactive aggression ratings on the child self-report measures. RTV was not significantly associated with parent report of social functioning or relationship impairment. This study provides preliminary evidence that RTV may be associated with social functioning in children at risk for ADHD. We propose that lapses of attention affecting cognitive control may also negatively impact social information processing thereby affecting social functioning. Replication is warranted and longitudinal studies are needed to investigate whether RTV predicts social dysfunction in ADHD.

Introduction: The neuronal isoform of the nitric oxide synthase (NOS-I) encoded by NOS1 is the main source of nitric oxide (NO) in the brain. Reduced NO signaling in the prefrontal cortex has been linked to schizophrenia and cognitive processes while reduced striatal NOS1 expression has been associated with impulsive behavior., Methods: To evaluate the effect of two functional polymorphisms in alternative first exons of NOS1, ex1f-VNTR and ex1c-SNP rs41279104, on the HPA stress axis and neurocognitive abilities, 280 healthy subjects were genotyped, had their salivary cortisol levels measured and were assessed in verbal memory, verbal fluency, working memory and verbal IQ by using the California Verbal Learning Test (CVLT), the Regensburger test of verbal fluency (RWT), a n-back task and subscales of the Wechsler Adult Intelligence Scale III (WAIS-III)., Results: Schizophrenia risk (A)-allele carriers of NOS1 ex1c-SNP rs41279104 displayed significantly lower baseline cortisol levels (p = 0.004). NOS1 ex1f-VNTR genotype carriers showed differences in working memory performance (p = 0.05) in a gene-dose effect manner, with homozygous carriers of the short impulsivity-risk allele committing most commission errors. Finally, A-allele carriers of the NOS1 ex1c-SNP rs41279104 tended to react faster during the working memory task (p = 0.065)., Conclusion: For the first time, we demonstrated an influence of the NOS1 ex1c-SNP rs41279104 on salivary cortisol levels and additionally implicate the A-allele in an enhanced reaction time during a working memory task. Regarding the NOS1 ex1f-VNTR our study supports the previously reported influence on impulsivity, lending further support to the hypothesis that this genetic variant underlies impulsive behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Visual-spatial neglect (VSN) is a neuropsychological syndrome, and right-hemisphere stroke is the most common cause. The pathogenetic mechanism of VSN remains unclear. This study aimed to investigate the behavioral and event-related potential (ERP) changes in patients with or without VSN after right-hemisphere stroke., Methods: Eleven patients with VSN with right-hemisphere stroke (VSN group) and 11 patients with non-VSN with right-hemisphere stroke (non-VSN group) were recruited along with one control group of 11 age- and gender-matched healthy participants. The visual-spatial function was evaluated using behavioral tests, and ERP examinations were performed., Results: The response times in the VSN and non-VSN groups were both prolonged compared with those of normal controls (P < 0.001). In response to either valid or invalid cues in the left side, the accuracy in the VSN group was lower than that in the non-VSN group (P < 0.001), and the accuracy in the non-VSN group was lower than that in controls (P < 0.05). The P1 latency in the VSN group was significantly longer than that in the control group (F[2, 30] = 5.494, P = 0.009), and the N1 amplitude in the VSN group was significantly lower than that in the control group (F[2, 30] = 4.343, P = 0.022). When responding to right targets, the left-hemisphere P300 amplitude in the VSN group was significantly lower than that in the control group (F[2, 30] = 4.255, P = 0.025). With either left or right stimuli, the bilateral-hemisphere P300 latencies in the VSN and non-VSN groups were both significantly prolonged (all P < 0.05), while the P300 latency did not differ significantly between the VSN and non-VSN groups (all P > 0.05)., Conclusions: Visual-spatial attention function is impaired after right-hemisphere stroke, and clinicians should be aware of the subclinical VSN. Our findings provide neuroelectrophysiological evidence for the lateralization of VSN.

Increased intrasubject variability in reaction times (RT-ISV) is frequently found in individuals with autism spectrum disorder (ASD). However, how dimensional attention deficit/hyperactivity disorder (ADHD) symptoms impact RT-ISV in individuals with ASD remains elusive. We assessed 97 high-functioning youths with co-occurring ASD and ADHD (ASD+ADHD), 124 high-functioning youths with ASD only, 98 youths with ADHD only, and 249 typically developing youths, 8-18 years of age, using the Conners Continuous Performance Test (CCPT). We compared the conventional CCPT parameters (omission errors, commission errors, mean RT and RT standard error (RTSE) as well as the ex-Gaussian parameters of RT (mu, sigma, and tau) across the four groups. We also conducted regression analyses to assess the relationships between RT indices and symptoms of ADHD and ASD in the ASD group (i.e., the ASD+ADHD and ASD-only groups). The ASD+ADHD and ADHD-only groups had higher RT-ISV than the other two groups. RT-ISV, specifically RTSE and tau, was significantly associated with ADHD symptoms rather than autistic traits in the ASD group. Regression models also revealed that sex partly accounted for RT-ISV variance in the ASD group. A post hoc analysis showed girls with ASD had higher tau and RTSE values than their male counterparts. Our results suggest that RT-ISV is primarily associated with co-occurring ADHD symptoms/diagnosis in children and adolescents with ASD. These results do not support the hypothesis of response variability as a transdiagnostic phenotype for ASD and ADHD and warrant further validation at a neural level.

BACE1 is a β-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer's disease (AD). The entorhinal cortex and the dentate gyrus are important for learning and memory, which are affected in the early stages of AD. Since BACE1 is a potential target for AD therapy, it is crucial to understand its physiological role in these brain regions. Here, we examined the function of BACE1 in the dentate gyrus. We show that loss of BACE1 in the dentate gyrus leads to increased granule cell excitability, indicated by enhanced efficiency of synaptic potentials to generate granule cell spikes. The increase in granule cell excitability was accompanied by prolonged paired-pulse inhibition, altered network gamma oscillations, and impaired synaptic plasticity at entorhinal-dentate synapses of the perforant path. In summary, this is the first detailed electrophysiological study of BACE1 deletion at the network level in vivo. The results suggest that BACE1 is important for normal dentate gyrus network function. This has implications for the use of BACE1 inhibitors as therapeutics for AD therapy, since BACE1 inhibition could similarly disrupt synaptic plasticity and excitability in the entorhinal-dentate circuitry.

Anterior cingulate cortex (ACC) and midcingulate cortex (MCC) have been implicated in the regulation of aggressive behaviour. For instance, patients with conduct disorder (CD) show increased levels of aggression accompanied by changes in ACC and MCC volume. However, accounts of ACC/MCC changes in CD patients have been conflicting, likely due to the heterogeneity of the studied populations. Here, we address these discrepancies by studying volumetric changes of ACC/MCC in the BALB/cJ mouse, a model of aggression, compared to an age- and gender-matched control group of BALB/cByJ mice. We quantified aggression in BALB/cJ and BALB/cByJ mice using the resident-intruder test, and related this to volumetric measures of ACC/MCC based on Nissl-stained coronal brain slices of the same animals. We demonstrate that BALB/cJ behave consistently more aggressively (shorter attack latencies, more frequent attacks, anti-social biting) than the control group, while at the same time showing an increased volume of ACC and a decreased volume of MCC. Differences in ACC and MCC volume jointly predicted a high amount of variance in aggressive behaviour, while regression with only one predictor had a poor fit. This suggests that, beyond their individual contributions, the relationship between ACC and MCC plays an important role in regulating aggressive behaviour. Finally, we show the importance of switching from the classical rodent anatomical definition of ACC as cingulate area 2 and 1 to a definition that includes the MCC and is directly homologous to higher mammalian species: clear behaviour-related differences in ACC/MCC anatomy were only observed using the homologous definition.

Posttraumatic stress disorder is developed by exposure to a threatening and/or a horrifying event and characterized by the presence of anxiety, hyperarousal, avoidance, and sleep abnormality for a prolonged period of time. To elucidate the potential molecular mechanisms, we constructed a mouse model by electric foot shock followed by situational reminders and performed transcriptome analysis in brain tissues. The stressed mice acquired anxiety-like behavior after 2 weeks and exaggerated startle response after 4 weeks. Avoidance latency and freezing behavior were sustained up to 5 weeks post stress and abnormal static behavior was observed during the sleep period. RNA sequencing was performed in two of the emotional regulatory regions, anterior cingulate cortex and amygdala, at 2 and 5 weeks post stress. More than 1000 differentially expressed genes were identified at 2 weeks in both regions. The number of the regulated genes remained constant in amygdala at 5 weeks post stress, whereas those in anterior cingulate cortex were plummeted. Although synaptic remodeling and endocrine system were the most enriched signaling pathways in both anterior cingulate cortex and amygdala, the individual gene expression profile was regulated in a region- and time-dependent manner. In addition, several genes associated with PTSD involved in Hypothalamic-Pituitary-Adrenal axis were differentially regulated. These findings suggested that global gene expression profile was dynamically regulated in accordance with the disease development stage, and therefore targeting the distinct signaling molecules in different region and development stage might be critical for effective treatment to PTSD.

Despite evidence of a relationship between Apolipoprotein E (APOE) ε4+ and later-life cognitive decline, the lifespan effects of carrying an ε4+ allele on cognitive ageing are not well understood. Evidence of ε4+ advantages in early-life are inconsistent, but not inconsiderable. We explored the proposal that APOE ε4+ cognitive advantages arise only in response to complex and sensitive tasks targeting specific executive functions. We systematically manipulated executive demand within verbal fluency, decision-making, prospective memory, and sustained attention tasks. Participants aged 18-25 years (21 ε4+, 63 ε33) also completed a measure of subjective effort. Under low executive demand, ε4+ made fewer verbal fluency word repeats compared to ε33 carriers. Under high executive demand, ε4+ showed lower costs associated with performing concurrent tasks, greater switching errors, and more verbal fluency root repetition errors. Overall, ε4+ appeared to be showing working memory updating advantages under conditions of low executive demand, more effective resource allocation under elevated levels of executive demand, and errors indicating different strategy use compared to ε33 carriers, including speed-accuracy trade-offs., (Copyright © 2018. Published by Elsevier B.V.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that results in cognitive decline and a number of other neuropsychiatric symptoms. One area that is often affected by neuropsychiatric disease is the response to sudden, loud noises, as measured by the acoustic startle response (ASR), and prepulse inhibition (PPI), which indicates sensory-gating abilities. Evidence suggests AD patients, even early in the disease, show alteration in ASR. Studies have also shown changes in this measure in transgenic mouse models of AD. To assess the homology of 5xFAD mice to AD patients, the current study analyzed several aspects of the startle response in these mice using a protocol with fewer trials than previous studies. It was found that the 5xFAD mice had a delayed startle response, similar to what has been observed in AD sufferers. These results suggest the ASR may be a useful tool in assessing the efficacy of potential therapeutics, and that a simplified protocol may be more sensitive to between-groups differences for this task., (Copyright © 2018 Elsevier B.V. All rights reserved.)

There exists solid evidence that endogenous galanin and galanin agonists exert anticonvulsive actions mediated both by galanin 1 receptor (GAL1-R) and galanin 2 receptor (GAL2-R). We have now investigated whether depletion of the recently identified third galanin receptor, GAL3-R, and that of GAL2-R, alters the threshold to the systemically applied γ-aminobutyric acid (GABA) antagonist pentylenetetrazole (PTZ) or to intrahippocampally administered kainic acid (KA). In neither model, GAL3-KO mice differed in their latency to the first seizure, mean seizure duration, total number of seizures, or time spent in seizures compared to wild-type controls. In addition, consistent with previous data, the response to PTZ was not altered in GAL2-KO mice. In contrast, intrahippocampal KA resulted in a significantly increased number of seizures and time spent in seizures in GAL2-KO mice, although the latency to the first seizure and the duration of individual seizures was not altered. These results are consistent with the previous data showing that GAL2-R knockdown does not affect the number of perforant path stimulations required for initiating status epilepticus but significantly increases the seizure severity during the ongoing status. In conclusion, our data support a specific role of GAL2-R but not of GAL3-R in mediating the anticonvulsive actions of endogenous galanin., (© The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

The objective of this study was to characterize an attention deficit hyperactivity disorder (ADHD) endophenotype in non-affected parents of adolescents with a history of ADHD, based on the relationship between performance on a sustained attention test (continuous performance task, or CPT) and polymorphisms of the DRD4 gene. In a sample of 25 non-affected parents of adolescents with ADHD history obtained from a longitudinal study of a nonclinical population, and 25 non-affected parents of adolescents with no ADHD history, four groups were evaluated with respect to the presence or absence of the long allele polymorphism of the DRD4 gene (i.e., over seven repeats). Comparisons of CPT performance among the four study groups included the number of commission errors, the number of omission errors, mean reaction time on correct responses (MRT), and reaction time (RT) variability (mean standard deviation of RT in each block [SDRT, as variability], and the sigma and tau components of the ex-Gaussian approach). The group of non-affected parents of adolescents with ADHD history and at least one long allele of the DRD4 gene showed greater RT variability (measured by SDRT), which is best explained by the greater frequency of abnormally slow responses (measured by tau). An association between the presence of the long allele of the DRD4 gene polymorphism and ADHD-like failure in CPT performance was evident in the non-affected parents of adolescents with ADHD in childhood. These findings suggest that certain traits of CPT performance could be considered an ADHD endophenotype., (© 2018 Wiley Periodicals, Inc.)

The signal transducer and activator of transcription 5 (STAT5) is a transcription factor recruited by numerous cytokines. STAT5 is important for several physiological functions, including body and tissue growth, mammary gland development, immune system and lipid metabolism. However, the role of STAT5 signaling for brain functions is still poorly investigated, especially regarding cognitive aspects. Therefore, the objective of the present study was to investigate whether brain STAT5 signaling modulates learning and memory formation. For this purpose, brain-specific STAT5 knockout (STAT5 KO) mice were studied in well-established memory tests. Initially, we confirmed a robust reduction in STAT5a and STAT5b mRNA levels in different brain structures of STAT5 KO mice. STAT5 KO mice showed no significant alterations in metabolism, growth, somatotropic axis and spontaneous locomotor activity. In contrast, brain-specific STAT5 ablation impaired learning and memory formation in the novel object recognition, Barnes maze and contextual fear conditioning tests. To unravel possible mechanisms that might underlie the memory deficits of STAT5 KO mice, we assessed neurogenesis in the hippocampus, but no significant differences were observed between groups. On the other hand, reduced insulin-like growth factor-1 (IGF-1) mRNA expression was found in the hippocampus and hypothalamus of STAT5 KO mice. These findings collectively indicate that brain STAT5 signaling is required to attain normal learning and memory. Therefore, STAT5 is an important downstream cellular mechanism shared by several cytokines to regulate cognitive functions.

Currently there is a very limited understanding of how mental wellbeing versus anxiety and depression symptoms are associated with emotion processing behaviour. For the first time, we examined these associations using a behavioural emotion task of positive and negative facial expressions in 1668 healthy adult twins. Linear mixed model results suggested faster reaction times to happy facial expressions was associated with higher wellbeing scores, and slower reaction times with higher depression and anxiety scores. Multivariate twin modelling identified a significant genetic correlation between depression and anxiety symptoms and reaction time to happy facial expressions, in the absence of any significant correlations with wellbeing. We also found a significant negative phenotypic relationship between depression and anxiety symptoms and accuracy for identifying neutral emotions, although the genetic or environment correlations were not significant in the multivariate model. Overall, the phenotypic relationships between speed of identifying happy facial expressions and wellbeing on the one hand, versus depression and anxiety symptoms on the other, were in opposing directions. Twin modelling revealed a small common genetic correlation between response to happy faces and depression and anxiety symptoms alone, suggesting that wellbeing and depression and anxiety symptoms show largely independent relationships with emotion processing at the behavioral level., (Copyright © 2018 Elsevier B.V. All rights reserved.)

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10 -8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

This protocol describes a modified serial reaction time (SRT) task used to study implicit motor sequence learning. Unlike the classic SRT task that involves finger-pressing movements while sitting, the modified SRT task requires participants to step with both feet while maintaining a standing posture. This stepping task necessitates whole body actions that impose postural challenges. The foot-stepping task complements the classic SRT task in several ways. The foot-stepping SRT task is a better proxy for the daily activities that require ongoing postural control, and thus may help us better understand sequence learning in real-life situations. In addition, response time serves as an indicator of sequence learning in the classic SRT task, but it is unclear whether response time, reaction time (RT) representing mental process, or movement time (MT) reflecting the movement itself, is a key player in motor sequence learning. The foot-stepping SRT task allows researchers to disentangle response time into RT and MT, which may clarify how motor planning and movement execution are involved in sequence learning. Lastly, postural control and cognition are interactively related, but little is known about how postural control interacts with learning motor sequences. With a motion capture system, the movement of the whole body (e.g., the center of mass (COM)) can be recorded. Such measures allow us to reveal the dynamic processes underlying discrete responses measured by RT and MT, and may aid in elucidating the relationship between postural control and the explicit and implicit processes involved in sequence learning. Details of the experimental set-up, procedure, and data processing are described. The representative data are adopted from one of our previous studies. Results are related to response time, RT, and MT, as well as the relationship between the anticipatory postural response and the explicit processes involved in implicit motor sequence learning.

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43 Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene. Furthermore, a new approach to stratify transcriptomic data by phenotype in differentially affected mutant mice revealed 471 changes linked with improved behavior. These changes included downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.

It is well known that voluntary running can enhance synaptic plasticity and improve learning and memory abilities. The Notch1 receptor is also reported to be associated with these processes, but its role in running-induced alterations is unclear. In this study, we aimed to investigate whether the Notch1 signalling pathway was involved in voluntary running-induced enhancement of synaptic plasticity, learning and memory. Notch1 heterozygous deficient (Notch1 +/- ) mice and wildtype (WT) C57BL littermates were randomly divided into runner group and non-runner group. Mice were given free access to running wheels for 14 days in both the Notch1 +/- runner group and the WT runner group. Our results demonstrate that Notch1 knockdown impairs the performance in the novel object recognition (NOR) test and Morris water maze test and decreases the synaptic plasticity. Voluntary running improves spatial learning and memory abilities, promotes synaptic plasticity and increases expressions of postsynaptic proteins in WT mice but not in Notch1 +/- mice. Our results suggest that Notch1 plays a vital role in spatial learning and memory, synaptic plasticity under normal physiological conditions and voluntary running conditions. These findings will set the groundwork and fill in some gaps for understanding the role of Notch1 signalling in voluntary running-induced phenomena.

Accumulating evidence points to a genetic contribution to explain inter-individual vulnerability to sleep deprivation. A functional polymorphism in the BDNF gene, which causes a valine (Val) to methionine (Met) amino acid substitution at Codon 66, has been associated with cognitive impairment, particularly in populations with impaired frontal functioning. We hypothesised that sleep deprivation, which affects frontal function, may lead to cognitive dysfunction in Met allele carriers. To examine this, we investigated, in different BDNF genotypes, the effects of sleep deprivation on cognitive flexibility, as measured by response inhibition using the Stroop Color Naming Task. Thirty healthy, adults of European ancestry, including 12 heterozygous Met allele carriers and 18 Val/Val homozygotes, underwent 30-h of extended wakefulness under constant routine conditions. A computerised Stroop task was administered every 2h. Error rate and reaction times increased with time awake for all individuals. Participants with the Val/Met genotype made more errors on incongruent trials after 20h awake. While Val/Met participants also took significantly longer to respond when inhibiting a prepotent response irrespective of time awake, this was particularly evident during the biological night. Our study shows that carriers of the BDNF Met allele are more vulnerable to the impact of prolonged wakefulness and the biological night on a critical component of executive function, as measured by response inhibition on the Stroop task., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Acid-sensing ion channels (ASICs) are cation channels activated by protons. ASIC1a, a primary ASIC subunit in the brain, was recently characterized in the olfactory bulb. The present study tested the hypothesis that ASIC1a is essential for normal olfactory function. Olfactory behavior of wild-type (WT) and ASIC1-/- mice was evaluated by using three standard olfactory tests: (1) the buried food test, (2) the olfactory habituation test, and (3) the olfactory preference test. In buried food test, ASIC1-/- mice had significantly longer latency to uncover buried food than WT mice. In olfactory habituation test, ASIC1-/- mice had increased sniffing time with acidic odorants. In olfactory preference test, ASIC1-/- mice did not exhibit normal avoidance behavior for 2, 5- dihydro-2, 4, 5-trimethylthiazoline (TMT). Consistent with ASIC1 knockout, ASIC1 inhibition by nasal administration of PcTX1 increased the latency for WT mice to uncover the buried food. Together, these findings suggest a key role for ASIC1a in normal olfactory function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Reduced cerebral blood flow in Alzheimer's disease (AD) may occur in early AD, which contributes to the pathogenesis and/or pathological progression of AD. Reversing this deficit may have therapeutic potential. Certain traditional Chinese herbal medicines (e.g., Saponin and its major component Xueshuantong [XST]) increase blood flow in humans, but whether they could be effective in treating AD patients has not been tested. We found that systemic XST injection elevated cerebral blood flow in APP/PS1 transgenic mice using two-photon time-lapse imaging in the same microvessels before and after injection. Subchronic XST treatment led to improved spatial learning and memory and motor performance in the APP/PS1 mice, suggesting improved neural plasticity and functions. Two-photon time lapse imaging of the same plaques revealed a reduction in plaque size after XST treatment. In addition, western blots experiments showed that XST treatment led to reduced processing of amyloid-β protein precursor (AβPP) and enhanced clearance of amyloid-β (Aβ) without altering the total level of AβPP. We also found increased synapse density in the immediate vicinity of amyloid plaques, suggesting enhanced synaptic function. We conclude that targeting cerebral blood flow can be an effective strategy in treating AD.

To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging.

Background: It was previously shown that inactivation of gamma-synuclein which is a small soluble neuronal protein affects psycho-emotional status and cognitive abilities in knock-out mice., Objective: Determine the role of gamma-synuclein inactivation on memory performance in aging animals., Method: We used the passive avoidance test and acute amphetamine administration in aging gammasynuclein knock-out mice., Results: As a result, we found moderate aging-unlinked deficit of dopaminergic neurotransmitter system of gamma-synuclein knock-out mice. At the same time, the evidence of progressive synaptic vesicle trafficking machinery impairment was obtained., Conclusion: Therefore most likely these dysfunctions are associated with a reduction in the highefficient learning performance in tests that require intact working memory., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer's disease (AD) quantitative clinical outcome measures, including amyloid-β (Aβ), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of Aβ (Aβ40, Aβ42) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R2 = 0.064, n = 116, p < 0.05); only soluble Aβ or directly measured Aβ meaningfully contribute. Tau expression in 3xTg-AD mice was within 10-20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R2 = 0.176, n = 113, p < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau's lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after Aβ levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3β, GSK3β, CDK5), identified phosphorylated ser9 GSK3β as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aβ. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aβ and pTau, possibly through the GSK3 pathway.

Amyloid β (Aβ) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of Aβ is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using Aβ-injected as well as 5XFAD AD model mice. Oligomeric Aβ injections into the 3rd ventricle caused concentration-dependent and time-dependent impairments in learning/memory and synaptic plasticity. Moreover, Aβ aberrantly regulated caspase-3, GSK-3β, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3β inhibitor ameliorated memory impairments and synaptic deficits in Aβ-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both Aβ-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Although previous research suggests that genetic variation in dopaminergic genes may affect recognition memory, the role dopamine transporter expression may have on the behavioral and EEG correlates of recognition memory has not been well established., Objectives: The study aims to reveal how individual differences in dopaminergic functioning due to genetic variations in the dopamine transporter gene influences behavioral and EEG correlates of recognition memory., Methods: Fifty-eight participants performed an item recognition task. Participants were asked to retrieve 200 previously presented words while brain activity was recorded with EEG. Regions of interest were established in scalp locations associated with recognition memory. Mean ERP amplitudes and event-related spectral perturbations when correctly remembering old items (hits) and recognizing new items (correct rejections) were compared as a function of dopamine transporter group., Results: Participants in the dopamine transporter group that codes for increased dopamine transporter expression (10/10 homozygotes) display slower reaction times compared to participants in the dopamine transporter group associated with the expression of fewer dopamine transporters (9R-carriers). 10/10 homozygotes further displayed differences in ERP and oscillatory activity compared to 9R-carriers. 10/10 homozygotes fail to display the left parietal old/new effect, an ERP signature of recognition memory associated with the amount of information retrieved. 10/10 homozygotes also displayed greater decreases of alpha and beta oscillatory activity during item memory retrieval compared to 9R-carriers., Conclusion: Compared to 9R-carriers, 10/10 homozygotes display slower hit and correct rejection reaction times, an absence of the left parietal old/new effect, and greater decreases in alpha and beta oscillatory activity during recognition memory. These results suggest that dopamine transporter polymorphisms influence recognition memory.

Sevoflurane is the most widely used anaesthetic administered by inhalation. Exposure to sevoflurane in neonatal mice can induce learning deficits and abnormal social behaviours. MicroRNA (miR)-27a-3p, a short, non-coding RNA that functions as a tumour suppressor, is up-regulated after inhalation of anaesthetic, and peroxisome proliferator-activated receptor γ (PPAR-γ) is one of its target genes. The objective of this study was to investigate how the miR-27a-3p-PPAR-γ interaction affects sevoflurane-induced neurotoxicity. A luciferase reporter assay was employed to identify the interaction between miR-27a-3p and PPAR-γ. Primary hippocampal neuron cultures prepared from embryonic day 0 C57BL/6 mice were treated with miR-27a-3p inhibitor or a PPAR-γ agonist to determine the effect of miR-27a-3p and PPAR-γ on sevoflurane-induced cellular damage. Cellular damage was assessed by a flow cytometry assay to detect apoptotic cells, immunofluorescence to detect reactive oxygen species, western blotting to detect NADPH oxidase 1/4 and ELISA to measure inflammatory cytokine levels. In vivo experiments were performed using a sevoflurane-induced anaesthetic mouse model to analyse the effects of miR-27a-3p on neurotoxicity by measuring the number of apoptotic neurons using the Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) method and learning and memory function by employing the Morris water maze test. Our results revealed that PPAR-γ expression was down-regulated by miR-27a-3p following sevoflurane treatment in hippocampal neurons. Down-regulation of miR-27a-3p expression decreased sevoflurane-induced hippocampal neuron apoptosis by decreasing inflammation and oxidative stress-related protein expression through the up-regulation of PPAR-γ. In vivo tests further confirmed that inhibition of miR-27a-3p expression attenuated sevoflurane-induced neuronal apoptosis and learning and memory impairment. Our findings suggest that down-regulation of miR-27a-3p expression ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-γ signalling pathway. MicroRNA-27a-3p may, therefore, be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity., (© 2017 International Society for Neurochemistry.)

Testosterone, a male sex hormone, has been suggested to partly explain mixed findings in males and females when investigating behavioral tendencies associated with the MAOA polymorphism. Prior studies indicated that the MAOA polymorphism represents a vulnerability factor for financial risk-taking and harm avoidance and that testosterone increases human risk-taking. We therefore assumed an interactive influence of the MAOA polymorphism and testosterone application on decision making and corresponding neural correlates in a risk and reward context. Stratified for the MAOA polymorphism (S =short, L =long), 103 healthy males were assigned to a placebo or testosterone group (double blind, randomized) receiving a topical gel containing 50 mg testosterone. During a functional MRI scan, the participants performed a sequential decision making task. Our results indicate that testosterone and the MAOA polymorphism jointly influence sequential decision making. The MAOA-S variant was associated with less automatic harm avoidance as reflected in response times on safe decisions. Moreover, after testosterone administration, MAOA-S carriers were more risk-taking. Overall activity in the anterior cingulate cortex, anterior insula and inferior frontal gyrus increased with growing risk for losses. In the anterior insula, testosterone administration mitigated this effect solely in MAOA-S carriers. This might be a reflection of an improved coping during risk-reward conflicts subsequently modulating risky decision making. While the molecular basis is not well defined so far, our results support the assumption of testosterone as a modulatory factor for previously reported sex differences of behavioral associations with the MAOA-S variant. Hum Brain Mapp 38:4574-4593, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Distal axon degeneration seen in many peripheral neuropathies is likely to share common molecular mechanisms with Wallerian degeneration. Although several studies in mouse models of peripheral neuropathy showed prevention of axon degeneration in the slow Wallerian degeneration (Wlds) mouse, the role of a recently identified player in Wallerian degeneration, Sarm1, has not been explored extensively. In this study, we show that mice lacking the Sarm1 gene are resistant to distal axonal degeneration in a model of chemotherapy induced peripheral neuropathy caused by paclitaxel and a model of high fat diet induced putative metabolic neuropathy. This study extends the role of Sarm1 to axon degeneration seen in peripheral neuropathies and identifies it as a likely target for therapeutic development., (© 2017 Peripheral Nerve Society.)

The lipid sphingosine 1-phosphate (S1P) is a potent neuroprotective signalling molecule that signals through its own family of five G-protein coupled receptors. S1P signalling enhances presynaptic glutamate release and is essential for neural development. S1P is synthesized by the enzymes sphingosine kinases 1 and 2 (SPHK1 and SPHK2), of which SPHK2 mRNA and activity is more abundant in the brain. In this study we investigated the consequences of global SphK2 knockout (SphK2 -/- ) on basic motor capabilities, anxiety, learning, and memory in mice, using a range of tests including the elevated plus maze, the cheeseboard, contextual and cued fear conditioning, and fear extinction. Loss of SphK2 resulted in an 85-90% reduction in brain S1P levels, and was associated with a notably higher freezing response in a novel context. SphK2 knockout mice also exhibited increased contextual fear conditioning but the extinction of contextual fear memory was similar to control mice. SphK2 -/- mice, contrary to their control littermates, did not respond to cue presentation with increased freezing. Anxiety measures in the elevated plus maze were not different between SphK2 -/- mice and control littermates. Also, knockout mice showed no deficits in neurological reflexes or motor functions, and performed as well as their control littermates in the spatial memory test. Our findings demonstrate that SphK2 is responsible for the vast majority of S1P synthesis in the mouse brain, and plays a role in freezing responses as evaluated in the fear conditioning paradigm., (Copyright © 2017 Elsevier B.V. All rights reserved.)

ADHD, schizophrenia and bipolar disorder are psychiatric diseases with a strong genetic component which share dopaminergic alterations. Dopamine transporter (DAT) genetics might be potentially implicated in all these disorders. However, in contrast to DAT absence, the effects of DAT hypofunction especially in developmental trajectories have been scarcely addressed. Thus, we comprehensively studied DAT hypofunctional mice (DAT+/-) from adolescence to adulthood to disentangle DAT-dependent alterations in the development of psychiatric-relevant phenotypes. From pre-adolescence onward, DAT+/- displayed a hyperactive phenotype, while responses to external stimuli and sensorimotor gating abilities were unaltered. General cognitive impairments in adolescent DAT+/- were partially ameliorated during adulthood in males but not in females. Despite this, attentional and impulsivity deficits were evident in DAT+/- adult males. At the molecular level, DAT+/- mice showed a reduced expression of Homer1a in the prefrontal cortex, while other brain regions as well as Arc and Homer1b expression were mostly unaffected. Amphetamine treatments reverted DAT+/- hyperactivity and rescued cognitive deficits. Moreover, amphetamine shifted DAT-dependent Homer1a altered expression from prefrontal cortex to striatal regions. These behavioral and molecular phenotypes indicate that a genetic-driven DAT hypofunction alters neurodevelopmental trajectories consistent with ADHD, but not with schizophrenia and bipolar disorders., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Previous research on the association between intra-subject variability (ISV) in reaction times (RTs) and the Val 158 Met polymorphism of the catechol-o-methyltransferase gene (COMT; rs4680) has yielded mixed results. The present study compared the associations between COMT genotype and ISV in P3b latency measured during working and secondary memory tasks using residue iteration decomposition (RIDE) of single trial latencies. We compared the outcome of the present analyses with a previous analysis of the same data (N=70, n-back tasks) using an alternative single-trial method. Additionally, we used RIDE to analyse the association between COMT genotype and ISV in an independent sample performing a different task (N=91, face-recognition task). Analyses reconfirmed previous results from the n-back tasks, showing that Val alleles are associated with lower ISV. In the face recognition tasks, genotype interacted with task conditions, so Val homozygotes had higher ISV to unfamiliar faces than familiar ones but Met carriers showed no effect of familiarity. Moreover, in both datasets trial-by-trial RTs were predicted by P3b latencies. Therefore, the present data suggests that associations between COMT genotype and ISV depend on the type of cognitive processes, which may explain heterogeneity in previous results., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Na v 1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). Patients with SCN1A mutations often experience prolonged early-life febrile seizures (FSs), raising the possibility that these events may influence epileptogenesis and lead to more severe adult phenotypes. To test this hypothesis, we subjected 21-23-day-old mice expressing the human SCN1A GEFS+ mutation R1648H to prolonged hyperthermia, and then examined seizure and behavioral phenotypes during adulthood. We found that early-life FSs resulted in lower latencies to induced seizures, increased severity of spontaneous seizures, hyperactivity, and impairments in social behavior and recognition memory during adulthood. Biophysical analysis of brain slice preparations revealed an increase in epileptiform activity in CA3 pyramidal neurons along with increased action potential firing, providing a mechanistic basis for the observed worsening of adult phenotypes. These findings demonstrate the long-term negative impact of early-life FSs on disease outcomes. This has important implications for the clinical management of this patient population and highlights the need for therapeutic interventions that could ameliorate disease progression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The later stages of long-term potentiation (LTP) in vitro and spatial memory in vivo are believed to depend upon gene transcription. Accordingly, considerable attempts have been made to identify both the mechanisms by which transcription is regulated and indeed the gene products themselves. Previous studies have shown that deletion of one regulator of transcription, the mitogen- and stress-activated kinase 1 (MSK1), causes an impairment of spatial memory. Given the ability of MSK1 to regulate gene expression via the phosphorylation of cAMP response element binding protein (CREB) at serine 133 (S133), MSK1 is a plausible candidate as a prime regulator of transcription underpinning synaptic plasticity and learning and memory. Indeed, prior work has revealed the necessity for MSK1 in homeostatic and experience-dependent synaptic plasticity. However, using a knock-in kinase-dead mouse mutant of MSK1, the current study demonstrates that, while the kinase function of MSK1 is important in regulating the phosphorylation of CREB at S133 and basal synaptic transmission in hippocampal area CA1, it is not required for metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD), two forms of LTP or several forms of spatial learning in the watermaze. These data indicate that other functions of MSK1, such as a structural role for the whole enzyme, may explain previous observations of a role for MSK1 in learning and memory.

Introduction: The enzyme steroid sulfatase (STS) converts sulfated steroids to their non-sulfated forms. Deficiency for this enzyme is associated with inattention but preserved response control. The polymorphism rs17268988 within the X-linked STS gene is associated with inattentive, but not other, symptoms in boys with attention deficit hyperactivity disorder (ADHD)., Methods: We initially tested whether rs17268988 genotype was associated with attention, response control, and underlying aspects of cognition, using questionnaires and neuropsychological tasks, in two independent cohorts of healthy adult males. In an additional analysis based upon existing data, the performance of mice with genetic or pharmacological manipulations of the STS axis under attentionally demanding conditions was investigated., Results: G-allele carriers at rs17268988 exhibited reduced reaction time, enhanced attention, and reduced reaction time variability relative to C-allele carriers. Mice with genetic or pharmacological manipulations of the STS axis were shown to have perturbed reaction time variability., Discussion: Our findings provide additional support for an association between rs17268988 genotype and attention, which may be partially mediated by reaction time variability; they also indicate that, in contrast to the situation in boys with ADHD, in healthy men, the G-allele at rs17268988 is associated with enhanced cognition. As reaction time variability is a predictor of well-being, rs17268988 genotype may represent a biomarker for long-term health.

Objective: Canonical transient receptor potential (TRPC) channels constitute a family of cation channels that exhibit a regional and cell-specific expression pattern throughout the brain. It has been reported previously that TRPC3 channels are effectors of the brain-derived neurotrophic factor (BDNF)/trkB signaling pathway. Given the long postulated role of BDNF in epileptogenesis, TRPC3 channels may be a critical component in the underlying pathophysiology of seizure and epilepsy. In this study, we investigated the precise role of TRPC3 channels in pilocarpine-induced status epilepticus (SE)., Methods: The role of TRPC3 channels was investigated using TRPC3 knockout (KO) mice and TRPC3-selective inhibitor Pyr3. Video and electroencephalography (EEG) recording of pilocarpine-induced seizures were performed., Results: We found that genetic ablation of TRPC3 channels reduces behavioral manifestations of seizures and the root-mean-square (RMS) power of SE, indicating a significant contribution of TRPC3 channels to pilocarpine-induced SE. Furthermore, the reduction in SE in TRPC3KO mice is caused by a selective attenuation of pilocarpine-induced theta activity, which dominates both the preictal phase and SE phase. Pyr3 also caused a reduction in the overall RMS power of pilocarpine-induced SE and a selective reduction in the theta activity during SE., Significance: Our results demonstrate that TRPC3 channels unequivocally contribute to pilocarpine-induced SE and could be a novel molecular target for new anticonvulsive drugs., Competing Interests: of Conflict of Interest: None of the authors has any conflict of interest to disclose., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Executive dysfunction has been demonstrated among premutation (PM) carriers (55-199 CGG repeats) of the Fragile X mental retardation 1 (FMR1) gene. Further, alterations to neural activation patterns have been reported during memory and comparison based functional magnetic resonance imaging (fMRI) tasks in these carriers. For the first time, the relationships between fMRI neural activation during an interleaved ocular motor prosaccade/antisaccade paradigm, and concurrent task performance (saccade measures of latency, accuracy and error rate) in PM females were examined. Although no differences were found in whole brain activation patterns, regions of interest (ROI) analyses revealed reduced activation in the right ventrolateral prefrontal cortex (VLPFC) during antisaccade trials for PM females. Further, a series of divergent and group specific relationships were found between ROI activation and saccade measures. Specifically, for control females, activation within the right VLPFC and supramarginal gyrus correlated negatively with antisaccade latencies, while for PM females, activation within these regions was found to negatively correlate with antisaccade accuracy and error rate (right VLPFC only). For control females, activation within frontal and supplementary eye fields and bilateral intraparietal sulci correlated with prosaccade latency and accuracy; however, no significant prosaccade correlations were found for PM females. This exploratory study extends previous reports of altered prefrontal neural engagement in PM carriers, and clearly demonstrates dissociation between control and PM females in the transformation of neural activation into overt measures of executive dysfunction. Hum Brain Mapp 38:1056-1067, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-β protein (Aβ) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of 'brain-training games.' In the present study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aβ deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health.

Rationale: Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear., Objective: In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment., Methods: Attentional function in mice haploinsufficient for Map2k7 (Map2k7 +/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT)., Results: Once stable performance had been achieved, Map2k7 +/- mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline-a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia-signs of improvement in attentional performance were detected., Conclusions: Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (Val 158 Met) that alters enzyme activity and influences PFC function. It has also been linked with cognition and anxiety, but the findings are mixed. We therefore developed a novel mouse model of altered COMT activity. The human Met allele was introduced into the native mouse COMT gene to produce COMT-Met mice, which were compared with their wild-type littermates. The model proved highly specific: COMT-Met mice had reductions in COMT abundance and activity, compared with wild-type mice, explicitly in the absence of off-target changes in the expression of other genes. Despite robust alterations in dopamine metabolism, we found only subtle changes on certain cognitive tasks under baseline conditions (eg, increased spatial novelty preference in COMT-Met mice vs wild-type mice). However, genotype differences emerged after administration of the COMT inhibitor tolcapone: performance of wild-type mice, but not COMT-Met mice, was improved on the 5-choice serial reaction time task after tolcapone administration. There were no changes in anxiety-related behaviors in the tests that we used. Our findings are convergent with human studies of the Val 158 Met polymorphism, and suggest that COMT's effects are most prominent when the dopamine system is challenged. Finally, they demonstrate the importance of considering COMT genotype when examining the therapeutic potential of COMT inhibitors.

Episodes of cerebral hypoxia/ischemia increase the risk of dementia, which is associated with impaired learning and memory. Previous studies in rodent models of dementia indicated a favorable effect of the hypoxia-inducible factor (HIF) targets VEGF (vascular endothelial growth factor) and erythropoietin (Epo). In the present study we thus investigated whether activation of the entire adaptive HIF pathway in neurons by cell-specific deletion of the HIF suppressor prolyl-4-hydroxylase 2 (PHD2) improves cognitive abilities in young (3months) and old (18-28months) mice suffering from chronic brain hypoperfusion. Mice underwent permanent occlusion of the left common carotid artery, and cognitive function was assessed using the Morris water navigation task. Under conditions of both normal and decreased brain perfusion, neuronal PHD2 deficiency resulted in improved and faster spatial learning in young mice, which was preserved to some extent also in old animals. The loss of PHD2 in neurons resulted in enhanced hippocampal mRNA and protein levels of Epo and VEGF, but did not alter local microvascular density, dendritic spine morphology, or expression of synaptic plasticity-related genes in the hippocampus. Instead, better cognitive function in PHD2 deficient animals was accompanied by an increased number of neuronal precursor cells along the subgranular zone of the dentate gyrus. Overall, our current pre-clinical findings indicate an important role for the endogenous oxygen sensing machinery, encompassing PHDs, HIFs and HIF target genes, for proper cognitive function. Thus, pharmacological compounds affecting the PHD-HIF axis might well be suited to treat cognitive dysfunction and neurodegenerative processes., (Copyright © 2016 Elsevier Inc. All rights reserved.)