Impaired Cognitive Flexibility Research Articles

Link Between Diabetes and Alzheimer's Disease due to the Shared Amyloid Aggregation and Deposition Involving both Neurodegenerative Changes and Neurovascular Damages.

Diabetes and Alzheimer’s disease are two highly prevalent diseases among the aging population and have become major public health concerns in the 21st century, with a significant risk to each other. Both of these diseases are increasingly recognized to be multifactorial conditions. The terms “diabetes type 3” or “brain diabetes” have been proposed in recent years to provide a complete view of the potential common pathogenic mechanisms between these diseases. While insulin resistance or deficiency remains the salient hallmarks of diabetes, cognitive decline and non-cognitive abnormalities such as impairments in visuospatial function, attention, cognitive flexibility, and psychomotor speed are also present. Furthermore, amyloid aggregation and deposition may also be drivers for diabetes pathology. Here, we offer a brief appraisal of social impact and economic burden of these chronic diseases and provide insight into amyloidogenesis through considering recent advances of amyloid-β aggregates on diabetes pathology and islet amyloid polypeptide on Alzheimer’s disease. Exploring the detailed knowledge of molecular interaction between these two amyloidogenic proteins opens new opportunities for therapies and biomarker development.

1331-P: Correlation between Sleep Deduction and Neurobehavioral Deficits in the Mouse Offspring of Mother with Diabetes

Lines of human cohort studies reported increased risk of neurobehavioral abnormalities as well as sleep problems in offspring of mother with diabetes (OMD). Preclinical studies demonstrated that forced sleep disturbance leads to poor cognitive function in mice. Based on these findings, our hypothesis posits that wide spectrum of neurobehavior issues in OMD is due to their sleep disturbance. To test this hypothesis, we first established mouse OMD models for examining the correlation between sleep disturbance and performance in a battery of neurobehavior tests. Female C57BL/6 mice received intraperitoneal injection of Streptozocin at 6 weeks old. DM was confirmed before start of mating. OMD in juvenile were placed to neurobehavior tests as well as piezoelectric sensor system of sleep under 12 h light/12 h dark cycles. In open field test, OMD spent significantly more time in the center of the field, suggesting the increased risk-taking behavior or/and reduced anxiety. Interestingly, several rodent models of autism showed similar behavior changes, and human OMD patients have increased risk of autism. Furthermore, the change of the behavior in our model was augmented in male and this may be consistent with the human OMD in which male patients has higher risk of autism than female. In water T maze test, the ability of spatial learning in OMD was comparable to that of control animals, while the reversal learning was impaired. Sleep time of OMD was significantly shorter than that of control in both dark and light phases. We also found positive correlation between sleep time and cognitive flexibility that was measured as reversal learning level in water T maze. However, the proxy for risk taking behavior did not show correlation with the sleep time. Altogether, our results demonstrate the correlation between sleep disturbance and impaired cognitive flexibility, and thus shed light on the potential mechanisms underlying intellectual disability that is frequently observed in OMD. Disclosure K. Sugai: None. J. Sasaki: None. M. Odawara: Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. M. Torii: None. K. Hashimoto-Torii: None. Funding Scott-Gentle Foundation

Large Neutral Amino Acids (LNAAs) Supplementation Improves Neuropsychological Performances in Adult Patients with Phenylketonuria.

Phenylketonuria is an inborn error of phenylalanine (Phe) metabolism diagnosed by newborn screening and treated early with diet. Although diet prevents intellectual disability, patients often show impairment of executive functions, working memory, sustained attention, and cognitive flexibility. Large neutral amino acids (LNAAs) have been proposed as a dietary supplement for PKU adults. Few studies show that LNAAs may help in improving metabolic control as well as cognitive functions. In this study, 10 adult PKU patients with poor metabolic control were treated for 12 months with LNAAs (MovisCom, 0.8–1 g/kg/day) and underwent Phe and Tyrosine (Tyr) monitoring monthly. Neuropsychological assessment was performed at T0, T+3, and T+12 months by using the American Psychological General Well-Being Index, the Wisconsin Card Sorting Test, the Test of Attentional Performance, and the 9-Hole Peg Test. No change in plasma Phe levels was observed during LNAAs supplementation, while Tyr levels significantly improved during LNAAs supplementation (p = 0.03). Psychometric tests showed an improvement of distress and well-being rates, of executive functions, attention, and vigilance, whereas no difference was noted regarding hand dexterity. This study adds evidence of the advantage of LNAAs supplementation in improving cognitive functions and well-being in patients with PKU with poor metabolic control.

Kissorphin improves spatial memory and cognitive flexibility impairment induced by ethanol treatment in the Barnes maze task in rats.

Acute and chronic ethanol intake, as well as ethanol withdrawal, exert learning disabilities. Of all the neurotransmitters in the brain, endogenous opioid peptides are thought to participate in ethanol effects. Kisspeptins, including kisspeptin-10, are peptides produced in the part of brain involved in the consolidation of memory and orientation. A new derivative of kisspeptin-10 is kissorphin (Tyr-Asn-Trp-Asn-Ser-Phe-NH2), a peptide with anti-opioid-activity. Hence, the aim of our study was to reveal whether kissorphin (1, 3, and 10 nmol, i.v.) was able to prevent or reverse learning deficits such as spatial memory retention and reversal learning induced by acute ethanol administration (1 × 1.75 g/kg., i.p.) and reversal learning induced by ethanol withdrawal (11-13 days from 'binge-like' ethanol input-5.0 g/kg, i.g. for 5 days) in the Barnes maze task in rats. Our study demonstrated that acute kissorphin administration prevented spatial memory (higher doses) impairments and attenuated reversal learning deficits induced by acute ethanol administration, although the reversal learning impairment may have been due to spatial learning impairments rather than cognitive flexibility impairments. Moreover, kissorphin given prior to first reversal learning trial for 3 consecutive days in the Barnes maze task during withdrawal from 'binge-like' ethanol administration, significantly attenuated cognitive flexibility impairment in the ethanol-withdrawal rats. In the acute and chronic ethanol experiments, kissorphin was the most effective at the dose of 10 nmol. In conclusion, the ethanol-induced spatial memory impairment may be reversed by pharmacological manipulation of the endogenous opioid system.

Characteristics of autism spectrum disorders are associated with longer duration of anorexia nervosa: A systematic review and meta-analysis.

Anorexia nervosa (AN) is associated with neuropsychological characteristics such as impairments in central coherence, cognitive flexibility, and emotion recognition. The same features also manifest in autism spectrum disorders (ASD) and have been suggested to be associated with illness prolongation in AN. The purpose of this meta-analysis was to examine whether pronounced neuropsychological characteristics related to ASD are associated with illness duration in AN. Four databases (Medline, PsycINFO, Scopus, PubMed) were searched for eligible studies. Search terms were (a) "anorexia nervosa" and (b) "cognitive flexibility" or "set-shifting" or "central coherence" or "emotion recognition" or "theory of mind". The final sample consisted of 53 studies. Duration of AN was divided into three categories in order to investigate differences between the groups with varying illness duration. The meta-analysis was performed with Review Manager using a random-effects model. Deficits in central coherence, cognitive flexibility, and emotion recognition were pronounced among individuals with prolonged AN compared to those with shorter illness duration. A prolonged course of AN appears to be associated with underlying neuropsychological characteristics that are also distinctive to ASD. Neuropsychological impairments may lead to prolonged AN, and prolonged illness may contribute to the subsequent "neurological scar effect," further strengthening these impairments.

Moral judgments in obsessive-compulsive disorder: a narrative mini-review

Obsessive-compulsive disorder (OCD) is a prevalent mental disorder characterized by intrusive thoughts (obsessions) and ensuing rituals (compulsions). Although OC patients exhibit various cognitive and behavioral problems, rigid and hypersensitive moral judgments are known to be one of the most striking problems in these patients. There is evidence indicating that OC patients often tend to make deontological judgments in moral dilemmas, significantly more than the healthy population. Therefore, numerous studies are dedicated to understanding the underlying cognitive processes responsible for such variation of moral judgments in OCD, which are reviewed and discussed in the current paper. First, it is previously discussed that abnormal moral judgments in OCD are due to executive dysfunctions. These dysfunctions include impaired cognitive control resulting in the domination of strong, uncontrolled emotional responses, impaired cognitive flexibility resulting in the inability to switch between aspects of a scenario, and decreased capacity and overload of working memory and its inability to resist the interfering information. The dual-process theory also emphasizes and acknowledges the role of executive functions in moral judgments. Second, it is thought that disobeying moral norms results in the abnormal feeling of deontological guilt in OC patients, to which these patients are highly sensitive. Feeling of guilt is also thought to be correlated with OCD symptomatology. The third impairment contributing to abnormal moral judgments in OCD is known to be the abnormal feeling of disgust for moral violations and immoral unwanted intrusive thoughts, which is regarded as one of the major causes of OCD symptoms. Finally, the abnormal fear of responsibility and being criticized due to not acting morally is regarded as one of the primary impairments contributing to the abnormal moral judgments in OCD. In conclusion, this review sheds light on the most striking cognitive and affective impairments contributing to abnormal moral judgments in OCD.

Effects of frequent marijuana use on risky decision-making in young adult college students

IntroductionMarijuana (MJ) is the most widely used illicit substance among adolescents and young adults. Frequent MJ use has been associated with impairments in cognitive flexibility and inhibition, both of which play important roles in decision-making. However, the impact of frequent MJ use on decision-making performance is mixed and not well understood. The current study examined the influence of frequent MJ use on risky decision-making in college students, 18–22 years old. Methods: From 2017 to 2019, data was collected from young adult college students (n = 65) consisting of 32 healthy controls (HC) and 33 frequent marijuana users (MJ+). Participants completed the Iowa Gambling Task (IGT), a measure of risky decision-making, and net IGT scores (advantageous-disadvantageous decisions) were used as a measure of optimal decision-making. Results: The main finding indicated there was a significant effect of group on net IGT scores (p = 0.018), which remained significant when sex was included in the model (p = 0.006), such that MJ+ had lower net IGT scores than HC. Conclusions: These findings highlight potential differences in risky decision-making between MJ+ and HC, but it is uncertain whether these differences are pre-existing and increase vulnerability for frequent MJ use or if they are related to the effects of frequent MJ use on decision-making.

Modelling associations between neurocognition and functional course in young people with emerging mental disorders: a longitudinal cohort study

Neurocognitive impairment is commonly associated with functional disability in established depressive, bipolar and psychotic disorders. However, little is known about the longer-term functional implications of these impairments in early phase transdiagnostic cohorts. We aimed to examine associations between neurocognition and functioning at baseline and over time. We used mixed effects models to investigate associations between neurocognitive test scores and longitudinal social and occupational functioning (“Social and Occupational Functioning Assessment Scale”) at 1–7 timepoints over five-years in 767 individuals accessing youth mental health services. Analyses were adjusted for age, sex, premorbid IQ, and symptom severity. Lower baseline functioning was associated with male sex (coefficient −3.78, 95% CI −5.22 to −2.34 p < 0.001), poorer verbal memory (coefficient 0.90, 95% CI 0.42 to 1.38, p < 0.001), more severe depressive (coefficient −0.28, 95% CI −0.41 to −0.15, p < 0.001), negative (coefficient −0.49, 95% CI −0.74 to −0.25, p < 0.001), and positive symptoms (coefficient −0.25, 95% CI −0.41 to −0.09, p = 0.002) and lower premorbid IQ (coefficient 0.13, 95% CI 0.07 to 0.19, p < 0.001). The rate of change in functioning over time varied among patients depending on their sex (male; coefficient 0.73, 95% CI 0.49 to 0.98, p < 0.001) and baseline level of cognitive flexibility (coefficient 0.14, 95% CI 0.06 to 0.22, p < 0.001), such that patients with the lowest scores had the least improvement in functioning. Impaired cognitive flexibility is common and may represent a meaningful and transdiagnostic target for cognitive remediation in youth mental health settings. Future studies should pilot cognitive remediation targeting cognitive flexibility while monitoring changes in functioning.

Dorsal and ventral striatal dopamine D1 and D2 receptors differentially modulate distinct phases of serial visual reversal learning

Impaired cognitive flexibility in visual reversal-learning tasks has been observed in a wide range of neurological and neuropsychiatric disorders. Although both human and animal studies have implicated striatal D2-like and D1-like receptors (D2R; D1R) in this form of flexibility, less is known about the contribution they make within distinct sub-regions of the striatum and the different phases of visual reversal learning. The present study investigated the involvement of D2R and D1R during the early (perseverative) phase of reversal learning as well as in the intermediate and late stages (new learning) after microinfusions of D2R and D1R antagonists into the nucleus accumbens core and shell (NAcC; NAcS), the anterior and posterior dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) on a touchscreen visual serial reversal-learning task. Reversal learning was improved after dopamine receptor blockade in the nucleus accumbens; the D1R antagonist, SCH23390, in the NAcS and the D2R antagonist, raclopride, in the NAcC selectively reduced early, perseverative errors. In contrast, reversal learning was impaired by D2R antagonism, but not D1R antagonism, in the dorsal striatum: raclopride increased errors in the intermediate phase after DMS infusions, and increased errors across phases after DLS infusions. These findings indicate that D1R and D2R modulate different stages of reversal learning through effects localised to different sub-regions of the striatum. Thus, deficits in behavioral flexibility observed in disorders linked to dopamine perturbations may be attributable to specific D1R and D2R dysfunction in distinct striatal sub-regions.

Blended cognitive behavioural therapy for adolescents with panic disorder co-morbid with autism spectrum disorder: a case study

Abstract Cognitive behavioural therapy (CBT) is an effective treatment for improving anxiety symptoms in patients with autism spectrum disorder (ASD). However, some patients with ASD take extra time for learning, and they can find it hard to change their thinking styles and behaviour due to cognitive deficits. The therapist must be creative when implementing CBT in this context. Here, it may be helpful for the patient with ASD to understand CBT’s concepts by using visual aid material. Blended CBT during which the patient is shown visual aid material with his or her therapist has been suggested as effective for adults without ASD to reduce anxiety. Blended CBT combines face-to-face treatment with internet guided support and resource. Blended CBT may facilitate an understanding of essential knowledge and help people with ASD and anxiety acquire skills based on cognitive behavioural science. However, as far as we know, no previous studies have reported on the use of blended CBT for patients with panic disorder co-morbid with ASD. This study, therefore, consecutively performed 16 blended CBT sessions on a biweekly basis to treat panic disorder (PD) in an adolescent Japanese female co-morbid with ASD. The patient exhibited improvements in PD symptoms and agoraphobia after treatment: the Panic Disorder Severity Scale score decreased from 18 to 2. These results indicate that visual aid-assisted treatment may help patients with impaired imagination and social cognition related to ASD. Furthermore, this study’s therapist notes the need for paced treatments and repeated psychoeducation for patients with impairments in central coherence and cognitive flexibility. Key learning aims (1) Blended CBT may patients with panic disorder (PD) co-morbid with autism spectrum disorder (ASD) to understand concepts based on cognitive behavioural science and symptoms. (2) Blended CBT sessions can each be conducted in approximately 20 min (about one-third of the time needed for typical 45- to 90-min CBT sessions); in other words, it is less burdensome for the patient and therapist. (3) How to adjust blended CBT for those who have low average intelligence quotients (IQ) and/or ASD.

Double deficiency of toll-like receptors 2 and 4 alters long-term neurological sequelae in mice cured of pneumococcal meningitis

Toll-like receptor (TLR) 2 and 4 signalling pathways are central to the body’s defence against invading pathogens during pneumococcal meningitis. Whereas several studies support their importance in innate immunity, thereby preventing host mortality, any role in protecting neurological function during meningeal infection is ill-understood. Here we investigated both the acute immunological reaction and the long-term neurobehavioural consequences of experimental pneumococcal meningitis in mice lacking both TLR2 and TLR4. The absence of these TLRs significantly impaired survival in mice inoculated intracerebroventricularly with Streptococcus pneumoniae. During the acute phase of infection, TLR2/4-deficient mice had lower cerebrospinal fluid concentrations of interleukin-1β, and higher interferon-γ, than their wild-type counterparts. After antibiotic cure, TLR2/4 double deficiency was associated with aggravation of behavioural impairment in mice, as shown by diurnal hypolocomotion throughout the adaptation phases in the Intellicage of TLR-deficient mice compared to their wild-type counterparts. While TLR2/4 double deficiency did not affect the cognitive ability of mice in a patrolling task, it aggravated the impairment of cognitive flexibility. We conclude that TLR2 and TLR4 are central to regulating the host inflammatory response in pneumococcal meningitis, which may mediate diverse compensatory mechanisms that protect the host not only against mortality but also long-term neurological complications.

Research Progress on Cognitive Deficiencies of Specific Reading Com-prehension Disorders

&lt;p&gt;Specific dyslexia is a sub-type of dyslexia, which has gradually attracted the attention of researchers at home and abroad in recent years. Research on specific dyslexia mainly comes from cognitive field and focuses on language skills, general cognitive ability and impairment of cognitive flexibility. This paper sorts out and summarizes the basic viewpoints and related researches on cognitive deficits of specific dyslexics, and analyzes the causes and effects of specific dyslexics, so as to provide references for the identification, intervention training and research of specific dyslexics.&lt;/p&gt;

Brain and Cognitive Development in Adolescents with Anorexia Nervosa: A Systematic Review of fMRI Studies.

Anorexia nervosa (AN) is an eating disorder often occurring in adolescence. AN has one of the highest mortality rates amongst psychiatric illnesses and is associated with medical complications and high risk for psychiatric comorbidities, persisting after treatment. Remission rates range from 23% to 33%. Moreover, weight recovery does not necessarily reflect cognitive recovery. This issue is of particular interest in adolescence, characterized by progressive changes in brain structure and functional circuitries, and fast cognitive development. We reviewed existing literature on fMRI studies in adolescents diagnosed with AN, following PRISMA guidelines. Eligible studies had to: (1) be written in English; (2) include only adolescent participants; and (3) use block-design fMRI. We propose a pathogenic model based on normal and AN-related neural and cognitive maturation during adolescence. We propose that underweight and delayed puberty—caused by genetic, environmental, and neurobehavioral factors—can affect brain and cognitive development and lead to impaired cognitive flexibility, which in turn sustains the perpetuation of aberrant behaviors in a vicious cycle. Moreover, greater punishment sensitivity causes a shift toward punishment-based learning, leading to greater anxiety and ultimately to excessive reappraisal over emotions. Treatments combining physiological and neurobehavioral rationales must be adopted to improve outcomes and prevent relapses.

Transient upregulation of immune activity induced by adolescent social stress is involved in cognitive deficit in adult male mice and early intervention with minocycline

Increasing evidence shows that the developmental perturbation of immune activity can lead to long-lasting neurodevelopmental and behavioral abnormalities. In our previous study, we found that deficiencies of microglia and TNFα in the medial prefrontal cortex (mPFC) were involved in the impairment of cognitive flexibility induced by adolescent social stress in adult mice. It remains unclear how and when immune changes occur following adolescent stress exposure and whether it is possible to prevent the delayed occurrence of cognitive impairment through early immune intervention. Firstly, the present study investigated the time courses of microglia and TNFα changes in the mPFC following adolescent social stress. The results showed that compared to the controls, stress-exposed animals showed parallel variations in the protein expression of ionized calcium-binding adaptor molecule 1 (Iba1), a biomarker specific to microglia, and TNFα in the mPFC, with a transient increase during stress exposure, then a gradual decrease after the end of stress, leading to a significantly decreased level in adulthood. We further investigated the preventive effect of chronic treatment with the immune inhibitor minocycline during stress exposure on the cognitive and molecular alterations induced by adolescent social stress. The results showed that minocycline prevented the delayed cognitive deficit and the decreased immune changes in the mPFC of previously stressed adult mice. These results suggest that the transient upregulation of microglia and TNFα in the mPFC induced by adolescent social stress may participate in the development of cognitive flexibility deficit and that immunomodulation may act as a potential target for the early prevention of cognitive deficits in psychiatric disorders.

Correlation of Cognitive Resilience, Cognitive Flexibility and Impulsivity in Attempted Suicide.

Context:Impaired cognitive flexibility and resilience and increased impulsivity are presumed to underlie an attempt of suicide. There is, however, a paucity of research examining their relationship in those who attempted suicide.Aims:To know the correlation of cognitive flexibility and resilience and impulsivity in attempted suicide.Materials and Methods:Two hundred seventy subjects with suicide attempt (s) were assessed with sociodemographic and clinical proforma, cognitive flexibility scale (CFS), cognitive resilience scale (CRS), and Barratt impulsiveness scale (BIS-15).Statistical Analysis Used:Descriptive statistics, linear regression model.Results:Mean scores on CFS, CRS, and BIS-15 were 44.93 (SD ± 2.50), 4.49 (SD ± 0.25), and 36.13(SD ± 2.13), respectively. On linear regression analysis, BIS-15 nonplanning had statistically significant negative correlation with CFS and CRS scores, and BIS-15 attention had a positive correlation with CFS and CRS scores. CFS and CRS scores were positively correlated.Conclusions:In attempted suicide, cognitive flexibility and resilience are interrelated positively and inversely associated with impulsivity (nonplanning and inattention).

Photobiomodulation rescues cognitive flexibility in early stressed subjects

Neglectful parenting is one of the most prevalent forms of child mistreatment. This early life stress leads to long-term alterations in all the psychological domains, as well as brain alterations. Animal models have been developed to emulate and further study this early life stress, and one of most widely used models is maternal separation. In both human and animal models, cognitive flexibility has been found to be altered. In this study, we performed maternal separation (10 days, 4 h per day) in rats, and in adulthood, we tested their spatial navigation and cognitive flexibility. In addition, we delivered photobiomodulation treatment (Low-level light therapy: 1064 nm, 30 mW, 60 cycles) on the rats’ brains, and we tested energy oxidative metabolism using cytochrome c oxidase histochemistry. Early life stress delivered in the form of maternal separation on the first 10 postnatal days leads to cognitive flexibility impairment and a general increase in energy metabolism in adulthood. Low-level light therapy seems to be useful for treating these unwanted outcomes, because it rescued cognitive flexibility and returned the oxidative energy metabolism to balanced scores, without harming controls’ brains or behavior. Photobiomodulation is a promising tool in the treatment of chronic stress-related consequences because it rescued cognitive flexibility.

Impairment of cognitive flexibility in type 2 diabetic db/db mice

Impaired executive function is a major peril for patients with type 2 diabetes, reducing quality of life and ability for diabetes management. Despite the significance of this impairment, few animal models of type 2 diabetes examine domains of executive function such as cognitive flexibility or working memory. Here, we evaluated these executive function domains in db/db mice, an established model of type 2 diabetes, at 10 and 24 weeks of age. The db/db mice showed impaired cognitive flexibility in the Morris water maze reversal phase. However, the db/db mice did not show apparent working memory disturbance in the spatial working memory version of the Morris water maze or in the radial water maze. We also examined axon initial segments (AIS) and nodes of Ranvier, key axonal domains for action potential initiation and propagation. AIS were significantly shortened in medial prefrontal cortex and hippocampus of 26-week-old db/db mice compared with controls, similar to our previous findings in 10-week-old mice. Nodes of Ranvier in corpus callosum, previously shown to be unchanged at 10 weeks, were elongated at 26 weeks, suggesting an important role for this domain in disease progression. Together, the findings help establish db/db mice as a model of impaired cognitive flexibility in type 2 diabetes and advance our understanding of its pathophysiology.

Prefrontal Cortex Dopamine Transporter Gene Network Moderates the Effect of Perinatal Hypoxic-Ischemic Conditions on Cognitive Flexibility and Brain Gray Matter Density in Children

BackgroundGenetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show interactive effects. MethodsWe created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic–associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts—MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls). ResultsA history of exposure to several perinatal hypoxic-ischemic–associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism–based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic–associated conditions. ConclusionsThese findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.

Selective decrease of cholinergic signaling from pedunculopontine and laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress.

The pedunculopontine tegmental nucleus (PPT) and laterodorsal tegmental nucleus (LDT) are heterogeneous brainstem structures that contain cholinergic, glutamatergic, and GABAergic neurons. PPT/LDT neurons are suggested to modulate both cognitive and noncognitive functions, yet the extent to which acetylcholine (ACh) signaling from the PPT/LDT is necessary for normal behavior remains uncertain. We addressed this issue by using a mouse model in which PPT/LDT cholinergic signaling is highly decreased by selective deletion of the vesicular ACh transporter (VAChT) gene. This approach interferes exclusively with ACh signaling, leaving signaling by other neurotransmitters from PPT/LDT cholinergic neurons intact and sparing other cells. VAChT mutants were examined on different PPT/LDT-associated cognitive domains. Interestingly, VAChT mutants showed no attentional deficits and only minor cognitive flexibility impairments while presenting large deficiencies in both spatial and cued Morris water maze (MWM) tasks. Conversely, working spatial memory determined with the Y-maze and spatial memory measured with the Barnes maze were not affected, suggesting that deficits in MWM were unrelated to spatial memory abnormalities. Supporting this interpretation, VAChT mutants exhibited alterations in anxiety-like behavior and increased corticosterone levels after exposure to the MWM, suggesting altered stress response. Thus, PPT/LDT VAChT-mutant mice present little cognitive impairment per se, yet they exhibit increased susceptibility to stress, which may lead to performance deficits in more stressful conditions.-Janickova, H., Kljakic, O., Rosborough, K., Raulic, S., Matovic, S., Gros, R., Saksida, L. M., Bussey, T. J., Inoue, W., Prado, V. F., Prado, M. A. M. Selective decrease of cholinergic signaling from pedunculopontine and laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress.

Cognitive and neuropsychiatric impairments vary as a function of injury severity at 12 months post-experimental diffuse traumatic brain injury: Implications for dementia development.

Traumatic brain injury (TBI) is a common risk factor for later neurodegeneration, which can manifest as dementia. Despite this, little is known about the time-course of development of functional deficits, particularly cognitive and neuropsychiatric impairments, and whether these differ depending on the nature of the initiating insult. Therefore, this study investigated long term functional impairment at 12 months post-injury following diffuse TBI of different severities. Male Sprague-Dawley rats (420-480 g; 10-12 weeks) were either given a sham surgery (n = 14) or subjected to Marmarou's impact acceleration model of diffuse TBI for a single mild TBI (n = 12), repetitive mild TBI (3 mild diffuse injuries at 5 day intervals) (n = 14) or moderate to severe TBI (n = 14). At 12 months after injury, they were tested on a functional battery encompassing motor, neuropsychiatric (anxiety and depressive-like) and cognitive function. Our results showed that moderate to severe TBI animals exhibited significant impairments in cognitive flexibility (p = 0.009) on the Barnes maze when compared to age-matched sham animals. Neither repetitive mild TBI nor single mild TBI animals showed significant functional impairments when compared to shams. Thus, this study provides the first insight into chronic functional impairments associated with different severities of diffuse TBI, with moderate to severe TBI being a higher risk factor for impaired cognitive function at 12 months post-injury. Taken together, this may have implications for risk of dementia development following different severities of injury.