Extradimensional Set-shifting Research Articles

Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

Automatic Intra-/Extra-Dimensional Attentional Set-Shifting Task in Adolescent Mice.

Adolescence is a developmental period crucial for the maturation of higher-order cognitive functions. Indeed, adolescence deficits in executive functions are strong predictors of increased vulnerability to several mental disabilities later in life. Here, we tested adolescent mice in a fully-automated attentional set-shifting task equivalent to the humans’ Wisconsin Card Sorting Test (WCST) and the Cambridge Neuropsychological Test Automated Battery Intra-/Extra-Dimensional set-shift task (ID/ED). Compared to an adult, adolescent mice required more time to complete the task (≈16 days), and a higher percentage failed to finish the entire task. Nevertheless, adolescent mice completing this demanding task showed an increased effort in solving the extradimensional shift stage (EDS) compared to previous stages. Moreover, we found that this paradigm can be used to detect early cognitive dysfunctions in adolescent genetically modified mice. Thus, this automatic paradigm provides a further tool to assess attentional control in adolescent mice, and the development of dysfunctional executive functions from adolescence to adulthood.

Effect of a 5-HT7 Receptor Antagonist on Reversal Learning in the Rat Attentional Set-Shifting Test.

5-HT7 receptor antagonism has been shown to ameliorate ketamine-induced schizophrenia-like deficits in extradimensional set-shifting using the attentional set-shifting task (ASST). However, this rodent paradigm distinguishes between several types of cognitive rigidity associated with neuropsychiatric conditions. The goal of this study was to test 5-HT7 receptor involvement in the reversal learning component of the ASST because this ability depends primarily on the orbito-frontal cortex, which shows strong 5-HT7 receptor expression. We found that impaired performance on the ASST induced by NMDA receptor blockade (MK-801, 0.2 mg/kg) in 14 rats was reversed by coadministration of the 5-HT7 receptor antagonist SB-269970. The strongest effect was found on the reversal phases of ASST, whereas injection of SB-269970 alone had no effect. These results indicate that 5-HT7 receptor mechanisms may have a specific contribution to the complex cognitive deficits, increasing perseverative responding, in psychiatric diseases, including schizophrenia, depression, and anorexia nervosa, which express different forms of cognitive inflexibility.

Automated Two-Chamber Operon ID/ED Task for Mice.

Attentional set shifting is a measure of cognitive flexibility and executive functions widely assessed in humans by the Wisconsin Card Sorting Test (WCST) and the CANTAB Intra-/Extra-Dimensional set-shifting task (ID/ED). The recently established automated two-chamber "Operon ID/ED" task for mice has proved to be an effective preclinical tool for drug testing and genetic screening, with direct translational valence in healthy human subjects and patients with schizophrenia. Here, we describe an upgraded version of the Operon ID/ED task that is now commercially available. This automated task allows one to study the ability of mice to shift attention through different rules, using two or three different dimensions (i.e., lights, odors, and textures). This unit provides a detailed step-by-step protocol for preparing and testing the mice that includes all procedures required for this upgraded attentional set-shifting paradigm. A short manual for the use of the dedicated ANY-maze software and tools for adapting it to different needs are also provided. Overall, this is a comprehensive guideline for the use of this complex upgraded equipment and paradigm. © 2020 Wiley Periodicals LLC. Basic Protocol: Operon ID/ED testing Support Protocol: Use of ANY-maze software.

A new semi-nonverbal task glance, moderate role of cognitive flexibility in ADHD children’s theory of mind

ABSTRACTIntroduction: Studies have documented both executive functions (EF) impairment in children with Attention Deficit / Hyperactivity Disorders (ADHD) and Theory of Mind (ToM), yielding mixed results, possibly because of a variety of tasks used, all requiring different levels of language skills.Aim: To investigate the relationship between ToM and EF with non-language-based tasks.Methods: Thirty ADHD (7–9 years old) were compared to thirty controls (age and IQ matched). Participants’ ToM was assessed using the Animated Triangles task and two EF tasks, namely spatial control test, the Stockings Of Cambridge (SOC) and rule and acquisition test, the Intra–Extra Dimensional set shift (IED)—from the neuropsychological battery of the Cambridge Neuropsychological Test Automated Battery (CANTAB).Results: ADHD group had a significant ToM and EF impairment relative to the control group. ToM was not significantly correlated with EF; however, the performance on IED tasks affected the performance on ToM tasks.Discussion: The study provides evidence for a link between the abilities to attribute correct mental states to others, planning and shifting attention in ADHD children, suggesting the ability to rely on cognitive flexibility in the face of a changing environment plays a role in explaining the association between ToM and EF.

Prior stress followed by a novel stress challenge results in sex-specific deficits in behavioral flexibility and changes in gene expression in rat medial prefrontal cortex

Chronic stress leads to sex-specific changes in the structure and function of rat medial prefrontal cortex (mPFC). Little is known about whether these effects persist following the cessation of chronic stress, or how these initial effects may impact responses to future stressors. Here we examined attentional set-shifting in male and female rats following chronic restraint stress, a post-chronic stress rest period, and an acute novel stress challenge. Chronic stress resulted in a reversible impairment in extradimensional set-shifting in males, but had no effect on attentional set-shifting in females. Surprisingly, chronically stressed female, but not male, rats had impaired extradimensional set-shifting following a novel stress challenge. Alterations in the balance of excitation and inhibition of mPFC have been implicated in behavioral deficits following chronic stress. Thus, in a separate group of rats, we examined changes in the expression of genes related to glutamatergic (NR1, NR2A, NR2B, GluR1) and GABAergic (Gad67, parvalbumin, somatostatin) neurotransmission in mPFC after acute and chronic stress, rest, and their combination. Stress significantly altered the expression of NR1, GluR1, Gad67, and parvalbumin. Notably, the pattern of stress effects on NR1, Gad67, and parvalbumin expression differed between males and females. In males, these genes were upregulated following the post-chronic stress rest period, while minimal changes were found in females. In contrast, both males and females had greater GluR1 expression following a rest period. These findings suggest that chronic stress leads to sex-specific stress adaptation mechanisms that may contribute to sex differences in response to subsequent stress exposure.

B-33 Cognitive Mechanisms Associated with Emotion-Focused Pulling in Trichotillomania

Abstract Objective A revised version of the Milwaukee Inventory for Subtypes of Trichotillomania-Adult (MIST-A) provides scores for two distinct behavioral patterns of hair pulling in trichotillomania: emotion and intention pulling. The current study explored the relationship between these scales and several cognitive domains. Method This study used baseline data from a randomized controlled trial of a cognitive-behavior therapy intervention for trichotillomania. Participants from the general community were eligible if they met diagnostic criteria for trichotillomania. Thirty-two individuals were enrolled and completed baseline measures. The sample was 78% female, and the mean age was 34. At baseline, participants completed diagnostic interviews, self-report symptom questionnaires, and tasks from the Cambridge Neuropsychological Test Automated Battery (the stop-signal test, the intra/extra dimensional shift task, and the Cambridge gambling task ). These provided scores of intra and extra dimensional set-shifting, response inhibition, decision making quality, and sensitivity to risk. Correlational analyses were conducted comparing each cognitive score to each MIST-A score. Results Analyses revealed significant negative correlations between emotion pulling score and decision making quality r (30) = -.383, = .031 and emotion pulling score and sensitivity to risk r (30) = -.396, p = .025. Conclusion These findings provide initial insight into some of the cognitive mechanisms associated with emotion focused pulling. Individuals who pull their hair with the aim of reducing negative emotions (e.g. boredom, anxiety) showed themselves on the gambling task to be more willing to bet on an unlikely outcome, and less willing to adjust their betting amount according to the likelihood of an outcome.

Deficiencies of microglia and TNFα in the mPFC-mediated cognitive inflexibility induced by social stress during adolescence

The crucial roles played by microglia and their release of cytokines in the regulation of brain maturation are increasingly being recognized. Adolescence is a unique period characterized by continued brain maturation, especially in the area of the prefrontal cortex. Our previous studies showed that adolescent social stress induced impairment in extradimensional set-shifting (EDS), a core component of cognitive flexibility mediated by the medial prefrontal cortex (mPFC) in adult mice. The present study further determined the role of microglia and the inflammatory cytokine tumor necrosis factor alpha (TNFα) in cognitive dysfunction. Accompanied by a deficit in EDS in adulthood, previously stressed mice showed significant reductions in the expression of the microglial molecular biomarker Iba1, cell numbers, and the levels of TNFα mRNA and protein in the mPFC. Pharmacological inhibition of TNFα signaling by direct injection of a neutralizer into the mPFC also specifically impaired EDS performance. Moreover, the cognitive and immune alterations in previously stressed adult mice were ameliorated by both acute LPS and chronic antidepressant treatment. Together, our data suggest that microglia and TNFα play important roles in cognitive flexibility and can provide attractive therapeutic targets for the treatment of cognitive deficits in psychiatric disorders.

Novel Smartphone Interventions Improve Cognitive Flexibility and Obsessive-Compulsive Disorder Symptoms in Individuals with Contamination Fears

One type of obsessive–compulsive disorder (OCD) is characterized by contamination fears and compulsive cleansing. Few effective treatments are available for this debilitating condition. Compulsive symptoms, such as excessive washing, are believed to be mediated by cognitive inflexibility—arguably the most striking cognitive impairment in OCD. In this study, we investigated the effects of two novel smartphone interventions on cognitive flexibility and OCD symptoms in healthy individuals with OCD-like contamination fears. In the first intervention, participants watched a brief video recording of themselves engaging in handwashing on a smartphone, four times a day, for a total of one week (N = 31). The second intervention was similar except that participants watched themselves repeatedly touching a disgust-inducing object (N = 31). In a third (control) “intervention”, participants watched themselves performing sequential hand movements (N = 31). As hypothesized, the two smartphone interventions, unlike the control, improved cognitive flexibility; as assessed on the Intradimensional–Extradimensional Set Shifting task (a sensitive marker of cognitive flexibility). The two interventions, unlike the control, also improved OCD symptoms (measured with the Obsessive–Compulsive Inventory–Revised and Yale–Brown Obsessive–Compulsive Scale). Finally, we found high levels of adherence to the interventions. These findings have significant clinical implications for OCD.

T157. FRONTOSTRIATAL CONNECTIVITY IN TREATMENT-RESISTANT SCHIZOPHRENIA: RELATIONSHIP TO POSITIVE SYMPTOMS AND COGNITIVE FLEXIBILITY

BackgroundThe frontostriatal circuits linking different parts of the frontal cortex to subregions of the striatum are proposed to regulate different aspects of cognition, executive function, affect and reward processing. Dysregulation of these brain circuits is also known to be important in the etiology of psychotic disorders, with the magnitude of dysfunction correlating with the severity of positive symptoms. These observations suggest that the integrity of brain circuits connected to the striatum is important for antipsychotic treatment response as well as specific cognitive processes. However, not all individuals with schizophrenia benefit from antipsychotic treatment, with up to 20% of individuals considered to be treatment-resistant. These individuals also show pervasive impairments in cognition, including cognitive flexibility. Nevertheless, few studies have examined striatal connectivity in treatment-resistant schizophrenia (TRS), particularly in relation to positive symptomatology and specific cognitive deficits subserved by the striatal circuits. This study therefore aimed to (i) assess for disruptions in frontostriatal connectivity in a sample of TRS and (ii) assess the relationship between the frontostriatal circuits with positive symptoms and attentional set-shifting (cognitive flexibility) given recent associations with the dorsal striatal circuit.MethodsResting-state functional magnetic resonance imaging was used to investigate functional connectivity (FC) in 42 TRS participants prescribed clozapine (30 males, mean age=41.3(10)), and 42 healthy controls (24 males, mean age=38.4(10)). The whole striatum (caudate, putamen and nucleus accumbens) and the left and right dorsal striatum were separately seeded as regions of interest, and Pearson’s correlations between the seeds and all other voxels comprising cortical and subcortical gray matter were investigated. For brain regions that showed significant group differences in FC with the striatal seeds, Pearson’s correlations explored the relationship between the strength of connectivity with positive symptoms and attentional set-shifting (extradimensional shift errors) as measured with the CANTAB intra-/extradimensional set shift task.ResultsIn comparison with healthy controls, TRS patients displayed significantly reduced FC between the whole striatum and the bilateral anterior cingulate, cerebellum, precuneus, right and left frontal pole and left insular/temporal pole, and reduced FC of the left and right dorsal striatum with cerebellum, and between the right dorsal striatum and bilateral cingulate and right frontal pole. Reduced FC between the whole striatum and precuneus and insular/temporal pole was associated with greater delusions of jealousy (p<.002 uncorrected); no other associations with positive symptoms were detected. In the entire sample, reduced FC from all striatal seeds was associated with greater extradimensional errors, indicating worse cognitive flexibility. These associations were not detected in TRS and controls separately.DiscussionOur preliminary findings reveal reduced striatal FC in TRS, including hypoconnectivity of the dorsal striatal circuit. In contrast to early psychosis, reduced dorsal striatal connectivity does not appear to mediate positive symptoms. Our finding relating hypoconnectivity of the striatal circuits with impaired cognitive flexibility is partly consistent with recent observations in other psychiatric disorders, although such deficits appear not specific to the dorsal circuit and to TRS. Future work will examine connectivity of the ventral striatum, as well as striatal connectivity in early-onset psychosis and siblings of patients with schizophrenia.

Spatial Rule Learning and Corresponding CA1 Place Cell Reorientation Depend on Local Dopamine Release

Incentives drive goal-directed behavior; however, how they impact the formation and stabilization of goal-relevant hippocampal maps remains unknown. Since dopamine is involved in reward processing, affects hippocampal-dependent behavior, and modulates hippocampal plasticity, we hypothesized that local dopaminergic transmission in the hippocampus serves to mold the formation and updating of hippocampal cognitive maps to adaptively represent reward-predicting space of sensory inputs. We recorded CA1 place cells of rats throughout training on a spatial extra-dimensional set-shift task. After learning to rely on one of two orthogonal sets of cues, we introduced a rule shift and infused locally the D1/5 receptor (D1/5R) antagonist SCH23390. Successful learning was accompanied by place cellreorientation to represent rule-relevant spatial dimension. SCH23390 infusion prevented this remapping and, consequently, impaired learning, causing perseveration. These findings suggest that dopaminergic innervation provides reward information to the hippocampus and is critical for the stabilization of goal-related hippocampal representation, contributing to successful goal-directed behavior.

Npas4 deficiency interacts with adolescent stress to disrupt prefrontal GABAergic maturation and adult cognitive flexibility.

Healthy cognitive and emotional functioning relies on a balance between excitatory and inhibitory neurotransmission in the prefrontal cortex (PFC). This balance is largely established during early postnatal and adolescent developmental periods by maturation of the γ-aminobutyric acid (GABA) system, including increased density of parvalbumin (PV) cells and perineuronal nets (PNNs). Genetic and/or environmental factors during adolescence can disrupt GABAergic maturation and lead to behavioral dysfunction in adulthood. The present study examined the interaction between chronic mild stress during adolescence and genetic deficiency of neuronal Per-Arnt-Sim domain 4 (Npas4), a brain-specific transcription factor that regulates inhibitory neurotransmission and that contributes to adolescent prefrontal GABAergic maturation. Male Npas4 wild-type (WT) and heterozygous (HET) mice were exposed to adolescent chronic stress and tested in adulthood for cognitive function using the attention set shifting task. When Npas4 deficiency was combined with adolescent stress, mice displayed impaired cognitive flexibility as observed by poor performance on the extra-dimensional set shift task. At the cellular level, adolescent stress increased the percentage of PV cells surrounded by PNNs in the PFC of adult WT animals, an effect that was not observed in HET mice. Additionally, Npas4 deficiency and/or adolescent stress dysregulated expression of certain GABAergic system markers. These results suggest that Npas4 mediates susceptibility to adolescent stress and subsequent cognitive functioning and inhibitory tone in adulthood. This shows a novel gene by environment interaction related to resilience vs vulnerability to stress, with implications for adolescent onset disorders like schizophrenia.

Attentional set-shifting and social abilities in children with schizotypal and comorbid autism spectrum disorders.

While diagnostically independent, autism and schizotypal disorders can co-occur. Their concurrent impact on outcomes and phenotypes has not been investigated. We investigated the impact of comorbid autism and schizotypal disorders in children on executive functioning and socio-pragmatic skills - core features of both disorders. Executive functioning (assessed with the Cambridge Neuropsychological Test Automated Battery) and socio-pragmatic skills (assessed using the Melbourne Assessment of Schizotypy in Kids) were investigated in a total of 67 (6-12 year old) children with autism ( n = 15; M/F = 10/5), schizotypal disorder ( n = 8; M/F = 5/3) and comorbid autism and schizotypal disorder ( n = 12; M/F = 5/7) and typically developing children ( n = 32; M/F = 17/15). Both the autism and schizotypal disorder groups performed more poorly than the typically developing group on socio-pragmatic skills and overall performance (i.e. number of stages completed) of the intra-/extra-dimensional set-shifting task (all ps < 0.001). Clear distinctions between the autism and schizotypal groups were present in the intra-/extra-dimensional task relative to the typically developing group - the autism group had difficulties with extra-dimensional shifts ( p < 0.001), and the schizotypal disorder group with intra-dimensional shifts ( p = 0.08). Interestingly, the overall performance of the comorbid group on the intra-/extra-dimensional task was not significantly different from the typically developing group, and they were superior to both the autism ( p = 0.019) and schizotypal disorder ( p = 0.042) groups on socio-pragmatic skills. The phenotypical overlap between autism and schizotypal disorders may be precipitated by different cognitive styles and/or mechanisms associated with attention and information processing. We propose that sustaining and switching attention represent two poles of irregularities across the autism and schizotypal spectra, which appear to converge in a compensatory manner in the comorbid group. Our findings highlight the importance of investigating children with a dual diagnosis of autism and schizotypal disorders, and raise intriguing questions about possible mechanisms to explain the attenuated impairment observed in the group of children with comorbid autism and schizotpyal disorders.

Executive functioning impairments in adolescents with early diagnosis of obsessive compulsive disorder

Despite the neuropsychology literature provide reliable evidence of impaired executive functions in obsessive-compulsive disorder (OCD), it has not been determined whether these deficits are prior to onset of the disorder or they begin to appear as consequence. To investigate whether recent onset of OCD in adolescence is characterized by executive functioning difficulties in behavioral inhibition, attentional flexibility, and decision-making. Executive functions were compared in adolescents with recent (past year) appearance of OCD symptoms (n = 40) and control group (n = 40). Three computerized tests within the CANTAB battery were completed by all subjects (the Affective Go/No Go task, the Intra-Dimensional, Extra-Dimensional Set-Shifting task, and the Decision-Making task). Using one-way ANOVA showed that compared with control group, the OCD adolescents displayed a bias towards negative stimuli with less errors on sad and hopeless words on the Affective Go/No Go task. They also made faster decisions while they bet more of their available points compared to controls, in the Decision-Making task. Adolescents with recent OCD diagnosis (less than one year) showed greater attention towards sad and hopeless stimuli and more impulsive behavior when making decisions. However, they were able to switch attentional set to neutral stimuli. These findings suggest that executive functioning impairments can characterize adolescence OCD from early beginning of the disorder.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex

Deficits in cognitive flexibility, the ability to modify behavior in response to changes in the environment, contribute to the onset and maintenance of stress-related neuropsychiatric illnesses, such as depression. Cognitive flexibility depends on medial prefrontal cortex (mPFC) function, and in depressed patients, cognitive inflexibility is associated with hypoactivity and decreased glutamate receptor expression in the mPFC. Rats exposed to chronic unpredictable stress (CUS) exhibit compromised mPFC function on the extradimensional (ED) set-shifting task of the attentional set-shifting test. Moreover, CUS-induced ED deficits are associated with dendritic atrophy and decreased glutamate receptor expression in the mPFC. This evidence suggests that impaired glutamate signaling may underlie stress-induced deficits in cognitive flexibility. To test this hypothesis, we first demonstrated that blocking NMDA or AMPA receptors in the mPFC during ED replicated CUS-induced deficits in naïve rats. Secondly, we found that expression of activity-regulated cytoskeleton-associated protein (Arc) mRNA, a marker of behaviorally induced glutamate-mediated plasticity, was increased in the mPFC following ED. We then showed that CUS compromised excitatory afferent activation of the mPFC following pharmacological stimulation of the mediodorsal thalamus (MDT), indicated by a reduced induction of c-fos expression. Subsequently, in vivo recordings of evoked potentials in the mPFC indicated that CUS impaired afferent activation of the mPFC evoked by MDT stimulation, but not the ventral hippocampus. Lastly, glutamate microdialysis showed that CUS attenuated the acute stress-evoked increase in extracellular glutamate in the mPFC. Together, these results demonstrate that CUS-induced ED deficits are associated with compromised glutamate neurotransmission in the mPFC.

The relationship between executive function and fine motor control in young and older adults

The present study examined the relationship between executive function (EF) and fine motor control in young and older healthy adults. Participants completed 3 measures of executive function; a spatial working memory (SWM) task, the Stockings of Cambridge task (planning), and the Intra-Dimensional Extra-Dimensional Set-Shift task (set-shifting). Fine motor control was assessed using 3 subtests of the Purdue Pegboard (unimanual, bimanual, sequencing). For the younger adults, there were no significant correlations between measures of EF and fine motor control. For the older adults, all EFs significantly correlated with all measures of fine motor control. Three separate regressions examined whether planning, SWM and set-shifting independently predicted unimanual, bimanual, and sequencing scores for the older adults. Planning was the primary predictor of performance on all three Purdue subtests. A multiple-groups mediation model examined whether planning predicted fine motor control scores independent of participants’ age, suggesting that preservation of planning ability may support fine motor control in older adults. Planning remained a significant predictor of unimanual performance in the older age group, but not bimanual or sequencing performance. The findings are discussed in terms of compensation theory, whereby planning is a key compensatory resource for fine motor control in older adults.

EP 56. Optogenetic control of the locus coeruleus in mice: Behavioral and electrophysiological data

The locus coeruleus (LC) is the sole source of noradrenergic projections to the cortex and to better understand its essential role for attention-dependent cognitive processes, we first expressed the halorhodopsin eNpHR3.0 to reversibly silence LC activity in naive male B6.Cg-Tg(Th-cre)1Tmd/J hemizygous mice (Th-cre mice) that express Cre-recombinase under the control of the tyrosine hydroxylase (TH) promoter. Unilateral optogenetic silencing of the LC during the performance of an attentional set-shifting task (ASST) selectively impaired learning of those parts of the ASST that most strongly rely on cognitive flexibility. In particular, extra-dimensional set-shifting (EDS) and reversal learning was impaired. However, those parts of the task that are less dependent on cognitive flexibility, i.e. compound discrimination (CD) and the intra-dimensional shifts (IDS), as well as attentional set formation were unaffected by LC silencing. Therefore, our results suggest a modulatory influence of the LC on cognitive flexibility, mediated by different frontal networks. Subsequently, we used AAV8-Ef1a-DIO-Chronos-eYFP to stimulate LC activity in Th-cre mice and performed electrophysiological recordings during optogenetic stimulation by using an optetrode. Laser pulses of different intensities (0.5, 1, 2, 5, and 10 mW) and different pulse durations (5, 10, 20, 50, 100, 200, and 500 ms) were tested. Results showed that pulses at 5 mW of 5 ms pulse duration are optimal and that those laser pulses are able to induce bursts of 20 Hz discharges and sustained 10 Hz discharges of LC neurons.

Adolescent Social Defeat Induced Alterations in Social Behavior and Cognitive Flexibility in Adult Mice: Effects of Developmental Stage and Social Condition.

Negative social experiences during adolescence increase the risk of psychiatric disorders in adulthood. Using “resident-intruder” stress, the present study aimed to investigate the effects of adolescent social defeat on emotional and cognitive symptoms associated with psychiatric disorders during adulthood and the effects of the developmental stage and social condition on this process. In Experiment 1, animals were exposed to social defeat or manipulation for 10 days during early adolescence (EA, postnatal days [PND] 28–37), late adolescence (LA, PND 38–47), and adulthood (ADULT, PND 70–79) and then singly housed until the behavioral tests. Behaviors, including social avoidance of the defeat context and cortically mediated cognitive flexibility in an attentional set-shifting task (AST), were assessed during the week following stress or after 6 weeks during adulthood. We determined that social defeat induced significant and continuous social avoidance across age groups at both time points. The mice that experienced social defeat during adulthood exhibited short-term impairments in reversal learning (RL) on the AST that dissipated after 6 weeks. In contrast, social defeat during EA but not LA induced a delayed deficit in extra-dimensional set-shifting (EDS) in adulthood but not during adolescence. In Experiment 2, we further examined the effects of social condition (isolation or social housing after stress) on the alterations induced by social defeat during EA in adult mice. The adult mice that had experienced stress during EA exhibited social avoidance similar to the avoidance identified in Experiment 1 regardless of the isolation or social housing after the stress. However, social housing after the stress ameliorated the cognitive flexibility deficits induced by early adolescent social defeat in the adult mice, and the social condition had no effect on cognitive function. These findings suggest that the effects of social defeat on emotion and cognitive function are differentially affected by the developmental stage and social condition. EA may comprise a particularly sensitive developmental period in which social defeat may produce a delayed impairment in cognitive flexibility during adulthood, and the social condition following stress appears to play an important intermediary role in the development of these cognitive deficits.

Are obsessive–compulsive symptoms impulsive, compulsive or both?

BackgroundThe relationships between obsessive–compulsive symptoms and distinct forms of impulsivity and compulsivity are unclear. Such examination would be relevant in terms of how best to classify psychiatric disorders and in understanding candidate ‘traits’ that extend across a continuum between normalcy and clinical disorders. Method515 young adults (aged 18–29years) completed the Padua Inventory and undertook detailed clinical and neurocognitive assessments. Relationships between obsessive–compulsive symptoms and distinct types of impulsivity and compulsivity were evaluated using linear regression modeling. ResultsObsessive–Compulsive symptoms were significantly predicted by female gender, lower quality of life, psychiatric disorders in general (but not impulse control disorders), and worse extra-dimensional set-shifting. Obsessive–Compulsive symptoms were not significantly predicted by alcohol/nicotine consumption, stop-signal reaction times, or decision-making abilities. ConclusionThese data indicate that obsessive–compulsive symptoms are more related to certain forms of compulsivity than to impulsivity. These findings have important implications for diagnostic conceptualizations and neurobiological models.

Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice

Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0–100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher and lower order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108,390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with⩾95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher order cognitive flexibility, lower order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher and lower order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli.