Deficits In Cognitive Flexibility Research Articles

Comparison of Cognitive Functions between Healthy Controls and Individuals with Chronic Low Back Pain with High and Low Pain Catastrophizing: A Cross-sectional Study.

Researchers suggested that the interruptive effects of chronic pain on cognitive functions may be modulated by the level of pain catastrophizing (PC). However, in individuals with chronic low back pain (CLBP), domains of cognitive function that may be affected by the level of PC remain largely unclear. Therefore, this study was aimed to compare cognitive functions between healthy controls and individuals with CLBP with high and low PC. This cross-sectional study examined cognitive functions of 42 individuals with CLBP and 21 healthy controls. The PC scale was used to stratify participants with CLBP into high and low PC. Participants performed 5 cognitive tests from the Cambridge Neuropsychological Test Automated Battery, namely five-choice reaction time, rapid visual processing, spatial working memory, attention switching task, and stop signal task. The statistical analyses revealed that compared to individuals with CLBP with low PC and healthy controls, individuals with high PC demonstrated greater values of the between errors (P=0.01), reaction latency (P<0.001), and stop signal reaction time variables (P=0.004, P=0.003, respectively) but lower values of probability of hit (P=0.02, P=0.01, respectively), A' (P=0.01, P<0.001, respectively), and percent correct trials variables (P=0.002, P<0.001, respectively). The results of the current study showed deficits in sustained attention, working memory, cognitive flexibility, and inhibitory control in individuals with CLBP with high PC. From a clinical perspective, therapeutic interventions targeting PC should be considered to decrease catastrophic thinking about pain in individuals with CLBP. Additional research is warranted to explore cognitive functioning as an outcome of these interventions in individuals with CLBP.

Impaired cognitive flexibility in major depressive disorder: Evidences from spatial-temporal ERPs analysis

BackgroundMajor Depressive Disorder (MDD) may exhibit impairments in cognitive flexibility. This study investigated whether the cognitive flexibility deficits in MDD are evident across general stimuli or specific to emotional stimuli, while exploring the underlying neuropsychological mechanism. MethodsA total of 41 MDD patients and 42 healthy controls (HCs) were recruited. Event-related potentials (ERPs) were recorded when participants performed a non-emotional and an emotional task switching paradigm (N-ETSP and ETSP), both of which assessed cognitive flexibility. Microstate and source localization analysis were applied to reflect brain activity among different brain areas during task switching. ResultsIn the N-ETSP, MDD group showed larger P3 difference wave (Pd3) amplitudes and longer P2 difference wave (Pd2) latencies. In the ETSP, MDD group displayed smaller N2 difference wave (Nd2) amplitudes and larger Pd3 amplitudes. The comparison of sLORETA images of emotional switch task and emotional repeat task showed that MDD group had increased activation in the precentral gyrus in microstate2 of the P2 time window and had reduced activation in the middle occipital gyrus in microstate3 of the N2 time window. LimitationsThe cross-sectional design failed to capture dynamic changes in cognitive flexibility in MDD. ConclusionsMDD demonstrated impaired cognitive flexibility respond to both non-emotional and emotional stimuli, with greater impairment for negative emotional stimuli. These deficits are evident in abnormal ERPs component during the early attention stage and the later task preparation stage. Furthermore, abnormal emotional switching cost in MDD appears to be related to early abnormal perceptual control in the parietal-occipital cortex.

Effects of Memantine on Cognitive Flexibility in a Valproic Acid Rat Model of Autism

Abstract Autistic children frequently struggle with cognitive flexibility. The potential molecular mechanism underlying cognitive inflexibility remains unclear. Decreased level of brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity may have a role. This study aimed to investigate the effects of memantine on (BDNF) expression in hippocampus of prenatal VPA exposed rats, and its consequent effects on cognitive flexibility. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) on gestational day 12.5 to induce autistic-like behaviors in their offspring. Afterwards, the 23-day-old male Wistar rat pups received daily intraperitoneal injections of memantine (20 mg/kg) for 4 weeks. The prenatal VPA-exposed rats exhibited reduced cognitive flexibility in the attentional set- shifting task (ASST) reflecting ASD-associated cognitive flexibility deficits, a common ASD- associated problem with accompanied reduction in hippocampal BDNF. The defective performance in ASST was more prominent in the reversal stages. Memantine associated increased hippocampal BDNF could alleviate cognitive inflexibility in ASD. This study draws attention to the potential favorable effect of memantine on cognitive performance in autistic subjects.

Hyperglycemia and cognitive impairments anticipate the onset of an overt type 2 diabetes-like phenotype in TALLYHO/JngJ mice

Type 2 Diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, resulting from deficits in insulin secretion, insulin action, or both. Whilst the role of insulin in the peripheral nervous system has been ascertained in countless studies, its role in the central nervous system (CNS) is emerging only recently. Brain insulin has been lately associated with brain disorders like Alzheimer’s disease, obsessive compulsive disorder, and attention deficit hyperactivity disorder. Thus, understanding the role of insulin as a common risk factor for mental and somatic comorbidities may disclose novel preventative and therapeutic approaches. We evaluated general metabolism (glucose tolerance, insulin sensitivity, energy expenditure, lipid metabolism, and polydipsia) and cognitive capabilities (attention, cognitive flexibility, and memory), in adolescent, young adult, and adult male and female TALLYHO/JngJ mice (TH, previously reported to constitute a valid experimental model of T2DM due to impaired insulin signaling). Adult TH mice have also been studied for alterations in gut microbiota diversity and composition. While TH mice exhibited profound deficits in cognitive flexibility and altered glucose metabolism, we observed that these alterations emerged either much earlier (males) or independent of (females) a comprehensive constellation of symptoms, isomorphic to an overt T2DM-like phenotype (insulin resistance, polydipsia, higher energy expenditure, and altered lipid metabolism). We also observed significant sex-dependent alterations in gut microbiota alpha diversity and taxonomy in adult TH mice. Deficits in insulin signaling may represent a common risk factor for both T2DM and CNS-related deficits, which may stem from (partly) independent mechanisms.

A process model of parental executive functioning as a spillover mechanism linking interparental conflict and parenting difficulties across parenting domains.

There is a well-documented interdependency between destructive interparental conflict (IPC) and parenting difficulties (i.e., spillover effect), yet little is known about the mechanisms that "carry" spillover between IPC and parenting. Guided by a cascade model framework, the current study used a longitudinal, multimethod, multi-informant design to examine a process model of spillover that tested whether parental executive functioning (working memory, cognitive flexibility, inhibitory control) served as a mediator of the prospective associations between IPC and subsequent changes in parenting over a 2-year period. Mothers and fathers were separated into differentiated models and multiple domains of parenting were examined (i.e., authoritarian discipline and scaffolding behavior). Participants included 231 families (both mothers and fathers of preschoolers). Race was reported as White (62%), Black (21%), Mixed (8%), Asian (3%), or Other (6%) and 14% considered their ethnicity to be Hispanic/Latino. Median household income was $65,000. Results indicated that for fathers, IPC indirectly predicted domain-general parenting difficulties (increased authoritarian parenting and decreased scaffolding) via deficits in paternal cognitive flexibility (but not inhibitory control or working memory). In mothers, IPC directly predicted domain-specific parenting difficulties (decreased scaffolding only) that did not operate via maternal executive functions. Notably, these effects occurred over and above the influence of parental socioeconomic status. This study constitutes a first step toward documenting parental executive functioning as a mechanism underlying the spillover of IPC to the parent-child relationship. Family interventions intended to interrupt IPC spillover should emphasize father involvement and consider targeting parental executive functions as change mechanisms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Characterisation of behaviours relevant to apathy syndrome in the aged male rat

Apathy is a complex psychiatric syndrome characterised by motivational deficit, emotional blunting and cognitive changes. It occurs alongside a broad range of neurological disorders, but also occurs in otherwise healthy ageing. Despite its clinical prevalence, apathy does not yet have a designated treatment strategy. Generation of a translational animal model of apathy syndrome would facilitate the development of novel treatments. Given the multidimensional nature of apathy, a model cannot be achieved with a single behavioural test. Using a battery of behavioural tests we investigated whether aged rats exhibit behavioural deficits across different domains relevant to apathy. Using the effort for reward and progressive ratio tasks we found that aged male rats (21–27 months) show intact reward motivation. Using the novelty supressed feeding test and position-based object exploration we found aged rats showed increased anxiety-like behaviour inconsistent with emotional blunting. The sucrose preference test and reward learning assay showed intact reward sensitivity and reward-related cognition in aged rats. However, using a bowl-digging version of the probabilistic reversal learning task, we found a deficit in cognitive flexibility in aged rats that did not translate across to a touchscreen version of the task. While these data reveal important changes in cognitive flexibility and anxiety associated with ageing, aged rats do not show deficits across other behavioural domains relevant to apathy. This suggests that aged rats are not a suitable model for age-related apathy syndrome. These findings contrast with previous work in mice, revealing important species differences in behaviours relevant to apathy syndrome in ageing.

Transient demyelination causes long-term cognitive impairment, myelin alteration and network synchrony defects.

In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination. However, reformed myelin, although functional, may not exhibit the same morphological characteristics as developmental myelin, which can have an impact on the activity of neural networks. In this context, we used the cuprizone-treated mouse model to analyze the structural, functional, and cognitive long-term effects of transient demyelination. Our results show that an episode of demyelination induces despite remyelination long-term cognitive impairment, such as deficits in spatial working memory, social memory, cognitive flexibility, and hyperactivity. These deficits were associated with a reduction in myelin content in the medial prefrontal cortex (mPFC) and hippocampus (HPC), as well as structural myelin modifications, suggesting that the remyelination process may be imperfect in these structures. In vivo electrophysiological recordings showed that the demyelination episode altered the synchronization of HPC-mPFC activity, which is crucial for memory processes. Altogether, our data indicate that the myelin repair process following transient demyelination does not allow the complete recovery of the initial myelin properties in cortical structures. These subtle modifications alter network features, leading to prolonged cognitive deficits in mice.

Mapping causal links between prefrontal cortical regions and intra-individual behavioral variability

Intra-individual behavioral variability is significantly heightened by aging or neuropsychological disorders, however it is unknown which brain regions are causally linked to such variabilities. We examine response time (RT) variability in 21 macaque monkeys performing a rule-guided decision-making task. In monkeys with selective-bilateral lesions in the anterior cingulate cortex (ACC) or in the dorsolateral prefrontal cortex, cognitive flexibility is impaired, but the RT variability is significantly diminished. Bilateral lesions within the frontopolar cortex or within the mid-dorsolateral prefrontal cortex, has no significant effect on cognitive flexibility or RT variability. In monkeys with lesions in the posterior cingulate cortex, the RT variability significantly increases without any deficit in cognitive flexibility. The effect of lesions in the orbitofrontal cortex (OFC) is unique in that it leads to deficits in cognitive flexibility and a significant increase in RT variability. Our findings indicate remarkable dissociations in contribution of frontal cortical regions to behavioral variability. They suggest that the altered variability in OFC-lesioned monkeys is related to deficits in assessing and accumulating evidence to inform a rule-guided decision, whereas in ACC-lesioned monkeys it results from a non-adaptive decrease in decision threshold and consequently immature impulsive responses.

Prefrontal Dopamine in Flexible Adaptation to Environmental Changes: A Game for Two Players.

Deficits in cognitive flexibility have been characterized in affective, anxiety, and neurodegenerative disorders. This paper reviews data, mainly from studies on animal models, that support the existence of a cortical-striatal brain circuit modulated by dopamine (DA), playing a major role in cognitive/behavioral flexibility. Moreover, we reviewed clinical findings supporting misfunctioning of this circuit in Parkinson's disease that could be responsible for some important non-motoric symptoms. The reviewed findings point to a role of catecholaminergic transmission in the medial prefrontal cortex (mpFC) in modulating DA's availability in the nucleus accumbens (NAc), as well as a role of NAc DA in modulating the motivational value of natural and conditioned stimuli. The review section is accompanied by a preliminary experiment aimed at testing weather the extinction of a simple Pavlovian association fosters increased DA transmission in the mpFC and inhibition of DA transmission in the NAc.

MMP-9 inhibition alleviates postoperative cognitive dysfunction by improving glymphatic function via regulating AQP4 polarity

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, characterized by deficits in memory, attention and cognitive flexibility. However, the underlying mechanisms of POCD remain unclear. Neuroinflammation and blood–brain barrier disruption have been implicated as potential pathological processes. This study explores the neuroprotective effects and mechanisms of the matrix metalloproteinase（MMP-9）inhibitor GM6001 against POCD. We hypothesize GM6001 may reduce neuroinflammation and preserve blood–brain barrier integrity through direct inhibition of MMP-9. Moreover, GM6001 may stabilize aquaporin-4 polarity and glymphatic clearance function by modulating MMP-9-mediated cleavage of dystroglycan, a key protein for aquaporin-4 anchoring. Our results demonstrate GM6001 alleviates postoperative cognitive deficits and neuroinflammation. GM6001 also preserves blood–brain barrier integrity and rescues aquaporin-4 mislocalization after surgery. This study reveals a novel dual role for MMP-9 inhibition in cognitive protection through direct anti-neuroinflammatory effects and regulating aquaporin-4 membrane distribution. Targeting MMP-9 may represent a promising strategy to prevent postoperative cognitive dysfunction by integrating multiple protective mechanisms.

Melatonin enhances the restoration of neurological impairments and cognitive deficits during drug withdrawal in methamphetamine-induced toxicity and endoplasmic reticulum stress in rats

Methamphetamine (METH) is a psychostimulant with a very high addiction rate. Prolonged use of METH has been observed as one of the root causes of neurotoxicity. Melatonin (Mel) has been found to have a significant role in METH-induced neurotoxicity. This study aimed to investigate the restorative effect of Mel on behavioral flexibility in METH-induced cognitive deficits. Male Sprague-Dawley rats were randomly assigned to be intraperitoneally injected with saline (control) or Meth at 5 mg/kg for 7 consecutive days. Then, METH injection was withdrawn and rats in each group were subcutaneously injected with saline or Mel at 10 mg/kg for 14 consecutive days. The stereotypic behavioral test and attentional set-shifting task (ASST) were used to evaluate neurological functions and cognitive flexibility, respectively. Rats developed abnormal features of stereotyped behaviors and deficits in cognitive flexibility after 7 days of METH administration. However, post-treatment with Mel for 14 days after METH withdrawal dramatically ameliorated the neurological and cognitive deficits in METH-treated rats. Blood biomarkers indicated METH-induced systemic low-grade inflammation. Moreover, METH-induced endoplasmic reticulum (ER) stress in the prefrontal cortex was diminished by melatonin supplementation. These findings might reveal the therapeutic potential of Mel in METH toxicity-induced neurological and cognitive deficits.

Language comprehension and cognitive orientation switching in Brocas syndrome and Parkinsons disease

This paper reviews researches on sentence comprehension deficits and the cognitive orientation switching abilities in two neurological disorders Brocas aphasia and Parkinsons disease (PD). Both patient groups exhibit challenges in sentence comprehension. Individuals with Brocas aphasia show reduced lexical activation and struggle with processing syntactic information when comprehending sentences. While they may retain some comprehension abilities, complex grammatical processing is significantly hindered. In PD, sentence comprehension deficits arise from disruptions in attention, executive control, and action-language networks in the brain which are critical for integrating linguistic information. Regarding cognitive orientation switching, patients with both Brocas aphasia and PD demonstrate impairments, likely due to dysfunction in frontal brain regions that enable flexibility in thinking. Broca's patients struggle with changing response strategies, while PD patients have difficulty learning new classification rules and are challenged by distractions. There is evidence that reduced cognitive switching abilities can interfere with effective syntactic processing during sentence comprehension. The review highlights neurological underpinnings and manifestations of comprehension and cognitive flexibility deficits in these two disorders. Further research can provide greater insight into the nuanced interactions between language and domain-general cognition.

Alerting network, cognitive flexibility in children with attention deficit hyperactivity disorder and the moderating effect of neuroticism.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, and cognitive flexibility is a sub-component of executive functioning. Studies have shown impairments in cognitive flexibility in ADHD, which is affected by attentional processes. Personality, as a long-standing trait, has a profound effect on ADHD. However, previous studies have not assessed the relationship between attentional function, personality traits, and cognitive flexibility in children with ADHD. This study explored the association between attention networks, personality, and cognitive flexibility in ADHD, filling a gap in the related field. We expect our findings will provide insights into and clues for the prevention and interventional treatment of ADHD. This study primarily aimed to analyze differences in cognitive flexibility between individuals with ADHD and those without and further examine associations between attention networks, personality, and cognitive flexibility in children with ADHD. Overall, 55 children aged 7 to 11 years diagnosed with ADHD and 40 children without ADHD participated in this study. Cognitive flexibility, personality traits, and attentional networks were assessed using the Wisconsin Card Sorting Test, Eysenck Personality Questionnaire, and Attention Network Test, respectively. Additionally, the association between personality traits and strong attentional functioning and cognitive flexibility was investigated using multiple regression analysis. Children with ADHD had significant deficits in cognitive flexibility. A multiple regression analysis revealed that the alerting effect was highly associated with cognitive flexibility at high levels of neuroticism. This association was not salient in individuals with low levels of neuroticism. This study demonstrated that the ADHD group experienced lower cognitive flexibility than the control group. In addition, we showed the effect of neuroticism and alerting networks on cognitive flexibility. These findings may help psychiatrists provide intervention strategies to mitigate the impairment of social functioning in ADHD with cognitive spirituality deficits.

Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease

Huntington’s disease (HD) is a devastating monogenic neurodegenerative disease characterized by early, selective pathology in the basal ganglia despite the ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to the development of early cognitive phenotypes are poorly understood. Here we show that there is selective loss of synaptic connections between the cortex and striatum in postmortem tissue from patients with HD that is associated with the increased activation and localization of complement proteins, innate immune molecules, to these synaptic elements. We also found that levels of these secreted innate immune molecules are elevated in the cerebrospinal fluid of premanifest HD patients and correlate with established measures of disease burden.In preclinical genetic models of HD, we show that complement proteins mediate the selective elimination of corticostriatal synapses at an early stage in disease pathogenesis, marking them for removal by microglia, the brain’s resident macrophage population. This process requires mutant huntingtin to be expressed in both cortical and striatal neurons. Inhibition of this complement-dependent elimination mechanism through administration of a therapeutically relevant C1q function-blocking antibody or genetic ablation of a complement receptor on microglia prevented synapse loss, increased excitatory input to the striatum and rescued the early development of visual discrimination learning and cognitive flexibility deficits in these models. Together, our findings implicate microglia and the complement cascade in the selective, early degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic HD; they also provide new preclinical data to support complement as a therapeutic target for early intervention.

Cognitive flexibility and DSM-5 severity criteria for eating disorders: assessing drive for thinness and duration of illness as alternative severity variables

BackgroundThe severity criteria for eating disorders (EDs) proposed in the DSM-5 have been established without sufficient empirical support. Drive for thinness (DT) and duration of illness have been proposed as two alternative severity measures, however their empirical evidence is also limited. To date, no research has assessed the validity of current eating disorder (ED) severity criteria regarding cognitive flexibility factors. Cognitive flexibility is often impaired in EDs, becoming a possible severity symptom. The current study assessed for the first time (1) whether the severity indexes for EDs proposed in the DSM-5 were associated with deficits in cognitive flexibility and, (2) whether drive for thinness and illness duration, acted as an alternative, more meaningful severity indices for deficiencies in cognitive flexibility.MethodsParticipants were 161 patients diagnosed with an ED, who were categorized according to DSM-5 severity categories, DT and duration of illness. Discriminative capacity of each classification was assessed for cognitive flexibility measured by Wisconsin card sorting test (WCST).ResultsThe findings for the DSM-5 classification comprised: (a) In the anorexia nervosa (AN) group, patients with moderate severity showed better scores in WCST than patients with mild and severe/extreme severity. Also, patients with moderate severity showed lower percentage of cognitive flexibility deficits than the other two severity categories; (b) For the binge spectrum disorders (BSD) group, the patients with mild severity showed a higher percentage of cognitive flexibility deficits than did the moderate and severe/extreme categories. When assessing the alternative severity index of DT, no differences were found in cognitive flexibility in any of the groups. Regarding illness duration, in the AN group the task performance of the patients with longer illness duration was worse than the performance of the short duration group and, in the BSD group, patients with longer duration also showed more deficits in cognitive flexibility than the patients with shorter duration of illness.ConclusionsOur findings point out the limitations of the DSM-5 severity criteria to categorize cognitive flexibility in EDs and support illness duration as an alternative severity approach for EDs.

Reduced volume of the left cerebellar lobule VIIb and its increased connectivity within the cerebellum predict more general psychopathology one year later via worse cognitive flexibility in children

Predicting the risk for general psychopathology (the p factor) requires the examination of multiple factors ranging from brain to cognitive skills. While an increasing number of findings have reported the roles of the cerebral cortex and executive functions, it is much less clear whether and how the cerebellum and cognitive flexibility (a core component of executive function) may be associated with the risk for general psychopathology. Based on the data from more than 400 children aged 6–12 in the Children School Functions and Brain Development (CBD) Project, this study examined whether the left cerebellar lobule VIIb and its connectivity within the cerebellum may prospectively predict the risk for general psychopathology one year later and whether cognitive flexibility may mediate such predictions in school-age children. The reduced gray matter volume in the left cerebellar lobule VIIb and the increased connectivity of this region to the left cerebellar lobule VI prospectively predicted the risk for general psychopathology and was partially mediated by worse cognitive flexibility. Deficits in cognitive flexibility may play an important role in linking cerebellar structure and function to the risk for general psychopathology.

Aging to 24 months increased C57BL/6J mouse social sniffing and hippocampal Neto1 levels, and impaired female spatial learning

Understanding how natural aging impacts rodent performance in translational behavior tests is critical to teasing apart impairments due to age-related decline from neurodegenerative disorder modeling. Reduced neuropilin and tolloid-like 1 (NETO1), an accessory protein of ionotropic glutamate receptors involved in synaptic plasticity, was associated with Alzheimer’s disease, yet aging effects on Neto1 remain unclear. For these reasons, our goal was to characterize how Neto1 expression corresponded with social, repetitive, and spatial learning behaviors and stress response across the C57BL/6J mouse lifespan. We measured social preferences in three-chamber tests, and motor stereotypies by marble burying. Cognitive flexibility is typically assessed in the Morris water maze (MWM), wherein C57BL/6J mice exhibit deficits with age. However, fatigue or locomotor impairment may confound interpretation of MWM performance. Therefore, we used a less arduous water T-maze (WTM) to compare spatial learning flexibility in 2, 9–15, and 24-month-old male and female mice to test the hypothesis that deficits would emerge with age. In both sexes, 9–15-month-olds made more chamber entries during social preference tests, while 2-month-olds did less social sniffing than aged mice. No age or sex differences emerged in marble burying or serum corticosterone measurements. In 24-month-olds hippocampal Neto1was increased relative to 2-month-olds, and male cognitive flexibility was strong, while spatial learning and reversal learning of 24-month-old females was impaired in WTM irrespective of Neto1 expression. The WTM is a useful alternative assessment for cognitive flexibility deficits in aged mice, and the role of hippocampal Neto1 in promoting social sniffing is of interest.

Ventral hippocampal input to infralimbic cortex is necessary for the therapeutic-like effects of extinction in stressed rats.

Post-traumatic stress disorder is characterized by deficits in cognitive flexibility related to dysfunction of the medial prefrontal cortex (mPFC). Exposure therapy can effectively reverse these deficits. Fear extinction in rodents bears similarity to exposure therapy. Extinction reverses chronic stress-induced deficits in cognitive flexibility on the attentional set-shifting test (AST), a mPFC-mediated process. This therapeutic effect requires activity of pyramidal neurons and BDNF signaling in infralimbic cortex (IL). However, the circuit mechanisms governing BDNF-mediated plasticity initiated by extinction in IL are unknown. The ventral hippocampus (vHipp) plays a role in regulating IL activity during extinction, and plasticity in vHipp is necessary for extinction memory consolidation. Therefore, we investigated the role of vHipp input to IL in the effects of extinction in reversing stress-induced cognitive deficits. vHipp input to IL was silenced using a Gi-DREADD via local infusion of CNO into IL before extinction. A day later, rats were tested on AST. In a separate experiment, we tested whether vHipp input to the IL induces BDNF signaling to exert therapeutic effects. We activated the vHipp using a Gq-DREADD, and injected an anti-BDNF neutralizing antibody into IL. Rats were tested on the AST 24 hours later. Silencing the vHipp input to IL prevented the beneficial effects of extinction in reversing stress-induced cognitive deficits. Activating vHipp input to IL in the absence of extinction was sufficient to reverse stress-induced deficits in set-shifting. The beneficial effects of were blocked by local infusion of a neutralizing anti-BDNF antibody into IL. vHipp-driven BDNF signaling in IL is critical for extinction to counteract the deleterious cognitive effects of chronic stress.

Perseveration and Shifting in Obsessive-Compulsive Disorder as a Function of Uncertainty, Punishment, and Serotonergic Medication

BackgroundThe nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD. MethodsWe recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with uncertain feedback and a single reversal measuring win-stay and lose-shift. Bayesian computational modeling provided measures of learning rate, reinforcement sensitivity, and stimulus stickiness. ResultsUnmedicated patients with OCD were impaired on the deterministic reversal task under punishment only at the first and third reversals compared with both control participants and medicated patients with OCD, who had no deficit. Perseverative errors were correlated with OCD severity. On the probabilistic reversal task, unmedicated patients were only impaired at reversal, whereas medicated patients were impaired at both the learning and reversal stages. Computational modeling showed that the overall change was reduced feedback sensitivity in both OCD groups. ConclusionsBoth perseveration and increased shifting can be observed in OCD, depending on test conditions including the predictability of reinforcement. Perseveration was related to clinical severity and remediated by serotonergic medication.

Ubiquitination of the GluA1 Subunit of AMPA Receptors Is Required for Synaptic Plasticity, Memory, and Cognitive Flexibility.

Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, thereby regulating their stability at synapses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synaptic plasticity, learning, and memory. Our results reveal that these male mice have normal basal synaptic transmission but exhibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination in bidirectional synaptic plasticity and cognition in male mice.SIGNIFICANCE STATEMENT Subcellular targeting and membrane trafficking determine the precise number of AMPA-type glutamate receptors at synapses, processes that are essential for synaptic plasticity, learning, and memory. Post-translational ubiquitination of the GluA1 subunit marks AMPARs for degradation, but its functional role in vivo remains unknown. Here we demonstrate that the GluA1 ubiquitin-deficient mice exhibit an altered threshold for synaptic plasticity accompanied by deficits in short-term memory and cognitive flexibility. Our findings suggest that activity-dependent ubiquitination of GluA1 fine-tunes the optimal number of synaptic AMPARs required for bidirectional synaptic plasticity and cognition in male mice. Given that increases in amyloid-β cause excessive ubiquitination of GluA1, inhibiting that GluA1 ubiquitination may have the potential to ameliorate amyloid-β-induced synaptic depression in Alzheimer's disease.