Attentional Set-shifting Task Research Articles

CHEMOGENETIC INACTIVATION OF THE NUCLEUS REUNIENS AND ITS PROJECTIONS TO THE ORBITAL CORTEX PRODUCE DEFICITS ON DISCRETE MEASURES OF BEHAVIORAL FLEXIBILITY IN THE ATTENTIONAL SET-SHIFTING TASK

The nucleus reuniens (RE) of the ventral midline thalamus is a critical node in the communication between the orbitomedial prefrontal cortex (OFC) and the hippocampus (HF). While RE has been shown to directly participate in memory-associated functions through its connections with the medial prefrontal cortex and HF, less is known regarding the role of RE in executive functioning. Here, we examined the involvement of RE and its projections to the orbital cortex (ORB) in attention and behavioral flexibility in male rats using the attentional set shifting task (AST). Rats expressing the hM4D DREADD receptor in RE were implanted with indwelling cannulas in either RE or the ventromedial ORB to pharmacologically inhibit RE or its projections to the ORB with intracranial infusions of clozapine-N-oxide hydrochloride (CNO). Chemogenetic-induced suppression of RE resulted in impairments in reversal learning and set-shifting. This supports a vital role for RE in behavioral flexibility – or the ability to adapt behavior to changing reward or rule contingencies. Interestingly, CNO suppression of RE projections to the ventromedial ORB produced impairments in rule abstraction – or dissociable effects elicited with direct RE suppression. In summary, the present findings indicate that RE, mediated in part by actions on the ORB, serves a critical role in the flexible use of rules to drive goal directed behavior. The cognitive deficits of various neurological disorders with impaired communication between the HF and OFC, may be partly attributed to alterations of RE -- as an established intermediary between these cortical structures.

Sex Differences in Response-Contingent Cannabis Vapor Administration During Adolescence Mediate Enduring Effects on Behavioral Flexibility and Prefrontal Microglia Activation in Rats.

Introduction: Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. Materials and Methods: We used a response-contingent vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Results: Adolescent (35- to 55-day-old) female rats had significantly higher rates of responding for vaporized Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared with adolescent males. In adulthood (70-110 days old), female, but not male, CANTHC rats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared with vehicle rats, thereby indicating sex differences in behavioral flexibility impairments. Notably, sex-treatment interactions were not observed when rats of each sex were exposed to a noncontingent CANTHC vapor dosing regimen that approximated CANTHC vapor deliveries earned by females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHC rats displayed more reactive microglia with no changes in myelin basic protein expression or dendritic spine density. Conclusion: Altogether, these data reveal important sex differences in rates of responding for CANTHC vapor in adolescence that may confer enduring alterations to mPFC structure and function and suggest that there may be subtle differences in the effects of response-contingent versus noncontingent cannabis exposure that should be systematically examined in future studies.

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.

MPFC TNFR2 modulated the impairment of cognitive flexibility induced by adolescent social stress and the relevant neuroplastic molecules

The impairment of cognitive flexibility (CF) exists to varying degrees in several psychiatric disorders and is increasingly recognized as the important etiological and pathological factors in these disorders. Our previous research has demonstrated that adolescent social stress (ASS) can lead to cognitive dysfunction in adult mice, accompanied by immune changes in the medial prefrontal cortex (mPFC), mainly manifested by reduced levels of cytokine TNFα. The present study aimed to further investigate the mechanisms of TNFα receptor and the downstream neuroplasticity-related molecules involved in cognitive dysfunction induced by ASS. Cognitive flexibility was assessed using Attentional Set Shifting Task (AST). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) methods were use to determine mRNA and protein level of TNFα receptor (TNFR) and downstream signaling molecules, including nuclear transcript factor NF-κB and CREB, pCREB and Brain-derived neurotrophic factor (BDNF). We found that ASS significantly decreased the mRNA and protein expression of TNFα receptor 2 (TNFR2), but not TNFR1 of the mPFC in adult mice. Direct up-regulation TNFR2 expression by microinjection of adeno-associated virus (AAV) encoding TNFR2 into the mPFC reversed the impairment of CF and the decrease of BDNF protein levels in stressed adult mice compared to that in controls. These findings demonstrated that mPFC TNFR2 plays critical roles in cognitive inflexibility induced by ASS, which effects may be mediated by neuroplastic molecules, and could be a promising target for treating cognitive dysfunction in psychiatric disorders.

Automation at the service of the study of executive functions in preclinical models

Cognitive flexibility involves the capability to switch between different perspectives and implement novel strategies upon changed circumstances. The Wisconsin Card Sorting Test (in humans) and the Attentional Set-Shifting Task (ASST, in rodents) evaluate individual capability to acquire a reward-associated rule and subsequently disregard it in favour of a new one. Both tasks entail consecutive stages wherein subjects discriminate between: two stimuli of a given category (simple discrimination, SD); the stimuli of SD confounded by an irrelevant stimulus of a different category (compound discrimination, CD); different stimuli belonging to the SD category (intradimensional shift, IDS); and two stimuli of the confounding category (extradimensional shift, EDS). The ASST is labour intensive, not sufficiently standardised, and prone to experimental error. Here, we tested the validity of a new, commercially available, automated version of ASST (OPERON) in two independent experiments conducted in: different mouse strains (C57BL/6 and CD1 mice) to confirm their differential cognitive capabilities (Experiment 1); and an experimental model of chronic stress (administration of corticosterone in the drinking water; Experiment 2). In both experiments, OPERON confirmed the findings obtained through the manual version. Just as in Experiment 1 both versions captured the deficit of C57BL/6 mice on the reversal of the CD (CDR), so also in Experiment 2 they provided analogous evidence that corticosterone treated mice have a remarkable impairment in the IDS. Thus, OPERON capitalises upon automated phenotyping to overcome the limitation of the manual version of the ASST while providing comparable results.

Proteomic Analysis Reveals the Neurotoxic Effects of Chronic Methamphetamine Self-Administration-Induced Cognitive Impairments and the Role of Melatonin-Enhanced Restorative Process during Methamphetamine Withdrawal.

Cognitive flexibility is a crucial ability in humans that can be affected by chronic methamphetamine (METH) addiction. The present study aimed to elucidate the mechanisms underlying cognitive impairment in mice chronically administered METH via an oral self-administration method. Further, the effect of melatonin treatment on recovery of METH-induced cognitive impairment was also investigated. Cognitive performance of the mice was assessed using an attentional set shift task (ASST), and possible underlying neurotoxic mechanisms were investigated by proteomic and western blot analysis of the prefrontal cortex (PFC). The results showed that mice-administered METH for 21 consecutive days exhibited poor cognitive performance compared to controls. Cognitive deficit in mice partly recovered after METH withdrawal. In addition, mice treated with melatonin during METH withdrawal showed a higher cognitive recovery than vehicle-treated METH withdrawal mice. Proteomic and western blot analysis revealed that METH self-administration increased neurotoxic markers, including disruption to the regulation of mitochondrial function, mitophagy, and decreased synaptic plasticity. Treatment with melatonin during withdrawal restored METH-induced mitochondria and synaptic impairments. These findings suggest that METH-induced neurotoxicity partly depends on mitochondrial dysfunction leading to autophagy-dependent cell death and that the recovery of neurological impairments may be enhanced by melatonin treatment during the withdrawal period.

The p75 Neurotrophin Receptor in Preadolescent Prefrontal Parvalbumin Interneurons Promotes Cognitive Flexibility in Adult Mice

BackgroundParvalbumin (PV)-positive GABAergic (gamma-aminobutyric acidergic) cells provide robust perisomatic inhibition to neighboring pyramidal neurons and regulate brain oscillations. Alterations in PV interneuron connectivity and function in the medial prefrontal cortex have been consistently reported in psychiatric disorders associated with cognitive rigidity, suggesting that PV cell deficits could be a core cellular phenotype in these disorders. The p75 neurotrophin receptor (p75NTR) regulates the time course of PV cell maturation in a cell-autonomous fashion. Whether p75NTR expression during postnatal development affects adult prefrontal PV cell connectivity and cognitive function is unknown. MethodsWe generated transgenic mice with conditional knockout of p75NTR in postnatal PV cells. We analyzed PV cell connectivity and recruitment following a tail pinch by immunolabeling and confocal imaging in naïve mice or following p75NTR re-expression in preadolescent or postadolescent mice using Cre-dependent viral vectors. Cognitive flexibility was evaluated using behavioral tests. ResultsPV cell-specific p75NTR deletion increased both PV cell synapse density and proportion of PV cells surrounded by perineuronal nets, a marker of mature PV cells, in adult medial prefrontal cortex, but not visual cortex. Both phenotypes were rescued by viral-mediated reintroduction of p75NTR in preadolescent, but not postadolescent, medial prefrontal cortex. Prefrontal cortical PV cells failed to upregulate c-Fos following a tail-pinch stimulation in adult conditional knockout mice. Finally, conditional knockout mice showed impaired fear memory extinction learning as well as deficits in an attention set-shifting task. ConclusionsThese findings suggest that p75NTR expression in adolescent PV cells contributes to the fine-tuning of their connectivity and promotes cognitive flexibility in adulthood.

Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats.

An age-associated decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic function contributes to impaired synaptic plasticity and is associated with cognitive impairments. Levels of serine racemase (SR), an enzyme that synthesizes D-serine, an NMDAR co-agonist, decline with age. Thus, enhancing NMDAR function via increased SR expression in middle age, when subtle declines in cognition emerge, was predicted to enhance performance on a prefrontal cortex-mediated task sensitive to aging. Middle-aged (~12 mo) male Fischer-344 rats were injected bilaterally in the medial prefrontal cortex (mPFC) with viral vector (LV), SR (LV-SR) or control (LV-GFP). Rats were trained on the operant attentional set-shift task (AST) to examine cognitive flexibility and attentional function. LV-SR rats exhibited a faster rate of learning compared to controls during visual discrimination of the AST. Extradimensional set shifting and reversal were not impacted. Immunohistochemical analyses demonstrated that LV-SR significantly increased SR expression in the mPFC. Electrophysiological characterization of synaptic transmission in the mPFC slices obtained from LV-GFP and LV-SR animals indicated a significant increase in isolated NMDAR-mediated synaptic responses in LV-SR slices. Thus, results of the current study demonstrated that prefrontal SR upregulation in middle age rats can improve learning of task contingencies for visual discrimination and increase glutamatergic synaptic transmission, including NMDAR activity.

Locus coeruleus noradrenergic neurons phase-lock to prefrontal and hippocampal infra-slow rhythms that synchronize to behavioral events.

The locus coeruleus (LC) is the primary source of noradrenergic projections to the forebrain, and, in prefrontal cortex, is implicated in decision-making and executive function. LC neurons phase-lock to cortical infra-slow wave oscillations during sleep. Such infra-slow rhythms are rarely reported in awake states, despite their interest, since they correspond to the time scale of behavior. Thus, we investigated LC neuronal synchrony with infra-slow rhythms in awake rats performing an attentional set-shifting task. Local field potential (LFP) oscillation cycles in prefrontal cortex and hippocampus on the order of 0.4 Hz phase-locked to task events at crucial maze locations. Indeed, successive cycles of the infra-slow rhythms showed different wavelengths, as if they are periodic oscillations that can reset phase relative to salient events. Simultaneously recorded infra-slow rhythms in prefrontal cortex and hippocampus could show different cycle durations as well, suggesting independent control. Most LC neurons (including optogenetically identified noradrenergic neurons) recorded here were phase-locked to these infra-slow rhythms, as were hippocampal and prefrontal units recorded on the LFP probes. The infra-slow oscillations also phase-modulated gamma amplitude, linking these rhythms at the time scale of behavior to those coordinating neuronal synchrony. This would provide a potential mechanism where noradrenaline, released by LC neurons in concert with the infra-slow rhythm, would facilitate synchronization or reset of these brain networks, underlying behavioral adaptation.

Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis

SummarySignificant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.

Long-term consequences of reduced availability and compensatory supplementation of sialylated HMOs on cognitive capabilities.

Breast milk (BM) is the optimal source of nutrition for mammals' early life. It exerts multiple benefits, including the development of cognitive capabilities and protection against several diseases like obesity and infection of the respiratory tract. However, which components of BM are involved in individual development has remained elusive. Sialylated human milk oligosaccharides (HMOs) may constitute a valid candidate, whereby they represent the principal source of sialic acid and act as building blocks for brain development. We hypothesize that the reduced availability of two HMOs, sialyl(alpha2,6)lactose (6'SL) and sialyl(alpha2,3)lactose (3'SL), may impair attention, cognitive flexibility, and memory in a preclinical model and that the exogenous supplementation of these compounds may contrast the observed deficits. We evaluated cognitive capabilities in a preclinical model exposed to maternal milk containing reduced concentrations of 6'SL and 3'SL during lactation. To modulate their concentrations, we utilized a preclinical model characterized by the absence of genes that synthesize 3'SL and 6'SL (B6.129-St3gal4 tm1.1Jxm and St6gal1tm2Jxm , double genetic deletion), producing milk lacking 3'SL and 6'SL. Then, to ensure exposure to 3'SL-6'SL-poor milk in early life, we adopted a cross-fostering protocol. The outcomes assessed in adulthood were different types of memory, attention and information processing, some of which are part of executive functions. Then, in the second study, we evaluated the long-term compensatory potential of the exogenous oral supplementation of 3'SL and 6'SL during lactation. In the first study, exposure to HMO-poor milk resulted in reduced memory and attention. Specifically, it resulted in impaired working memory in the T-maze test, in reduced spatial memory in the Barnes maze, and in impaired attentional capabilities in the Attentional set-shifting task. In the second part of the study, we did not observe any difference between experimental groups. We hypothesize that the experimental procedures utilized for the exogenous supplementation may have impacted our ability to observe the cognitive read-out in vivo. This study suggests that early life dietary sialylated HMOs play a crucial role in the development of cognitive functions. Future studies are needed to clarify if an exogenous supplementation of these oligosaccharides may compensate for these affected phenotypes.

The role of optogenetic stimulations of parvalbumin-positive interneurons in the prefrontal cortex and the ventral hippocampus on an acute MK-801 model of schizophrenia-like cognitive inflexibility

Schizophrenia research has increased in recent decades and focused more on its neural basis. Decision-making and cognitive flexibility are the main cognitive functions that are impaired and considered schizophrenia endophenotypes. Cognitive impairment was recently connected with altered functions of N-methyl-d-aspartate (NMDAR) glutamatergic receptors, which increased cortical activity. Selective NMDAR antagonists, such as MK-801, have been used to model cognitive inflexibility in schizophrenia. Decreased GABAergic inhibitory activity has been shown elsewhere with enhanced cortical activity. This imbalance in the excitatory/inhibitory may reduce the entrainment of prefrontal gamma and hippocampal theta rhythms and result in gamma/theta band de-synchronization.The current study established an acute MK-801 administration model of schizophrenia-like cognitive inflexibility in rats and used the attentional set-shifting task in which rats learned to switch/reverse the relevant rule. During the task, we used in vivo optogenetic stimulations of parvalbumin-positive interneurons at specific light pulses in the prefrontal cortex and ventral hippocampus.The first experiments showed that acute dizocilpine in rats produced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that specific optogenetic stimulation at specific frequencies of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus rescued the cognitive flexibility rats that received acute MK-801.These findings advance our knowledge of the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may guide further research on this severe psychiatric disorder.

The GluA1-Related BDNF Pathway Is Involved in PTSD-Induced Cognitive Flexibility Deficit in Attentional Set-Shifting Tasks of Rats.

Background: Post-Traumatic Stress Disorder (PTSD) is a severe psychological disorder characterized by intrusive thoughts, heightened arousal, avoidance, and flashbacks. Cognitive flexibility dysfunction has been linked with the emergence of PTSD, including response inhibition deficits and impaired attentional switching, which results in difficulties for PTSD patients when disengaging attention from trauma-related stimuli. However, the molecular mechanisms of cognitive flexibility deficits remain unclear. Methods: The animals were exposed to a single prolonged stress and electric foot shock (SPS&S) procedure to induce PTSD-like features. Once the model was established, the changes in cognitive flexibility were assessed using an attentional set-shifting task (ASST) in order to investigate the effects of traumatic stress on cognitive flexibility. Additionally, the molecular alterations of certain proteins (AMPA Receptor 1 (GluA1), brain-derived neurotrophic factor (BDNF), and Postsynaptic density protein 95 (PSD95) in the medial prefrontal cortex (mPFC) were measured using Western blot and immunofluorescence. Results: The SPS&S model exhibited PTSD-like behaviors and induced reversal learning and set-shifting ability deficit in the ASST. These behavioral changes are accompanied by decreased GluA1, BDNF, and PSD95 protein expression in the mPFC. Further analysis showed a correlative relationship between the behavioral and molecular alterations. Conclusions: The SPS&S model induced cognitive flexibility deficits, and the potential underlying mechanism could be mediated by GluA1-related BDNF signaling in the mPFC.

Adolescent nicotine administration impacts working memory and reversal learning but not cognitive flexibility.

There has been increased interest in early exposure to nicotine through tobacco products and vaping specifically as it relates to addiction, yet fewer studies have focused on whether behavioral effects resulting from early nicotine exposure may persist into adulthood. Our experiments tested the hypothesis that exposure to nicotine during adolescence would impair selective aspects of behavioral cognition in rodents in adulthood. Male and female adolescent rats received either nicotine (0.4mg/kg) or vehicle injections (intraperitoneal) once daily for 10 days (PND 29-38) followed by a washout period before behavioral testing. Animals were followed in a longitudinal design and evaluated on a battery of both behavioral and cognitive tasks during adulthood (PND 90+) that included locomotor activity, working memory (novel object recognition), cognitive flexibility (attentional set-shifting task, ASST), and anxiety-like behaviors. Data suggested that subchronic exposure to nicotine during adolescence produced significant changes in working memory, in two reversal problems in the ASST, and in anxiety-related behaviors. Taken together these data may suggest that limited early exposure to nicotine may produce selective longer term impairments in cognitive and behavioral processes related to working memory and reversal learning.

Effects of transcranial direct current stimulation on improving performance of delayed- reinforcement attentional set-shifting tasks in attention-deficit/hyperactivity disorder rat model

Behavioral flexibility (or set-shifting), which is regulated by the prefrontal cortex (PFC), is often impaired in patients with attention-deficit/hyperactivity disorder (ADHD), which is characterized by poor inhibitory control and reinforcement learning. Transcranial direct current stimulation (tDCS) has been proposed as a means of noninvasive brain stimulation and a potential therapeutic tool for modulating behavioral flexibility. Animal studies can pave the way to know if tDCS application can potentially benefit rule- and goal-based activities in ADHD. Spontaneously hypertensive rats (SHRs) and inbred Wistar–Kyoto (WKY) rats were used as an animal model of ADHD and controls, respectively, and their strategy set-shifting abilities, including initial discrimination, set-shifting, and reversal learning tasks under 0-s or 15-s reinforcer delivery delay conditions, were evaluated. The tDCS treatment had a limited effect on the performance of the SHRs and WKY rats in initial discrimination task under 0-s delay condition. Under the 15-s delay condition, the SHRs had longer lever-press reaction times and/or more trial omissions than the WKY rats did when completing set-shifting and reversal-learning tasks. Among the SHRs, tDCS treatment improved the rats’ reaction times and/or reduced their trial omissions in the set-shifting and reversal-learning tasks. Although tDCS may improve delayed reinforcement learning set-shifting performance in SHRs, further studies are required to clarify the responsible mechanism.

Milnacipran Ameliorates Executive Function Impairments following Frontal Lobe Traumatic Brain Injury in Male Rats: A Multimodal Behavioral Assessment.

Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3-4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 μL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors (p < 0.05), which generally normalized in MLN-treated rats (p < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation.

Interictal discharges delay target-directed eye movements and impair attentional set-shifting in children with epilepsy.

The theory of transient cognitive impairment in epilepsy posits that lapses in attention result from ephemeral disruption of attentional circuitry by interictal events. Eye movements are intimately associated with human attention and can be monitored in real time using eye-tracking technologies. Here, we sought to characterize the associations between interictal epileptiform discharges (IEDs), gaze, and attentional behavior in children with epilepsy. Eleven consecutive children undergoing invasive monitoring with stereotactic electrodes for localization-related epilepsy performed an attentional set-shifting task while tandem intracranial electroencephalographic signals and eye-tracking data were recorded. Using an established algorithm, IEDs were detected across all intracranial electrodes on a trial-by-trial basis. Hierarchical mixed-effects modeling was performed to delineate associations between trial reaction time (RT), eye movements, and IEDs. Hierarchical mixed-effects modeling revealed that both the presence of an IED (β±SE=72.74± 24.21 ms, p= .003) and the frequency of epileptiform events (β±SE=67.54± 17.30 ms, p< .001) were associated with prolonged RT on the attentional set-shifting task. IED occurrence at the time of stimulus presentation was associated with delays in gaze initiation toward the visual targets (p= .017). The occurrence of epileptiform activity in close temporal association with stimulus presentation is associated with delays in target-directed gaze and prolonged response time, hallmarks of momentary lapses in attention. These findings provide novel insights into the mechanisms of transient impairments in children and support the use of visual tracking as a correlate of higher order attentional behavior.

Nucleus Accumbens Core Dopamine D2 Receptor-Expressing Neurons Control Reversal Learning but Not Set-Shifting in Behavioral Flexibility in Male Mice.

The ability to use environmental cues to flexibly guide responses is crucial for adaptive behavior and is thought to be controlled within a series of cortico-basal ganglia-thalamo-cortical loops. Previous evidence has indicated that different prefrontal cortical regions control dissociable aspects of behavioral flexibility, with the medial prefrontal cortex (mPFC) necessary for the ability to shift attention to a novel strategy (set-shifting) and the orbitofrontal cortex (OFC) necessary for shifting attention between learned stimulus-outcome associations (reversal learning). The nucleus accumbens (NAc) is a major downstream target of both the mPFC and the OFC; however, its role in controlling reversal learning and set-shifting abilities is still unclear. Here we investigated the contribution of the two major NAc neuronal populations, medium spiny neurons expressing either dopamine D1 or D2 receptors (D1-/D2-MSNs), in guiding reversal learning and set-shifting in an attentional set-shifting task (ASST). Persistent inhibition of neurotransmitter release from NAc D2-MSNs, but not D1-MSNs, resulted in an impaired ability for reversal learning, but not set-shifting in male mice. These findings suggest that NAc D2-MSNs play a critical role in suppressing responding toward specific learned cues that are now associated with unfavorable outcomes (i.e., in reversal stages), but not in the suppression of more general learned strategies (i.e., in set-shifting). This study provides further evidence for the anatomical separation of reversal learning and set-shifting abilities within cortico-basal ganglia-thalamo-cortical loops.

D-cycloserine rescues scopolamine-induced deficits in cognitive flexibility in rats measured by the attentional set-shifting task

Cognitive flexibility facilitates adaptions to a changing environment in humans and animals and can be assessed with the attentional set shifting task (ASST). In various learning paradigms for laboratory rodents, the partial NMDA receptor agonist D-cycloserine has been found to have pro-cognitive effects. However, D-cycloserine has not yet been investigated for its effects on cognitive flexibility. The aim of the present study was to determine whether D-cycloserine is able to improve cognitive flexibility measured by the ASST in rats. Rats were first pre-treated with the muscarinic antagonist scopolamine (0.5 mg/kg) before the D-cycloserine administrations (20 mg/kg) to induce deficits in ASST performance. Our findings showed impaired ASST performance after scopolamine administration with significant effects on reversal phases and extra-dimensional shift. D-cycloserine treatment selectively improved the performance in the extra-dimensional shift and the last reversal phase, where scopolamine effects were most pronounced. These findings suggest that D-cycloserine can rescue deficits in cognitive flexibility.

Individual differences in behavioral flexibility predict future volitional ethanol consumption in mice.

Cognitive control is key to regulating alcohol intake and preventing relapse. Behavioral inflexibility can prevent adaptive strategies such as mindfulness or other relapse-prevention behaviors. In a mouse model we investigated whether individual variability in behavioral flexibility (using attentional set-shifting task; ASST) predicts future alcohol intake. Adult male and female C57BL/6J mice were subjected to ASST using a bowl-digging paradigm where mice identify a baited bowl based on compound odor and textural cues. This was completed prior to any alcohol exposure. Individual performance across mice varied within the group. We integrated several metrics, specifically ASST stage completed, trials to completion, and errors performed to produce an individual performance index measure of behavioral flexibility. Afterward, ASST mice were trained to drink ethanol (15%, v/v, 1h/day) for 3-4 weeks until intake stabilized. Using this prospective approach, we identified an inverse relationship between behavioral flexibility and drinking-less-flexible mice had a propensity to consume more alcohol. Similar relationships have been identified previously in non-human primates and rats. Our results show that the relationship between alcohol and behavioral flexibility is a robust trait that is conserved across species and can be used in mice to study neural substrates underlying these behaviors.