Attentional Set-shifting Task Research Articles

Procognitive effects of varenicline in the animal model of schizophrenia depend on α4β2- and α 7-nicotinic acetylcholine receptors.

Varenicline, a partial agonist of the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR), is currently used to facilitate smoking cessation. Preclinical and clinical studies have suggested that this compound may also be effective in treating cognitive impairments in schizophrenia. However, it is unclear which nicotinic acetylcholine receptor subtypes may be involved because varenicline is not only a partial agonist for α4β2-nAChRs but also a full agonist for α7 nicotinic acetylcholine receptors (α7-nAChRs). We investigated the effects of varenicline, compared to the α4β2-nAChR partial agonist TC-2403 and the α7-nAChR full agonist PNU-282987, in a ketamine-based model of schizophrenia-like cognitive deficits on the attentional set-shifting task in rats. The second goal was to elucidate whether the procognitive efficacy of varenicline was due to the compound's action on α4β2-nAChRs or α7-nAChRs. Ketamine was administered to rats for 10 consecutive days and the test was performed 14 days following the last injection. The tested compounds were administered 30 min prior to the attentional set-shifting task. Varenicline, TC-2403 and PNU-282987 ameliorated ketamine-evoked set-shifting deficits. While the α4β2-nAChR antagonist dihydro-β-erythroidine and the α7-nAChR antagonist methyllycaconitine completely prevented the procognitive actions of TC-2403 and PNU-282987, respectively, varenicline's effect was only partially blocked by any given antagonist. Moreover, the combined treatment with TC-2403 and PNU-282987 more effectively facilitated rats' set-shifting ability than activation of either type of nicotinic acetylcholine receptor alone. The present findings demonstrated that varenicline's actions on both α7-nAChRs and α4β2-nAChRs may be necessary to produce its full procognitive effect in the present experimental setting.

Perinatal Exposure to an Environmentally Relevant Mixture of Phthalates Results in a Lower Number of Neurons and Synapses in the Medial Prefrontal Cortex and Decreased Cognitive Flexibility in Adult Male and Female Rats

The growth and organization of the developing brain are known to be influenced by hormones, but little is known about whether disruption of hormones affects cortical regions, such as mPFC. This region is particularly important given its involvement in executive functions and implication in the pathology of many neuropsychiatric disorders. Here, we examine the long-term effects of perinatal exposure to endocrine-disrupting compounds, the phthalates, on the mPFC and associated behavior. This investigation is pertinent as humans are ubiquitously exposed to phthalates through a variety of consumer products and phthalates can readily cross the placenta and be delivered to offspring via lactation. Pregnant dams orally consumed an environmentally relevant mixture of phthalates at 0, 200, or 1000 μg/kg/d through pregnancy and for 10 d while lactating. As adults, offspring were tested in an attentional set-shifting task, which assesses cognitive flexibility. Brains were also examined in adulthood for stereological quantification of the number of neurons, glia, and synapses within the mPFC. We found that, independent of sex, perinatal phthalate exposure at either dose resulted in a reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. Interestingly, the number of synapses was correlated with cognitive flexibility, such that rats with fewer synapses were less cognitively flexible than those with more synapses. These results demonstrate that perinatal phthalate exposure can have long-term effects on the cortex and behavior of both male and female rats.SIGNIFICANCE STATEMENT Humans globally are exposed on a daily basis to a variety of phthalates, which are endocrine-disrupting chemicals. The effects of phthalate exposure on the developing brain, especially on cognitively relevant regions, such as the mPFC, are not known. Here, we use a rat model of human prenatal exposure to an environmentally relevant mixture of phthalates and find that there is an appreciable reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. These results may have serious implications for humans given that the mPFC is involved in executive functions and is implicated in the pathology of many neuropsychiatric disorders.

Low cognitive flexibility as a risk for heavy alcohol drinking in non-human primates.

Chronic alcohol abuse is frequently considered a habitual or inflexible behavior; however, measures of pre-existing cognitive flexibility prior to initiation of alcohol use are usually not available. This study used rhesus monkeys and an attentional set-shifting task to investigate whether pre-existing cognitive flexibility would predict increased risk for heavy alcohol drinking. As previously reported, monkeys were given 30 daily set-shifting sessions prior to alcohol access. These sessions consisted of the same sequence of eight unique visual discriminations (sets) of two objects that varied on two dimensions (shapes and colors). The ratio of errors per trials, session duration, and maximum set reached were primary dependent variables from each session and were used to compose a session performance index (PI) that ranged from a low performance PI of 31 to an optimal performance PI of 247. Here, animals underwent an alcohol induction period followed by 22 weeks of daily (22-h) self-administration sessions with free access to water and alcohol. Based on average daily alcohol intake during 22 weeks of 22-h/day access, the monkeys were categorized as non-heavy (mean=2.0±0.3g/kg/day; n=3) and heavy (mean=3.3±0.5g/kg/day; n=6) drinkers. The two groups diverged in performance on the set-shifting task across the 30 pre-alcohol sessions, and at the end of the pre-alcohol testing, the group average PI was 216±27 and 137±71 for the future non-heavy and heavy drinkers, respectively. The data show that low cognitive flexibility assessed with a set-shifting procedure was predictive of future classification as a heavy alcohol drinker. The data highlight individual differences in both cognitive flexibility and in alcohol self-administration in this population of rhesus monkeys.

T40. GPR52 AGONISTS REPRESENT A NOVEL APPROACH TO TREAT UNMET MEDICAL NEED IN SCHIZOPHRENIA

BackgroundThere are currently no treatment options for key symptom domains in certain psychiatric and neurological diseases. For example, antipsychotics effectively treat the positive symptoms of schizophrenia, however both the cognitive impairments associated with schizophrenia (CIAS) and negative symptoms, both key predictors of functional outcome, are not treated by current therapies. Additionally, psychotic symptoms associated with neurological diseases such as Alzheimer’s Disease (AD) are not adequately treated with current antipsychotics. Therefore, novel mechanisms to address these unmet medical needs are urgently required and are under investigation.GPR52 is a Gs-coupled orphan g-protein coupled receptor which has an intriguing pattern of brain expression. In cortex, GPR52 is expressed primarily on glutamatergic neurons and co-localized with the Gs-coupled D1 receptor (D1R). Deficiencies in D1R activation are associated with both cognitive deficit and negative symptoms of schizophrenia. In contrast, in the striatum, GPR52 is almost exclusively co-expressed with the Gi-coupled D2 receptor (D2R), which mediates the reduction in positive symptoms by antipsychotics. Based on GPR52’s functional coupling and co-localization, agonists may be predicted to resemble D1R agonists in cortical regions, thus treating cognitive or negative symptoms, while resembling D2R antagonists in striatal regions. Thus, GPR52 agonists have the potential to provide a novel therapeutic strategy for the currently untreated CIAS and negative symptom domains in addition to the psychotic symptoms of AD.MethodsTo assess the antipsychotic potential of GPR52 agonists, they were tested for their ability to decrease psychostimulant-induced hyperlocomotion. The efficacy of GPR52 agonists for CIAS and sociability, an aspect of negative symptoms, was assessed in the sub-chronic phencyclidine (scPCP) model for schizophrenia, known to induce long-lasting cognitive and social behaviour deficits, in addition to a reduction in parvalbumin-positive GABAergic interneurons in hippocampus and pre-frontal cortex. Rats were treated with PCP twice daily for 7 days followed by 7 days washout and then tested in the attentional set shifting task (ASST) for executive function and the social interaction test for sociability respectively following treatment with a GPR52 agonist.ResultsGPR52 agonist 1 dose-dependently reversed psychostimulant-induced hyperlocomotion in rats at doses which were behaviorally quiescent when administered alone. Additionally, GPR52 agonist 2 showed a robust, dose-dependent rescue of scPCP induced deficits in the extra dimensional shift phase of the ASST, achieving significance after a 4 mg/kg p.o. application. Likewise, GPR52 agonist 2 significantly rescued scPCP induced deficits in social interaction at identical doses as in ASST without effects on object exploration or locomotor activity.DiscussionGPR52 agonists were efficacious in animal models assessing the three main symptoms domains associated with schizophrenia. Efficacy in ASST and SI demonstrate both pro-cognitive efficacy and restoration of an aspect of negative symptoms, respectively, in a well-established model inducing behavioral and neuropathological deficits associated with schizophrenia. Furthermore, GPR52 agonists reduced psychostimulant-induced hyperlocomotion, an effect associated with antipsychotic efficacy. Taken together, these data demonstrate the potential of this innovative mechanism to simultaneously treat the three core symptoms domains of schizophrenia as well as potentially treat the psychotic symptoms associated with other neurological disorders.

BC RNA Mislocalization in the Fragile X Premutation.

Fragile X premutation disorder is caused by CGG triplet repeat expansions in the 5′ untranslated region of FMR1 mRNA. The question of how expanded CGG repeats cause disease is a subject of continuing debate. Our work indicates that CGG-repeat structures compete with regulatory BC1 RNA for access to RNA transport factor hnRNP A2. As a result, BC1 RNA is mislocalized in vivo, as its synapto-dendritic presence is severely diminished in brains of CGG-repeat knock-in animals (a premutation mouse model). Lack of BC1 RNA is known to cause seizure activity and cognitive dysfunction. Our working hypothesis thus predicted that absence, or significantly reduced presence, of BC1 RNA in synapto-dendritic domains of premutation animal neurons would engender cognate phenotypic alterations. Testing this prediction, we established epileptogenic susceptibility and cognitive impairments as major phenotypic abnormalities of CGG premutation mice. In CA3 hippocampal neurons of such animals, synaptic release of glutamate elicits neuronal hyperexcitability in the form of group I metabotropic glutamate receptor–dependent prolonged epileptiform discharges. CGG-repeat knock-in animals are susceptible to sound-induced seizures and are cognitively impaired as revealed in the Attentional Set Shift Task. These phenotypic disturbances occur in young-adult premutation animals, indicating that a neurodevelopmental deficit is an early-initial manifestation of the disorder. The data are consistent with the notion that RNA mislocalization can contribute to pathogenesis.

Region-Dependent Alterations in Cognitive Function and ERK1/2 Signaling in the PFC in Rats after Social Defeat Stress.

Cognitive dysfunctions are highly comorbid with depression. Impairments of cognitive flexibility, which are modulated by the monoaminergic system of the prefrontal cortex (PFC), are increasingly recognized as an important component of the pathophysiology and treatment of depression. However, the downstream molecular mechanisms remain unclear. Using a classical model of depression, this study investigated the effects of social defeat stress on emotional behaviors, on cognitive flexibility in the attentional set-shifting task (AST), and on the expression of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2) and their downstream signaling molecules cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in two subregions of the PFC, the medial prefrontal cortex (mPFC), and the orbitofrontal cortex (OFC). The results showed that stress induced emotional and cognitive alterations associated with depression, including a decreased sucrose intake ratio and impaired reversal learning and set-shifting performance in the AST. Additionally, rats in the stress group showed a significant decrease only in ERK2 signaling in the mPFC, while more extensive decreases in both ERK1 signaling and ERK2 signaling were observed in the OFC. Along with the decreased ERK signaling, compared to controls, stressed rats showed downregulation of CREB phosphorylation and BDNF expression in both the OFC and the mPFC. Further analysis showed that behavioral changes were differentially correlated with several molecules in subregions of the PFC. These results suggested that social defeat stress was an effective animal model to induce both emotional and cognitive symptoms of depression and that the dysfunction of ERK signaling activities in the PFC might be a potential underlying biological mechanism.

A Novel Dopamine Transporter Inhibitor CE-123 Improves Cognitive Flexibility and Maintains Impulsivity in Healthy Male Rats.

Reduced cognitive abilities are often characterized by an impairment of flexibility, i.e., the ability to switch from learned rules or categories that were important in certain contexts to different new modalities that rule the task. Drugs targeting the dopamine transporter (DAT) are widely used for their potential to enhance cognitive abilities. However, commercially available drugs are of limited specificity for DAT, blocking also noradrenaline and serotonine transporters, that can lead to unwanted side effects in healthy subjects. Therefore, we tested a newly synthetized compound (CE-123) with higher specificity for DAT in male rats in an attentional set-shifting task (ASST), that proves for cognitive flexibility and a 5-choice serial-reaction time task (5-CSRTT) assessing visuospatial attention and impulsivity. Treated rats at a dose of 0.3 and 1.0 but not 0.1 mg/kg bodyweight showed reduced extra-dimensional shifts in the ASST compared to controls indicating increased cognitive flexibility. Rats treated with R-Modafinil, a commercially available DAT inhibitor at a dose of 10 mg/kg bodyweight showed increased premature responses, an indicator of increased impulsivity, during a 10 s but not a 2.5, 5, or 7.5 s intertrial interval when compared to vehicle-treated rats in the 5-CSRTT. This was not found in rats treated with CE-123 at the same dose as for R-Modafinil. Visuospatial attention, except premature responses, did not differ between R-Modafinil and CE-123-treated rats and their respective controls. Thus, CE-123 increased cognitive flexibility with diminished impulsivity.

Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion

We have previously shown that prebiotics (dietary fibres that augment the growth of indigenous beneficial gut bacteria) such as Bimuno™ galacto-oligosaccharides (B-GOS®), increased N-methyl-D-aspartate (NMDA) receptor levels in the rat brain. The current investigation examined the functional correlates of these changes in B-GOS®-fed rats by measuring cortical neuronal responses to NMDA using in vivo NMDA micro-iontophoresis electrophysiology, and performance in the attentional set-shifting task. Adult male rats were supplemented with B-GOS® in the drinking water 3 weeks prior to in vivo iontophoresis or behavioural testing. Cortical neuronal responses to NMDA iontophoresis, were greater (+30%) in B-GOS® administered rats compared to non-supplemented controls. The intake of B-GOS® also partially hindered the reduction of NMDA responses by the glycine site antagonist, HA-966. In the attentional set-shifting task, B-GOS® -fed rats shifted from an intra-dimensional to an extra-dimensional set in fewer trials than controls, thereby indicating greater cognitive flexibility. An initial exploration into the mechanisms revealed that rats ingesting B-GOS® had increased levels of plasma acetate, and cortical GluN2B subunits and Acetyl Co-A Carboxylase mRNA. These changes were also observed in rats fed daily for 3 weeks with glyceryl triacetate, though unlike B-GOS®, cortical histone deacetylase (HDAC1, HDAC2) mRNAs were also increased which suggested an additional epigenetic action of direct acetate supplementation. Our data demonstrate that a pro-cognitive effect of B-GOS® intake in rats is associated with an increase in cortical NMDA receptor function, but the role of circulating acetate derived from gut bacterial fermentation of this prebiotic requires further investigation.

Attentional deficits and altered neuronal activation in medial prefrontal and posterior parietal cortices in mice with reduced dopamine transporter levels.

The executive control function of attention is regulated by the dopaminergic (DA) system. Dopamine transporter (DAT) likely plays a role in controlling the influence of DA on cognitive processes. We examined the effects of DAT depletion on cognitive processes related to attention. Mice with the DAT gene genetically deleted (DAT+/- heterozygotes) were compared to wild type (WT) mice on the Attentional Set-Shifting Task (ASST). Changes in neuronal activity during the ASST were shown with early growth response genes 1 and 2 (egr-1 and egr-2) immunohistochemistry in the medial prefrontal cortex (mPFC) and in the posterior parietal cortex (PPC). Heterozygotes were impaired in tasks that tax reversal learning, attentional-set formation and set-shifting. Densities of egr-2 labeled cells in the mPFC were lower in mutant mice when compared with wild-types in intradimensional shift of attention (IDS), extradimensional shift of attention and extradimensional shift of attention-reversal phases of the ASST task, and in PPC in the IDS phase of the task. The results demonstrate impairments of the areas associated with attentional functions in DAT+/- mice and show that an imbalance of the dopaminergic system has an impact on the complex attention-related executive functions.

The trait ‘pessimism’ does not interact with cognitive flexibility but makes rats more vulnerable to stress-induced motivational deficits: Results from the attentional set-shifting task

In the present study, we have investigated the effects of the traits ‘optimism’ and ‘pessimism’ on cognitive flexibility in an animal model of depression based on chronic restraint stress. For this, first, we trained and tested the rats in a series of ambiguous-cue interpretation (ACI) tests, which allowed us to classify them as ‘optimistic’ or ‘pessimistic’. Subsequently, we re-trained and re-tested the animals in the Attentional Set Shifting Task (ASST), which allowed evaluation of the differences between ‘optimists’ and ‘pessimists’ in terms of cognitive flexibility. Finally, we subjected half of the ‘optimistic’ and half of the ‘pessimistic’ rats to chronic (2 weeks) restraint stress and assessed the interaction between cognitive judgement bias and stress in the ASST. Although we did not observe statistically significant effects of the investigated traits and stress on cognitive flexibility, the ‘pessimistic' animals subjected to chronic restraint stress showed significantly longer latencies to approach experimental rewards than their ‘optimistic' conspecifics. This effect may indicate a stress-induced motivational deficit that is specific to ‘pessimistic' animals. The results of the present study, along with our previous reports, indicate that the trait ‘pessimism’ determines animals’ vulnerability to stress.

The role of NMDA receptor‐dependent activity of noradrenergic neurons in attention, impulsivity and exploratory behaviors

Activity of the brain's noradrenergic (NA) neurons plays a major role in cognitive processes, including the ability to adapt behavior to changing environmental circumstances. Here, we used the NR1DbhCre transgenic mouse strain to test how NMDA receptor-dependent activity of NA neurons influenced performance in tasks requiring sustained attention, attentional shifting and a trade-off between exploration and exploitation. We found that the loss of NMDA receptors caused irregularity in activity of NA cells in the locus coeruleus and increased the number of neurons with spontaneous burst firing. On a behavioral level, this was associated with increased impulsivity in the go/no-go task and facilitated attention shifts in the attentional set-shifting task. Mutation effects were also observed in the two-armed bandit task, in which mutant mice were generally more likely to employ an exploitative rather than exploratory decision-making strategy. At the same time, the mutation had no appreciable effects on locomotor activity or anxiety-like behavior in the open field. Taken together, these data show that NMDA receptor-dependent activity of brain's NA neurons influences behavioral flexibility.

Effect of clozapine on ketamine-induced deficits in attentional set shift task in mice

RationaleClozapine (CLZ) is an effective treatment for schizophrenia, producing improvements in both negative symptoms and cognitive impairments. Cognitive impairments can be modelled in animals by ketamine (KET) and assessed using the attentional set-shift task (ASST).ObjectiveOur first aim was to determine whether CLZ improves cognitive function and reverses KET-induced cognitive impairments using the ASST. Our second aim was to assess dose dependency of these effects.ResultsOur findings demonstrate that acute as well as sub-chronic administration of KET cause cognitive deficits observed as increase in number of trails and errors to reach the criterion in the EDS phase. CLZ 0.3 mg/kg reversed the effects of both acute and sub-chronic KET, with no effects on locomotor activity. However, clozapine’s effect after sub-chronic administration of dose 0.3 mg/kg was not as explicit as in the case of acute treatment. Moreover, administration of 1 mg/kg CLZ to KET-treated mice induced or enhanced deficits in the extra-dimensional shift phase compared to 1 mg/kg CLZ administration to mice not receiving KET. Locomotor activity test showed sedation effects of CLZ 1 mg/kg after acute treatment; therefore, effect of CLZ 1 mg/kg on KET-induced cognitive deficits was not evaluated in the attentional set-shift task (ASST) test.ConclusionsThe present findings support dose-dependent effects of CLZ to reverse KET-induced cognitive deficits. The observed dose dependency may be mediated by activation of different receptors, including monomers and/or heterodimers.

Prefrontal cortex dysfunction in hypoxic-ischaemic encephalopathy contributes to executive function impairments in rats: Potential contribution for attention-deficit/hyperactivity disorder

Objectives: The attention-deficit/hyperactivity disorder (ADHD) compromises the quality of life of individuals including adaptation to the social environment. ADHD aetiology includes perinatal conditions such as hypoxic-ischaemic events; preclinical studies have demonstrated attentional deficits and impulsive-hyperactive outcomes after neonatal hypoxic and/or ischaemic intervention, but data are missing to understand this relationship. Thus, the aim of this study was to evaluate executive function (EF) and impulsivity, and tissue integrity and dopaminergic function in the prefrontal cortex (PFC) of rats submitted to hypoxia-ischaemia (HI).Methods: At postnatal day (PND) 7, male Wistar rats were divided into control (n = 10) and HI groups (n = 11) and the HI procedure was conducted. At PND60, the animals were tested in the attentional set-shifting (ASS) task to EF and in the tolerance to delay of reward for assessment of impulsivity. After, morphological analysis and the dopaminergic system were evaluated in the PFC.Results: Animals subjected to HI had impairments in EF evidenced by a behavioural inflexibility that was correlated to PFC atrophy. Moreover, HI animals presented reduced D2 receptors in the ipsilateral side of ischaemia in the PFC.Conclusions: Animals submitted to HI presented impaired EF associated with tissue atrophy and dopaminergic disturbance in the PFC.

Potential role of dopamine transporter in behavioral flexibility

Behavioral flexibility is subserved by the prefrontal cortex and the basal ganglia. Orbitofrontal cortex (OFC) and dorsomedial striatum (DMS) form a functional frontocorticostriatal circuit crucial for the mediation of flexibility during reversal learning via dopamine (DA) neurotransmission. The regulatory control in maintaining DA homeostasis and function is provided by the dopamine transporter (DAT), which therefore likely plays a significant role in controlling the influence of DA on cognitive processes. Here we used a gene knockout mouse model to investigate the role of DAT in the performance on the Attentional Set-Shifting Task (ASST) stages dependent upon the OFC and the DMS. Additionally, behavior of mice after repeated administration of selective DAT inhibitor, GBR 12909, was examined. The animals were treated with the inhibitor to elicit a compensatory DAT up-regulation following withdrawal. Learning was slower and the number of errors during reversal learning and intra-dimensional shift stages was higher in DAT+/- mutant mice than in WT mice. GBR 12909-treated mice had deficits in reversal stages of the ASST. Neuronal activation in the OFC and DMS during the ASST was examined with early growth response proteins 1 and 2 (egr-1, egr-2) immunohistochemistry. Density of egr-2 labeled cells in the OFC was lower in mutant mice than in wild-types during reversal learning and the expression of the egr-1 was lower in mutant mice in the OFC and DMS during reversal and intra-dimensional shift stages. Mice with decreased DAT levels displayed behavioral difficulties that were accompanied by a lower task-induced activation of neurons in brain regions involved in the reversal learning. Altogether, these data indicate the role of the DAT in the behavioral flexibility.

Effects of Duloxetine Treatment on Cognitive Flexibility and BDNF Expression in the mPFC of Adult Male Mice Exposed to Social Stress during Adolescence

Early stress is a significant risk factor for the onset of mood disorders such as depression during adulthood. Impairments in cognitive flexibility mediated by prefrontal cortex (PFC) dysfunction are increasingly recognized as important etiological and pathological factors in the development of depression. Our previous study demonstrated that social defeat stress during early adolescence produced delayed deficits in cognitive flexibility in adult mice. The potential molecular mechanisms underlying these long-term consequences remain unclear. One candidate molecule is brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity. In this study, we initially examined the effects of adolescent social stress on cognitive flexibility and PFC BDNF expression within a week after the last stress exposure and 6 weeks later during adulthood. Adolescent (PND 28) male mice were subjected to stress or control manipulation for 10 days. The attentional set-shifting task (AST) was used to assess cognitive flexibility. Levels of BDNF mRNA and protein in the PFC were examined after behavioral testing. The results demonstrated that previously stressed mice exhibited delayed extra-dimensional set-shifting deficits in AST when tested as adults but not when tested as adolescents. Consistent with the cognitive alterations, adolescent stress induced dynamic alterations in BDNF expression in the medial PFC (mPFC), with a transient increase observed shortly after the stress, followed by a decrease 6 weeks later during adulthood. Next, we further determined the effects of chronic treatment with the antidepressant duloxetine during early adulthood on cognitive and molecular alterations induced by adolescent stress. Compared with the controls, duloxetine treatment reversed the cognitive deficits and increased the BDNF protein expression in the mPFC during adulthood in previously stressed mice. These findings demonstrated that BDNF expression in the mPFC was sensitive to adolescent social stress, which may contribute to the disturbance of the development and later functioning of this brain region.

3-Furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic receptor, reverses schizophrenia-like cognitive and social deficits in rats

The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of α7 nAChRs may represent an alternative strategy to that based on orthosteric agonists.The aim of the present study is to evaluate the efficacy of PAM-2 (3-furan-2-yl-N-p-tolyl-acrylamide) against cognitive deficits and negative-like symptoms in a rat model of schizophrenia based on administration of ketamine, a NMDAR antagonist. The activity of PAM-2 was compared to that elicited by DMXBA, an α7 nAChR partial agonist. For this purpose, the attentional set-shifting task (ASST) and the novel object recognition task (NORT) were used. The efficacies of PAM-2 and DMXBA against ketamine-induced social withdrawal were assessed using the social interaction test (SIT).The results demonstrated that PAM-2 and DMXBA ameliorated ketamine-induced cognitive impairments on the ASST and NORT as well as produced pro-social activities in the SIT. Moreover, the co-administration of inactive doses of PAM-2 and antipsychotic drugs, clozapine or risperidone, reversed ketamine-induced deficits.The present findings provide further support for the concept that α7-PAMs could be used either alone or in combination with antipsychotics for schizophrenia therapy.

The impact of clozapine on the dopamine D2 receptor binding in ketamine induced attentional set shift task model

The impact of clozapine on the dopamine D2 receptor binding in ketamine induced attentional set shift task model

Lesions of the ventral midline thalamus produce deficits in reversal learning and attention on an odor texture set shifting task

The nucleus reuniens (RE) of the ventral midline thalamus is strongly reciprocally connected with the hippocampus (HF) and the medial prefrontal cortex (mPFC) and has been shown to mediate the transfer of information between these structures. It has become increasingly well established that RE serves a critical role in mnemonic tasks requiring the interaction of the HF and mPFC, but essentially not tasks relying solely on the HF. Very few studies have addressed the independent actions of RE on prefrontal executive functioning. The present report examined the effects of lesions of the ventral midline thalamus, including RE and the dorsally adjacent rhomboid nucleus (RH) in rats on attention and behavioral flexibility using the attentional set shifting task (AST). The task uses odor and tactile stimuli to test for attentional set formation, attentional set shifting, behavioral flexibility and reversal learning. By comparison with sham controls, lesioned rats were significantly impaired on reversal learning and intradimensional (ID) set shifting. Specifically, RE/RH lesioned rats were impaired on the first reversal stage of the task which required a change in response strategy to select a previously non-rewarded stimulus for reward. RE/RH lesioned rats also exhibited deficits in the ability to transfer or generalize rules of the task which requires making the same modality-based choices (e.g., odor vs. tactile) to different sets of stimuli in the ID stage of the task. These results demonstrate that in addition to its role in tasks dependent on HF-mPFC interactions, nucleus reuniens is also critically involved cognitive/executive functions associated with the medial prefrontal cortex. As such, the deficits in the AST task produced by RE/RH lesions suggest the ventral midline thalamus directly contributes to flexible goal directed behavior.

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.