Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial.

The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values ≥ 4.21, p-values ≤ 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.

A selective serotonin reuptake inhibitor ameliorates obsessive-compulsive disorder-like perseverative behavior by attenuating 5-HT2C receptor signaling in the orbitofrontal cortex.

Perseveration is a characteristic of patients with obsessive-compulsive disorder (OCD). Clinically, neuronal activity in the lateral orbitofrontal cortex (OFC) is increased in OCD patients. Successful treatment with selective serotonin reuptake inhibitors (SSRIs) reduces activity in the lateral OFC of OCD patients, but the precise mechanisms underlying this effect are unclear. Previously, we reported that repeated injection of the dopamine D2 receptor agonist quinpirole (QNP) resulted in OCD-like deficits, including perseveration in a reversal learning task. QNP-treated mice showed hyperactivity in lateral OFC pyramidal neurons. The present study demonstrated that 4-week administration of an SSRI increased the rate of correct choice in a reversal learning task. Using the electrophysiological approach, we revealed that an SSRI decreased the activity of lateral OFC pyramidal neurons in QNP-treated mice by potentiating inhibitory inputs. The 4-week administration of an SSRI inhibited the potentiation of neuronal activity induced by a 5-HT2C receptor agonist. Additionally, both 4-week administration of SSRI and acute application of 5-HT2C receptor antagonist prevented the QNP-induced potentiation of inhibitory inputs to fast-spiking interneurons in the lateral OFC. Administration of a 5-HT2C receptor antagonist to mice for 4 days increased the rate of correct choice in a reversal learning task. Collectively, these results indicate that chronic SSRI ameliorated perseverative behavior in QNP-treated mice by modulating inhibitory inputs in the lateral OFC. Short-term 5-HT2C receptor blockade also ameliorated QNP-induced behavioral and neurological abnormalities by, at least in part, a common mechanism with chronic SSRI.

Effects of the Partial M1 Muscarinic Cholinergic Receptor Agonist CDD-0102A on Stereotyped Motor Behaviors and Reversal Learning in the BTBR Mouse Model of Autism.

BACKGROUND: Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders marked by a lack of social interaction, restrictive interests, and repetitive behaviors. There is a paucity of pharmacological treatments to reduce core ASD symptoms. Various lines of evidence indicate that reduced brain muscarinic cholinergic receptor activity may contribute to an ASD phenotype. METHODS: The present experiments examined whether the partial M1 muscarinic receptor agonist, 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A), alleviates behavioral flexibility deficits and/or stereotyped motor behaviors in the BTBR mouse model of autism. Behavioral flexibility was tested using a reversal learning test. Stereotyped motor behaviors were measured by eliciting digging behavior after removal of nesting material in a home cage and by measuring repetitive grooming. RESULTS: CDD-0102A (0.2 and 0.6 mg/kg but not 1.2 mg/kg) injected prior to reversal learning attenuated a deficit in BTBR mice but did not affect performance in B6 mice. Acute CDD-0102A treatment (1.2 and 3 mg/kg) reduced self-grooming in BTBR mice and reduced digging behavior in B6 and BTBR mice. The M1 muscarinic receptor antagonist VU0255035 (3 mg/kg) blocked the effect of CDD-0102A on grooming behavior. Chronic treatment with CDD-0102A (1.2 mg/kg) attenuated self-grooming and digging behavior in BTBR mice. Direct CDD-0102A infusions (1 µg) into the dorsal striatum reduced elevated digging behavior in BTBR mice. In contrast, CDD-0102A injections in the frontal cortex were not effective. CONCLUSIONS: The results suggest that treatment with a partial M1 muscarinic receptor agonist may reduce repetitive behaviors and restricted interests in autism in part by stimulating striatal M1 muscarinic receptors.

Sex-specific effect of prenatal alcohol exposure on N-methyl-D-aspartate receptor function in orbitofrontal cortex pyramidal neurons of mice.

BACKGROUND: Alcohol consumption during pregnancy can produce behavioral and cognitive deficits that persist into adulthood. These include impairments in executive functions, learning, planning, and cognitive flexibility. We have previously shown that moderate prenatal alcohol exposure (PAE) significantly impairs reversal learning, a measure of flexibility mediated across species by different brain areas that include the orbital frontal cortex (OFC). Reversal learning is likewise impaired by genetic or pharmacological inactivation of GluN2B subunit-containing N-methyl-D-aspartate receptors (NMDARs). In the current study, we tested the hypothesis that moderate PAE persistently alters the number and function of GluN2B subunit-containing NMDARs in OFC pyramidal neurons of adult mice. METHODS: We used a rodent model of fetal alcohol spectrum disorders and left offspring undisturbed until adulthood. Using whole-cell, patch-clamp recordings, we assessed NMDAR function in slices from 90- to 100-day-old male and female PAE and control mice. Pharmacologically isolated NMDA receptor-mediated evoked excitatory postsynaptic currents (NMDA-eEPSCs) were recorded in the absence and presence of the GluN2B antagonist, Ro25-6981(1 µM). In a subset of littermates, we evaluated the level of GluN2B protein expression in the synaptic fraction using Western blotting technique. RESULTS: Our results indicate that PAE females show significantly larger (~23%) NMDA-eEPSC amplitudes than controls, while PAE induced a significant decrease (~17%) in NMDA-eEPSC current density of pyramidal neurons recorded in slices from male mice. NMDA-eEPSC decay time was not affected in PAE-exposed mice from either sex. The contribution of GluN2B subunit-containing NMDARs to the eEPSCs was not significantly altered by PAE. Moreover, there were no significant changes in protein expression in the synaptic fraction of either PAE males or females. CONCLUSIONS: These findings suggest that low-to-moderate PAE modulates NMDAR function in pyramidal neurons in a sex-specific manner, although we did not find evidence that the effect is mediated by dysfunction of synaptic GluN2B subunit-containing NMDARs.

Acute vagus nerve stimulation enhances reversal learning in rats.

Cognitive flexibility is a prefrontal cortex-dependent neurocognitive process that enables behavioral adaptation in response to changes in environmental contingencies. Electrical vagus nerve stimulation (VNS) enhances several forms of learning and neuroplasticity, but its effects on cognitive flexibility have not been evaluated. In the current study, a within-subjects design was used to assess the effects of VNS on performance in a novel visual discrimination reversal learning task conducted in touchscreen operant chambers. The task design enabled simultaneous assessment of acute VNS both on reversal learning and on recall of a well-learned discrimination problem. Acute VNS delivered in conjunction with stimuli presentation during reversal learning reliably enhanced learning of new reward contingencies. Enhancement was not observed, however, if VNS was delivered during the session but was not coincident with presentation of to-be-learned stimuli. In addition, whereas VNS delivered at 30 HZ enhanced performance, the same enhancement was not observed using 10 or 50 Hz. Together, these data show that acute VNS facilitates reversal learning and indicate that the timing and frequency of the VNS are critical for these enhancing effects. In separate rats, administration of the norepinephrine reuptake inhibitor atomoxetine also enhanced reversal learning in the same task, consistent with a noradrenergic mechanism through which VNS enhances cognitive flexibility.

Roles of the ventral hippocampus and medial prefrontal cortex in spatial reversal learning and attentional set-shifting.

Neural components enabling flexible cognition and behavior are well-established, and depend mostly on proper intercommunication within the prefrontal cortex (PFC) and striatum. However, dense projections from the ventral hippocampus (vHPC) alter the functioning of the medial PFC (mPFC). Dysfunctional hippocampo-prefrontal connectivity negatively affects the integrity of flexible cognition, especially in patients with schizophrenia. In this study, we aimed to test the role of the vHPC and mPFC in a place avoidance task on a rotating arena using two spatial flexibility task variants - reversal learning and set-shifting. To achieve this, we inactivated each of these structures in adult male Long-Evans rats by performing bilateral local muscimol (a GABAA receptor agonist) injections. A significantly disrupted performance was observed in reversal learning in the vHPC-inactivated, but not in the mPFC-inactivated rats. These results confirm the notion that the vHPC participates in some forms of behavioral flexibility, especially when spatial cues are needed. It seems, rather unexpectedly, that the mPFC is not taxed in these flexibility tasks on a rotating arena.

Hidden talents: Poly (I:C)-induced maternal immune activation improves mouse visual discrimination performance and reversal learning in a sex-dependent manner.

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on developing brains, very little attention is directed towards potential advantages of early life challenges. In this study, we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual pairwise discrimination (PD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA reduced the latency for males to make a correct choice in the PD task while females reached criterion sooner, made fewer errors, and utilized fewer correction trials in RL compared to saline controls. These surprising improvements were accompanied by the sex-specific upregulation of several genes critical to cognitive functioning, indicative of compensatory plasticity in response to MIA. In contrast, when exposed to a 'two-hit' stress model (MIA + loss of the social component of environmental enrichment [EE]), mice did not display anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the prefrontal cortex. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in, delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right 'dose', early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

The role of oxytocin in delay of gratification and flexibility in non-social decision making.

Oxytocin is well-known for its impact on social cognition. This specificity for the social domain, however, has been challenged by findings suggesting a domain-general allostatic function for oxytocin by promoting future-oriented and flexible behavior. In this pre-registered study, we tested the hypothesized domain-general function of oxytocin by assessing the impact of intranasal oxytocin (24 IU) on core aspects of human social (inequity aversion) and non-social decision making (delay of gratification and cognitive flexibility) in 49 healthy volunteers (within-subject design). In intertemporal choice, patience was higher under oxytocin than under placebo, although this difference was evident only when restricting the analysis to the first experimental session (between-group comparison) due to carry-over effects. Further, oxytocin increased cognitive flexibility in reversal learning as well as generosity under conditions of advantageous but not disadvantageous inequity. Our findings show that oxytocin affects both social and non-social decision making, supporting theoretical accounts of domain-general functions of oxytocin.

The selective 5-HT2A receptor agonist 25CN-NBOH does not affect reversal learning in mice.

Psychedelic 5-hydroxytryptamine 2A receptor (5-HT2AR) agonists are showing promise in the treatment of psychiatric disorders, such as treatment-resistant depression and anxiety. Human studies suggest that enhanced cognitive flexibility may contribute to their clinical efficacy. Both improvement and impairment of cognitive flexibility has been reported with 5-HT2AR ligands, making the link between 5-HT2AR pharmacology and cognitive flexibility equivocal. We tested the selective 5-HT2AR agonist 25CN-NBOH in healthy male C57BL/6JOlaHsd mice in a touchscreen-based mouse reversal learning test. No effects were observed on acquisition of the new stimulus-reward contingency, learning errors, or perseverative responses during reversal. Our results suggest that 25CN-NBOH does not affect reversal learning in the schedule used in this study.

Chronic exposure to trace lead impairs honey bee learning.

Pollutants can have severe detrimental effects on insects, even at sublethal doses, damaging developmental and cognitive processes involved in crucial behaviours. Agrochemicals have been identified as important causes of pollinator declines, but the impacts of other anthropogenic compounds, such as metallic trace elements in soils and waters, have received considerably less attention. Here, we exposed colonies of the European honey bee Apis mellifera to chronic field-realistic concentrations of lead in food and demonstrated that consumption of this trace element impaired bee cognition and morphological development. Honey bees exposed to the highest of these low concentrations had reduced olfactory learning performances. These honey bees also developed smaller heads, which may have constrained their cognitive functions as we show a general relationship between head size and learning performance. Our results demonstrate that lead pollutants, even at trace levels, can have dramatic effects on honey bee cognitive abilities, potentially altering key colony functions and the pollination service.

Are methamphetamine users compulsive? Faulty reinforcement learning, not inflexibility, underlies decision making in people with methamphetamine use disorder.

Methamphetamine use disorder involves continued use of the drug despite negative consequences. Such 'compulsivity' can be measured by reversal learning tasks, which involve participants learning action-outcome task contingencies (acquisition-contingency) and then updating their behaviour when the contingencies change (reversal). Using these paradigms, animal models suggest that people with methamphetamine use disorder (PwMUD) may struggle to avoid repeating actions that were previously rewarded but are now punished (inflexibility). However, difficulties in learning task contingencies (reinforcement learning) may offer an alternative explanation, with meaningful treatment implications. We aimed to disentangle inflexibility and reinforcement learning deficits in 35 PwMUD and 32 controls with similar sociodemographic characteristics, using novel trial-by-trial analyses on a probabilistic reversal learning task. Inflexibility was defined as (a) weaker reversal phase performance, compared with the acquisition-contingency phases, and (b) persistence with the same choice despite repeated punishments. Conversely, reinforcement learning deficits were defined as (a) poor performance across both acquisition-contingency and reversal phases and (b) inconsistent postfeedback behaviour (i.e., switching after reward). Compared with controls, PwMUD exhibited weaker learning (odds ratio [OR] = 0.69, 95% confidence interval [CI] [0.63-0.77], p < .001), though no greater accuracy reduction during reversal. Furthermore, PwMUD were more likely to switch responses after one reward/punishment (OR = 0.83, 95% CI [0.77-0.89], p < .001; OR = 0.82, 95% CI [0.72-0.93], p = .002) but just as likely to switch after repeated punishments (OR = 1.03, 95% CI [0.73-1.45], p = .853). These results indicate that PwMUD's reversal learning deficits are driven by weaker reinforcement learning, not inflexibility.

Melamine disrupts spatial reversal learning and learning strategy via inhibiting hippocampal BDNF-mediated neural activity.

Although several studies showed adverse neurotoxic effects of melamine on hippocampus (HPC)-dependent learning and reversal learning, the evidence for this mechanism is still unknown. We recently demonstrated that intra-hippocampal melamine injection affected the induction of long-term depression, which is associated with novelty acquisition and memory consolidation. Here, we infused melamine into the HPC of rats, and employed behavioral tests, immunoblotting, immunocytochemistry and electrophysiological methods to sought evidence for its effects on cognitive flexibility. Rats with intra-hippocampal infusion of melamine displayed dose-dependent increase in trials to the criterion in reversal learning, with no locomotion or motivation defect. Compared with controls, melamine-treated rats avoided HPC-dependent place strategy. Meanwhile, the learning-induced BDNF level in the HPC neurons was significantly reduced. Importantly, bilateral intra-hippocampal BDNF infusion could effectively mitigate the suppressive effects of melamine on neural correlate with reversal performance, and rescue the strategy bias and reversal learning deficits. Our findings provide first evidence for the effect of melamine on cognitive flexibility and suggest that the reversal learning deficit is due to the inability to use place strategy. Furthermore, the suppressive effects of melamine on BDNF-mediated neural activity could be the mechanism, thus advancing the understanding of compulsive behavior in melamine-induced and other neuropsychiatric disorders.

Serotonergic Innervations of the Orbitofrontal and Medial-prefrontal Cortices are Differentially Involved in Visual Discrimination and Reversal Learning in Rats.

Cross-species studies have identified an evolutionarily conserved role for serotonin in flexible behavior including reversal learning. The aim of the current study was to investigate the contribution of serotonin within the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) to visual discrimination and reversal learning. Male Lister Hooded rats were trained to discriminate between a rewarded (A+) and a nonrewarded (B-) visual stimulus to receive sucrose rewards in touchscreen operant chambers. Serotonin was depleted using surgical infusions of 5,7-dihydroxytryptamine (5,7-DHT), either globally by intracebroventricular (i.c.v.) infusions or locally by microinfusions into the OFC or mPFC. Rats that received i.c.v. infusions of 5,7-DHT before initial training were significantly impaired during both visual discrimination and subsequent reversal learning during which the stimulus-reward contingencies were changed (A- vs. B+). Local serotonin depletion from the OFC impaired reversal learning without affecting initial discrimination. After mPFC depletion, rats were unimpaired during reversal learning but slower to respond at the stimuli during all the stages; the mPFC group was also slower to learn during discrimination than the OFC group. These findings extend our understanding of serotonin in cognitive flexibility by revealing differential effects within two subregions of the prefrontal cortex in visual discrimination and reversal learning.

Sequential reversal learning: a new touchscreen schedule for assessing cognitive flexibility in mice.

RATIONALE: The widespread deficits in cognitive flexibility observed across psychiatric disorders call for improved rodent tests to understand the biology of cognitive flexibility and development of better psychotherapeutics. Current reversal learning paradigms have a forced-choice setup that challenges the interpretation of results. OBJECTIVES: We aimed at developing a free-choice reversal learning test, where images are presented sequentially and animals are free to move, to enable investigation of the cognitive sub-processes that occur during reversal. METHODS: Behavior in female C57BL/6JOlaHsd mice was characterized using chronic fluoxetine as a reference compound. Additional tests were included to support the interpretation of results and exclude confounding pharmacological effects. Behaviors in vehicle-treated mice were furthermore analyzed for relatedness to deepen the understanding of parameters measured. RESULTS: We found that exploitation of the previously rewarded image was independent of exploration and acquisition of the new reward contingency and could be differentially modulated by fluoxetine, supporting recent theories that these processes are not mutually exclusive. Specifically, fluoxetine reduced mistake rate, premature and perseverative responses, and promoted conservative strategies during reversal without affecting hit rate. These effects appeared to be most prominent during the late stage of reversal learning, where accuracy was above chance level. Analysis of behaviors in vehicle-treated mice suggested that exploitation was related to an impulsive-like deficit in response inhibition, while exploration was more related to motivation. CONCLUSIONS: This new schedule was feasible, easy to implement, and can provide a deeper understanding of the cognitive sub-processes during reversal.

Neonatal phencyclidine and social isolation in the rat: effects of clozapine on locomotor activity, social recognition, prepulse inhibition, and executive functions deficits.

RATIONALE: There is a need to develop animal models of schizophrenia-like behaviors that have both construct and predictive validity. Recently, a neonatal phencyclidine (PCP) and post-weaning social isolation dual-hit model was developed; however, its face and predictive validities need to be further investigated. OBJECTIVE: The aims of this study were to extend the characterization of the behavioral changes occurring in the neonatal PCP and post-weaning social isolation dual-hit rat model and to evaluate the effects of chronic treatment with clozapine on signs related to schizophrenia. METHODS: Male Wistar rat pups were treated with PCP (10 mg/kg s.c.) on postnatal days (PND) 7, 9, and 11. Starting from weaning, neonatal PCP-treated rat pups were socially isolated, while control saline-treated rats were group housed. At adulthood, rats were assessed using behavioral tasks evaluating locomotor activity, social recognition, prepulse inhibition, and reversal learning. Clozapine (3 mg/kg i.p.) was administered daily starting from a week before behavioral tests and until the end of the study. RESULTS: Neonatal PCP-treated and post-weaning social isolated (PCP-SI) rats displayed persistent and robust locomotor hyperactivity as well as social recognition impairment. The latter could not be explained by variations in the motivation to interact with a juvenile rat. Weak-to-moderate deficits in prepulse inhibition and reversal learning were also observed. Chronic treatment with clozapine attenuated the observed locomotor hyperactivity and social recognition deficits. CONCLUSION: The PCP-SI model presents enduring and robust deficits (hyperactivity and social recognition impairment) associated with positive symptoms and cognitive/social deficits of schizophrenia, respectively. These deficits are normalized by chronic treatment with clozapine, thereby confirming the predictive validity of this animal model.

Phencyclidine-induced cognitive impairments in repeated touchscreen visual reversal learning tests in rats.

Reversal learning, a component of executive functioning, is commonly impaired among schizophrenia patients and is lacking effective treatment. N-methyl-ᴅ-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), impair reversal learning of rodents. Touchscreen-based pairwise visual discrimination and reversal test is a translational tool to assess reversal learning in rodents. However, to fully exploit this task in testing of novel compounds, it is necessary to perform several reversal learning experiments with trained animals. Firstly, we assessed whether PCP-induced deficits in visual reversal learning in rats would be detectable with a short (5 sessions) reversal learning phase, and whether the short reversal phases could be repeated with novel stimulus pairs. Secondly, we assessed whether the PCP-induced deficits in reversal learning could be seen upon repeated PCP challenges with the same animals. Finally, we tested the effect of a novel compound, a selective α2C adrenoceptor antagonist, ORM-13070, to reverse PCP-induced cognitive deficits in this model. A 4-day PCP treatment at a dose of 1.5 mg/kg/day impaired early reversal learning in male Lister Hooded rats without inducing non-specific behavioral effects. We repeated the reversal learning experiment four times using different stimulus pairs with the same animals, and the PCP-induced impairment was evident in every single experiment. The α2C adrenoceptor antagonist ameliorated the PCP-induced cognitive deficits. Our results suggest that repeated PCP challenges in the touchscreen set-up induce schizophrenia-like cognitive deficits in visual reversal learning, improve throughput of the test and provide a protocol for testing novel drugs.

Central CRF and acute stress differentially modulate probabilistic reversal learning in male and female rats.

Acute stress can have variable and sometimes sex-dependent effects on different executive functions, including cognitive flexibility, some of which may be mediated by increased corticotropin releasing factor (CRF). Previous studies on the effects of stress and CRF on cognitive flexibility have used procedures entailing deterministic rewards, yet how they may alter behavior when outcomes are probabilistic is unclear. The present study examined how acute stress and increased CRF activity alters probabilistic reversal learning (PRL) in male and female rats. Rats learned to discriminate between a 'correct' lever rewarded on 80 % of trials, and an "incorrect" lever delivering reward on 20 % of trials, with reward contingencies reversed after 8 consecutive correct choices. Separate groups received either intracerebroventricular infusions of CRF (3 µg) or restraint stress prior to a PRL session. Experiments examined how these manipulations affected learning when given prior to a one-day acquisition test or during performance in well-trained rats. Exogenous CRF, and to a lesser extent acute stress, impaired motivation across sexes, slowing deliberation times and increasing the number of trials omitted, particularly following a switch in reward contingencies. Neither manipulation significantly altered errors or reversal performance. However, increased CRF activity reduced negative feedback sensitivity. Across manipulations, females showed increased omissions and choice latencies, and were less sensitive to feedback than males. These results reveal the complexity with which stress, CRF, sex, and experience interact to alter aspects of motivation and probabilistic reinforcement learning and provide insight into how CRF activity may contribute to symptoms of stress-related disorders.

Cognitive flexibility deficits in rats with dorsomedial striatal 6-hydroxydopamine lesions tested using a three-choice serial reaction time task with reversal learning.

Lesions of the dorsomedial striatum elicit deficits in cognitive flexibility that are an early feature of Parkinson's disease (PD), and presumably reflect alterations in frontostriatal processing. The current study aimed to examine deficits in cognitive flexibility in rats with bilateral 6-hydroxydopamine lesions in the dorsomedial striatum. While deficits in cognitive flexibility have previously been examined in rodent PD models using the cross-maze, T-maze, and a food-digging task, the current study is the first to examine such deficits using a 3-choice serial reaction time task (3-CSRT) with reversal learning (3-CSRT-R). Although the rate of acquisition in 3-CSRT was slower in lesioned compared to control rats, lesioned animals were able to acquire a level of accuracy comparable to that of control animals following 4 weeks of training. In contrast, substantial and persistent deficits were apparent during the reversal learning phase. Our results demonstrate that deficits in cognitive flexibility can be robustly unmasked by reversal learning in the 3-CSRT-R paradigm, which can be a useful test for evaluating effects of dorsomedial striatal deafferentation and interventions.

Acute serotonin 2A receptor activation impairs behavioral flexibility in mice.

Serotonin 2A (5-HT2A) receptors are the primary site of action of hallucinogenic drugs and the target of atypical antipsychotics. 5-HT2A receptors are also implicated in executive function, including behavioral flexibility. Previous studies showed that 5-HT2A receptor blockade improved behavioral flexibility in rodent models related to autism spectrum disorder and schizophrenia. The current study instead was conducted to examine the impact of acute 5-HT2A receptor activation on behavior flexibility in the control C57BL/6 J strain. Because of the therapeutic potential of serotonergic hallucinogens and the unknown impact of many of these compounds on cognition, the present study examined how the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the more selective 5-HT2A agonist 25CN-NBOH impacted behavioral flexibility in C57BL/6 J mice. Male mice were tested on a probabilistic spatial discrimination and reversal learning task after an intraperitoneal injection of vehicle, 2.5 mg/kg DOI, 1.0 mg/kg 25CN-NBOH, 1.0 mg/kg of the 5-HT2C receptor antagonist SER-082 or combined treatment with SER-082 (1.0 mg/kg) and 2.5 mg/kg DOI before testing of probabilistic reversal learning. All groups demonstrated comparable performance on the initial spatial discrimination, i.e. similar trials to criterion. DOI alone did not impair reversal learning, whereas 25CN-NBOH increased the number of trials to criterion during reversal learning. Because 5-HT2A and 5-HT2C receptors have been shown to functionally antagonize each other in several behavioral paradigms, we also tested whether blockade of 5-HT2C receptors would unmask 5-HT2A receptor activation by DOI and impair reversal learning. Mice treated with SER-082 in combination with DOI required significantly more trials to reach criterion. In an additional experiment, a dose response experiment with 25CN-NBOH revealed that the 1.0 mg/kg dose tested in reversal learning did not affect locomotor activity. Together, these findings indicate that activation of 5-HT2A receptors impairs probabilistic reversal learning and that 5-HT2A and 5-HT2C receptors exert opposing effects on behavioral flexibility in male mice.

Short-active photoperiod gestation induces psychiatry-relevant behavior in healthy mice but a resiliency to such effects are seen in mice with reduced dopamine transporter expression.

A higher incidence of multiple psychiatric disorders occurs in people born in late winter/early spring. Reduced light exposure/activity level impacts adult rodent behavior and neural mechanisms, yet few studies have investigated such light exposure on gestating fetuses. A dysfunctional dopamine system is implicated in most psychiatric disorders, and genetic polymorphisms reducing expression of the dopamine transporter (DAT) are associated with some conditions. Furthermore, adult mice with reduced DAT expression (DAT-HT) were hypersensitive to short active (SA; 19:5 L:D) photoperiod exposure versus their wildtype (WT) littermates. Effects of SA photoperiod exposure during gestation in these mice have not been examined. We confirmed adult females exhibit a heightened corticosterone response when in SA photoperiod. We then tested DAT-HT mice and WT littermates in psychiatry-relevant behavioral tests after SA or normal active (NA; 12:12 L:D) photoperiod exposure during gestation and early life. SA-born WT mice exhibited sensorimotor gating deficits (males), increased reward preference, less immobility, open arm avoidance (females), less motivation to obtain a reward, and reversal learning deficits, vs. NA-born WT mice. DAT-HT mice were largely resilient to these effects, however. Future studies will determine the mechanism(s) by which SA photoperiod exposure influences brain development to predispose toward emergence of psychiatry-relevant behaviors.