Reversal Learning Test Research Articles

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.

Variation in reversal learning by three generalist mesocarnivores.

Urbanization imposes novel challenges for wildlife, but also provides new opportunities for exploitation. Generalist species are commonly found in urban habitats, but the cognitive mechanisms facilitating their successful behavioral adaptations and exploitations are largely under-investigated. Cognitive flexibility is thought to enable generalists to be more plastic in their behavior, thereby increasing their adaptability to a variety of environments, including urban habitats. Yet direct measures of cognitive flexibility across urban wildlife are lacking. We used a classic reversal-learning paradigm to investigate the cognitive flexibility of three generalist mesocarnivores commonly found in urban habitats: striped skunks (Mephitis mephitis), raccoons (Procyon lotor), and coyotes (Canis latrans). We developed an automated device and testing protocol that allowed us to administer tests of reversal learning in captivity without extensive training or experimenter involvement. Although most subjects were able to rapidly form and reverse learned associations, we found moderate variation in performance and behavior during trials. Most notably, we observed heightened neophobia and a lack of habituation expressed by coyotes. We discuss the implications of such differences among generalists with regard to urban adaptation and we identify goals for future research. This study is an important step in investigating the relationships between cognition, generalism, and urban adaptation.

Touchscreen-based location discrimination and paired associate learning tasks detect cognitive impairment at an early stage in an App knock-in mouse model of Alzheimer\u2019s disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline with accumulation of amyloid beta (Aβ) and neurofibrillary tangles that usually begins 15–30 years before clinical diagnosis. Rodent models that recapitulate aggressive Aβ and/or the pathology of neurofibrillary tangles are essential for AD research. Accordingly, non-invasive early detection systems in these animal models are required to evaluate the phenotypic changes, elucidate the mechanism of disease progression, and facilitate development of novel therapeutic approaches. Although many behavioral tests efficiently reveal cognitive impairments at the later stage of the disease in AD models, it has been challenging to detect such impairments at the early stage. To address this issue, we subjected 4–6-month-old male AppNL−G−F/NL−G−F knock-in (App-KI) mice to touchscreen-based location discrimination (LD), different object–location paired-associate learning (dPAL), and reversal learning tests, and compared the results with those of the classical Morris water maze test. These tests are mainly dependent on the brain regions prone to Aβ accumulation at the earliest stages of the disease. At 4–6 months, considered to represent the early stage of disease when mice exhibit initial deposition of Aβ and slight gliosis, the classical Morris water maze test revealed no difference between groups, whereas touchscreen-based LD and dPAL tasks revealed significant impairments in task performance. Our report is the first to confirm that a systematic touchscreen-based behavioral test battery can sensitively detect the early stage of cognitive decline in an AD-linked App-KI mouse model. This system could be applied in future translational research.

The influence of early life socialisation on cognition in the domestic pig (Sus scrofa domestica)

Previously, the benefits of early-life socialisation on later-life social development have been reported in pigs. Here we investigated the effect of pre-weaning socialisation on the later-life cognitive ability of pigs using a range of techniques. Pre-weaning, 101 piglets had access to a neighbouring pen from ~ 15 days of age and interacted with non-littermates (socialised). An additional 89 piglets remained isolated within their home pen (controls). After weaning, 100 individuals were selected for a range of cognitive tests including a food reward T-maze test, reversal learning T-maze test, a social preference T-maze test, and a puzzle box test. Performance during the food reward test was not influenced by treatment. Treatment effected improvement over the course of the reversal learning test, with controls showing a significant decrease in trial duration after the first two trials. During the social preference test, socialised pigs spent significantly more time in the presence of larger stimulus pigs than controls and were quicker to leave the middle of the maze, suggesting improved social skills. Neither sex nor treatment was observed to influence pig’s ability to solve the puzzle box. Thus, overall, evidence from the social preference test suggests an effect of pre-weaning socialisation on aspects of social cognitive development.

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

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. 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. 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. 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. This new schedule was feasible, easy to implement, and can provide a deeper understanding of the cognitive sub-processes during reversal.

Trait Sensitivity to Negative and Positive Feedback Does Not Interact With the Effects of Acute Antidepressant Treatment on Hedonic Status in Rats.

Aberrant cognition plays a pivotal role in the development and maintenance of depression. One of the most important cognitive distortions associated with depression is aberrant sensitivity to performance feedback. Under clinical conditions, this sensitivity can be measured using the probabilistic reversal learning (PRL) test, which has also been recently implemented in animal studies. Although the evidence for the coexistence of depression and altered feedback sensitivity is relatively coherent, it is unclear whether this sensitivity can influence the effectiveness of antidepressant treatment. In the present research, we investigated how trait sensitivity to negative and positive feedback interacts with the effects of acute antidepressant treatment on hedonic status in rats. We tested a cohort of rats with a series of 10 PRL tests, and based on this screening, we classified each animal as sensitive or insensitive to negative and positive feedback. Subsequently, in the Latin square design, we evaluated the effects of a single administration of two antidepressant drugs (each at three different doses: agomelatine: 5, 10, and 40 mg/kg; mirtazapine 0.5, 1, and 3 mg/kg) on the hedonic status of rats in the sucrose preference tests. There was no statistically significant interaction between trait sensitivity to feedback and the effects of acute antidepressant treatment on hedonic status in rats.

(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent.

Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT: This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.

133 - Impact of an Employee Behavioral Health Program on All-Cause Healthcare Utilization

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25 mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25 mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13 mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25 mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13 mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner.

Memory Traces Diminished by Exercise Affect New Learning as Proactive Facilitation.

Exercise enhances cognitive function through increased neurogenesis but can also cause neurogenesis-induced forgetting. It remains unclear whether the diminished memory traces are completely forgotten. Our goals were to determine whether spatial memory is diminished by exercise, and if so, whether the memory is completely gone or whether only the local details disappear but not the acquired strategy. Two-month-old male C57BL/6J mice were trained on a spatial memory task using the Morris water maze and tested to determine that they had learned the platform location. Another mouse group received no training. Half the mice in each group then exercised on a running wheel, while the other half remained sedentary in home cages. After 4 weeks of this, previously trained mice were tested for their retention of the platform location. All mice were then subjected to the task, but the platform was located in a different position (reversal learning for previously trained mice). We found that exercise significantly facilitated the forgetting of the first platform location (i.e., diminished spatial memory) but also significantly enhanced reversal learning. Compared with mice that received no pre-exercise training, mice that had been previously trained, even those in the exercise group that had decreased recall, showed significantly better performance in the reversal learning test. Activation of new adult-born neurons was also examined. Although newborn neuron activation between groups that had or had not received prior task training was not different, activation was significantly higher in exercise groups than in sedentary groups after the probe test for reversal learning. These results indicated that the experience of pre-exercise training equally facilitated new learning in the sedentary and exercise groups, even though significantly lower memory retention was found in the exercise group, suggesting rule-based learning in mice. Furthermore, newborn neurons equally participated in similar and novel memory acquisition.

Proactive common waxbills make fewer mistakes in a cognitive assay, the detour-reaching task

Reactive individuals explore and make decisions more slowly than proactive individuals, paying more attention to external cues. Reactive personality types are therefore predicted to make fewer mistakes in cognitive tasks, especially in tests of inhibitory control and reversal learning that require individuals to adjust behavioral routines. However, empirical evidence for this is mixed, and work relating cognition to a broader set of phenotypic traits has been called for. Here, using the common waxbill (Estrilda astrild), we relate performance in a cognitive assay, the detour-reaching task, to differences in personality, while controlling for putative confounding factors (including sex, breath rate, body size, and mass). Contrary to theoretical predictions, we found that proactive individuals, rather than reactive, made fewer mistakes in the detour-reaching task. We used body size and mass as proxies for condition, but neither predicted personality type or cognitive performance, thus providing no support for the hypothesis that condition dependence mediates the association between proactive personality and detour-reaching performance. This work adds to a growing number of studies contributing conflicting findings on how animal personality relates to cognitive performance, which, together, appear to require novel theory and more nuanced predictions. Theory predicts that reactive personality types (i.e., slower-acting and more attentive individuals) should perform better on cognitive tasks that involve inhibiting a response to an irrelevant stimulus to reach food (inhibitory control). Tests of this hypothesis have generated contradictory results and studies that account for confounding factors are needed. We quantified performance in an inhibitory control assay among common waxbills (Estrilda astrild), while controlling for the largest set of confounding factors to date. Contrary to predictions, waxbills with a reactive personality made more mistakes in the cognitive assay. These and other recent findings suggest that a more nuanced theory on the relation between cognition and personality is necessary.

Brain size does not predict learning strategies in a serial reversal learning test.

ABSTRACTReversal learning assays are commonly used across a wide range of taxa to investigate associative learning and behavioural flexibility. In serial reversal learning, the reward contingency in a binary discrimination is reversed multiple times. Performance during serial reversal learning varies greatly at the interspecific level, as some animals adopt a rule-based strategy that enables them to switch quickly between reward contingencies. A larger relative brain size, generating enhanced learning ability and increased behavioural flexibility, has been proposed to be an important factor underlying this variation. Here, we experimentally tested this hypothesis at the intraspecific level. We used guppies (Poecilia reticulata) artificially selected for small and large relative brain size, with matching differences in neuron number, in a serial reversal learning assay. We tested 96 individuals over 10 serial reversals and found that learning performance and memory were predicted by brain size, whereas differences in efficient learning strategies were not. We conclude that variation in brain size and neuron number is important for variation in learning performance and memory, but these differences are not great enough to cause the larger differences in efficient learning strategies observed at higher taxonomic levels.

Loss of NRF2 leads to impaired mitochondrial function, decreased synaptic density and exacerbated age-related cognitive deficits

Activation of the antioxidant regulatory transcription factor NRF2 (Nuclear factor erythroid-derived 2) regulates cellular bioenergetics and improves neuronal health in aging. Yet how NRF2 participates in maintaining synaptic, mitochondrial and cognitive function has not been fully elucidated. This study investigates how loss of NRF2 affects neuronal metabolism, synaptic density and cognitive performance in aged mice. Dendritic arborization as well as synaptic and mitochondrial gene expression was evaluated in hippocampal neurons isolated from mice lacking NRF2 (NRF2KO) and from wild-type (WT) C57BL6 mice. Mitochondrial function of these neurons was evaluated using the Seahorse XF platform. Additionally learning, memory and executive function were assessed in 20month old NRF2KO and age-matched WT mice using conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) tests. Hippocampal bioenergetics was profiled using mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial and synaptic genes. NRF2KO neurons had reduced dendritic complexity and diminished synaptic gene expression. This was accompanied by impaired mitochondrial function and decreased mitochondrial gene expression. Similar mitochondrial deficits were observed in the brains of aged NRF2KO mice. These animals also had significantly impaired cognitive performance and reduced synaptic gene expression as well. These data point to a role for NRF2 in maintaining mitochondrial and cognitive function during aging and suggest that the transcription factor may be a viable target for cognitive enhancing interventions. Because mitochondrial dysfunction and cognitive impairment also occur together in many neurodegenerative conditions there may be broad therapeutic potential of NRF2 activating agents.

Does Experience Enhance Cognitive Flexibility? An Overview of the Evidence Provided by the Environmental Enrichment Studies.

Neuroplasticity accounts for the ability of the brain to change in both structure and function in consequence of life experiences. An enhanced stimulation provided by the environment is able to create a form of brain, neural, and cognitive reserve, which allows an individual to cope better with the environmental demands, also in case of neural damage leading to cognitive decline. With its complex manipulation of several stimuli, the animal experimental paradigm of environmental enrichment (EE) appears particularly effective in modulating the ability to successfully respond to the ever-changing characteristics of the environment. According to this point, it could be very relevant to analyze the specific effects of EE on cognitive flexibility (CF). CF could be defined as the ability to effectively change behavior in response to the environmental condition changing. This review article is specifically aimed to summarize and focus on the available evidence in relation to the effects of EE on CF. To this aim, findings obtained in behavioral tasks specifically structured to investigate animal CF, such as reversal learning and attentional set-shifting tests (tasks based on the request of responding to a rewarding rule that changes, within one or multiple perceptual dimensions), are reviewed. Data provided on the structural and biochemical correlates of these findings are also enumerated. Studies realized in healthy animals and also in pathological models are considered. On the whole, the summarized evidence clearly supports the specific beneficial effects of EE on CF. However, further studies on this key topic are strictly required to gain a comprehensive and detailed framework on the mechanisms by which an enhanced stimulation could improve CF.

Effects of chronic supplementation of homotaurine on cognitive processes and spatial cognition in aged dogs: Preliminary results

Aged dogs may develop age-related neuropathological and behavioral changes including the reduction in their memory and learning abilities. The aim of the study was to assess the effects of dietary supplementation with tramiprosate (homotaurine) on spatial cognition of aging dogs. Twenty-four aged dogs, sheltered in the same kennel, were randomly assigned into two groups—one group receiving homotaurine supplementation (500 mg once daily) and the other group, living in the same environment, without any supplementation. Cognitive testing was conducted using a T-maze. The experimental procedure consisted of four stages: a one-time direction-determination trial and a learning task, memory task, and reversal learning task that were done at T zero (immediately before supplementation start) and repeated after 4, 8, and 12 months. Data were collected from video-recordings by a single observer. The homotaurine-supplemented dogs were able to maintain a better performance in learning and memory trials with the largest differences observed in the reversal learning test, with a higher number of dogs able to pass the test (P < 0.05). The results suggest that dietary supplementation with homotaurine together with the additional stimulation and exercise of a learning activity seems to slowdown the cognitive aging in dog.

Differences in the expression of restricted repetitive behaviors in female and male BTBR T + tf/J mice

Autism spectrum disorder (ASD) is characterized by the expression of restricted repetitive behaviors (RRBs) and impairments in social recognition and communication. Epidemiological studies demonstrate males are three times more likely than females to be affected. Although this is the case, more recent studies suggest females may be underrepresented in these numbers due to standard clinical measures of RRBs and social behaviors. In addition, many studies examining mouse models of ASD exclude females due to the sex disparity in diagnoses. The present study examined how female and male BTBR T + Itpr3tf /J (BTBR) compare to control C57BL/6J mice on tests of RRBs (probabilistic reversal learning, repetitive grooming, spontaneous alternation, and marble burying) and social behaviors (three chambered social approach task). Utilizing a spatial reversal learning test with 80/20 probabilistic feedback, in which ASD individuals have exhibited deficits, we find that female BTBR mice do not show the same impairment found in male BTBR mice. Interestingly, control female C57BL/6J mice required more trials to reach criterion. Female BTBR mice expressed comparable rates of repetitive grooming, marble burying and spontaneous alternation compared to female C57BL/6J mice. Male BTBR mice expressed higher rates of grooming behavior and locomotor activity compared to male C57BL/6J mice, as found in previous studies. Similarly, male BTBR mice showed a reduction in both measures of social approach compared to controls. Both male and female BTBR mice showed a reduction in sniff time for the stranger mouse compared to controls. Together these findings demonstrate how female BTBR mice do not display the RRB profile expressed by male BTBR mice. Testing of repetitive behaviors in ASD needs to better reflect the sex differences in how RRBs manifest in females compared to their extensively researched male counterparts.

Preclinical characterization of AMPA receptor potentiator TAK-137 as a therapeutic drug for schizophrenia.

The downregulation of the glutamate system may be involved in positive, negative, and cognitive symptoms of schizophrenia. Through enhanced glutamate signaling, the activation of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor, an ionotropic glutamate receptor, could be a new therapeutic strategy for schizophrenia. TAK‐137 is a novel AMPA receptor potentiator with minimal agonistic activity; in this study, we used rodents and nonhuman primates to assess its potential as a drug for schizophrenia. At 10 mg kg−1 p.o., TAK‐137 partially inhibited methamphetamine‐induced hyperlocomotion in rats, and at 3, 10, and 30 mg kg−1 p.o., TAK‐137 partially inhibited MK‐801‐induced hyperlocomotion in mice, suggesting weak effects on the positive symptoms of schizophrenia. At 0.1 and 0.3 mg kg−1 p.o., TAK‐137 significantly ameliorated MK‐801‐induced deficits in the social interaction of rats, demonstrating potential improvement of impaired social functioning, which is a negative symptom of schizophrenia. The effects of TAK‐137 were evaluated on multiple cognitive domains—attention, working memory, and cognitive flexibility. TAK‐137 enhanced attention in the five‐choice serial reaction time task in rats at 0.2 mg kg−1 p.o., and improved working memory both in rats and monkeys: 0.2 and 0.6 mg kg−1 p.o. ameliorated MK‐801‐induced deficits in the radial arm maze test in rats, and 0.1 mg kg−1 p.o. improved the performance of ketamine‐treated monkeys in the delayed matching‐to‐sample task. At 0.1 and 1 mg kg−1 p.o., TAK‐137 improved the cognitive flexibility of subchronic phencyclidine‐treated rats in the reversal learning test. Thus, TAK‐137‐type AMPA receptor potentiators with low intrinsic activity may offer new therapies for schizophrenia.

Plastic changes in brain morphology in relation to learning and environmental enrichment in the guppy (Poecilia reticulata).

Despite the common assumption that the brain is malleable to surrounding conditions mainly during ontogeny, plastic neural changes can occur also in adulthood. One of the driving forces responsible for alterations in brain morphology is increasing environmental complexity that may demand enhanced cognitive abilities (e.g. attention, memory and learning). However, studies looking at the relationship between brain morphology and learning are scarce. Here, we tested the effects of both learning and environmental enrichment on neural plasticity in guppies (Poecilia reticulata), by means of either a reversal-learning test or a spatial-learning test. Given considerable evidence supporting environmentally induced plastic alterations, two separate control groups that were not subjected to any cognitive test were included to account for potential changes induced by the experimental setup alone. We did not find any effect of learning on any of our brain measurements. However, we found strong evidence for an environmental effect, where fish given access to the spatial-learning environment had larger relative brain size and optic tectum size in relation to those exposed to the reversal-learning environment. Our results demonstrate the plasticity of the adult brain to respond adaptively mainly to environmental conditions, providing support for the environmental enhancement theory.

Impaired Cognitive Function after Perineuronal Net Degradation in the Medial Prefrontal Cortex.

Perineuronal nets (PNNs) are highly organized components of the extracellular matrix that surround a subset of mature neurons in the CNS. These structures play a critical role in regulating neuronal plasticity, particularly during neurodevelopment. Consistent with this role, their presence is associated with functional and structural stability of the neurons they ensheath. A loss of PNNs in the prefrontal cortex (PFC) has been suggested to contribute to cognitive impairment in disorders such as schizophrenia. However, the direct consequences of PNN loss in medial PFC (mPFC) on cognition has not been demonstrated. Here, we examined behavior after disruption of PNNs in mPFC of Long–Evans rats following injection of the enzyme chondroitinase ABC (ChABC). Our data show that ChABC-treated animals were impaired on tests of object oddity perception. Performance in the cross-modal object recognition (CMOR) task was not significantly different for ChABC-treated rats, although ChABC-treated rats were not able to perform above chance levels whereas control rats were. ChABC-treated animals were not significantly different from controls on tests of prepulse inhibition (PPI), set-shifting (SS), reversal learning, or tactile and visual object recognition memory. Posthumous immunohistochemistry confirmed significantly reduced PNNs in mPFC due to ChABC treatment. Moreover, PNN density in the mPFC predicted performance on the oddity task, where higher PNN density was associated with better performance. These findings suggest that PNN loss within the mPFC impairs some aspects of object oddity perception and recognition and that PNNs contribute to cognitive function in young adulthood.

Effects of cognitive judgement bias and acute antidepressant treatment on sensitivity to feedback and cognitive flexibility in the rat version of the probabilistic reversal-learning test

Depressive disorders are often associated with cognitive biases. In this study, we investigated, in an animal model, whether cognitive judgement bias, measured as a stable and enduring behavioural trait, could modulate the effects of antidepressant drugs on other cognitive processes associated with depression. For this purpose, we identified rats displaying ‘pessimistic’ and ‘optimistic’ traits in a series of ambiguous-cue interpretation (ACI) tests. Subsequently, in the preclinical version of the probabilistic reversal-learning (PRL) test, allowing multiple reversals within a test session, we compared the effects of acute administration of 5 different antidepressant (AD) drugs (agomelatine, escitalopram, clomipramine, mirtazapine and venlafaxine) on cognitive flexibility and sensitivity to positive/negative feedback in optimistic and pessimistic animals.We report that, following acute treatment with agomelatine, the proportion of lose-shift behaviours in the PRL test was significantly reduced in pessimistic animals compared to optimists. We also demonstrate that acute treatment with another antidepressant drug, mirtazapine, significantly increased the sensitivity of rats to positive feedback, as indexed by the increased proportion of win-stay behaviour following probabilistic reward. This effect was independent of cognitive bias and was associated with a reduced number of reversals made by the animals. Three other tested drugs had no significant effects on behavioural measures assessed in our study.

Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in β-amyloid overexpressing mice

Centella asiatica is a medicinal plant used to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates β-amyloid (Aβ)-induced spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its in vivo mechanism of improving Aβ-related cognitive impairment. This study investigates the effects of CAW on learning, memory and executive function as well as mitochondrial function and antioxidant response in the 5xFAD model of Aβ accumulation.Seven month old 5xFAD female mice were treated with CAW (2 mg/mL) in their drinking water for two weeks prior to behavioral testing. Learning, memory and executive function were assessed using the object location memory task (OLM), conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) test. Mitochondrial function was profiled using the Seahorse XF platform in hippocampal mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial, antioxidant and synaptic proteins.CAW improved performance in all behavioral tests in the 5xFAD but had no effect on WT animals. Hippocampal mitochondrial function was improved and hippocampal and cortical expression of mitochondrial genes was increased in CAW-treated 5xFAD mice. Gene expression of the transcription factor NRF2, as well as its antioxidant target enzymes, was also increased with CAW treatment in both WT and 5xFAD mice. CAW treatment also decreased Aβ-plaque burden in the hippocampus of treated 5xFAD mice but had no effect on plaques in the cortex.These data show that CAW can improve many facets of Aβ-related cognitive impairment in 5xFAD mice. Oral treatment with CAW also attenuates hippocampal mitochondrial dysfunction in these animals. Because mitochondrial dysfunction and oxidative stress accompany cognitive impairment in many pathological conditions beyond Alzheimer's disease, this suggests potentially broad therapeutic utility of CAW.