Acquisition Of Discrimination Research Articles

A further evaluation of picture prompts during auditory-visual conditional discrimination training.

This study was a systematic replication and extension of Fisher, Kodak, and Moore (2007), in which a picture prompt embedded into a least-to-most prompting sequence facilitated acquisition of auditory-visual conditional discriminations. Participants were 4 children who had been diagnosed with autism; 2 had limited prior receptive skills, and 2 had more advanced receptive skills. We used a balanced design to compare the effects of picture prompts, pointing prompts, and either trial-and-error learning or a no-reinforcement condition. In addition, we assessed the emergence of vocal tacts for the 2 participants who had prior tact repertoires. Picture prompts enhanced acquisition for all participants, but there were no differential effects on tact emergence. The results support a generality of the effect reported by Fisher et al. and suggest that a variety of learners may benefit from the incorporation of picture prompts into auditory-visual conditional discrimination training.

Assessment of the interoceptive effects of alcohol in rats using short-term training procedures

In the present study, we sought to determine whether the interoceptive effects of alcohol (1 g/kg, IG) could be assessed using a Pavlovian discrimination method, in which the alcohol drug state sets the occasion for which an environmental stimulus (e.g., light) will be followed by a sucrose reward. This procedure takes advantage of a naturally occurring behavior (i.e., food-seeking) which can be trained rapidly prior to the initiation of discrimination training. Given that the interoceptive effects of alcohol are routinely assessed using operant drug discrimination methods, another group of rats was trained using standard two-lever operant drug discrimination procedures in an effort to compare the Pavlovian procedure to a known behavioral benchmark. The results from this work show that, in addition to operant discrimination procedures, a Pavlovian discrimination task can be used to evaluate the interoceptive effects of alcohol. In addition to the brief behavioral sucrose access training (3 days) required prior to the initiation of the Pavlovian discrimination, the alcohol discrimination was acquired relatively rapidly (i.e., 8 training sessions), shortening the overall duration of the experiment. These features of the Pavlovian procedure make it a valuable method by which to assess the interoceptive effects of alcohol if a short experimental time frame is required, such as assessing the interoceptive effects of alcohol during a brief developmental window (e.g., adolescence) or determining the effects of a pretreatment (i.e., chronic stress, chronic drug pretreatment) on the acquisition of the alcohol discrimination. As such, this initial characterization confirms the feasibility of using this Pavlovian discrimination training method as an additional tool by which to assess the interoceptive effects of alcohol, as there may be experimental situations that necessitate short term discrimination training.

The role of the medial prefrontal cortex in the acquisition, retention, and reversal of a tactile visuospatial conditional discrimination task

The medial prefrontal cortex (mPFC) is responsible for executive functions such as abstract rule coding, strategy switching, and behavioral flexibility; however, there is some debate regarding the extent to which mPFC is involved in reversal learning, especially in complex multisensory tasks such as conditional discrimination. Therefore, we investigated the effects of mPFC inactivation on the acquisition, retention, and reversal of a visuospatial conditional discrimination (CD) task. In experiment 1, muscimol was infused through bilateral cannulae on days 1, 2, and 3 to test the effects of mPFC inactivation on task acquisition and days 19, 20, and 21 to test the effects on retention of the task. For experiment 2, rats were trained on the CD task for 21 days with no infusions given, after which the reward contingency was reversed, with infusions given during the first six days of reversal. The results of experiment 1 showed that the muscimol and saline groups did not differ on acquisition or retention. However, experiment 2 showed that the muscimol group displayed significantly more performance errors than the control group during reversal. Compared to the control group, the muscimol group also showed a decreased tendency to use a side-bias strategy during the intermediate stages of reversal. The failure of the muscimol group to exhibit a side bias suggests that the mPFC is necessary for sampling strategies necessary for the reversal of a visuospatial CD task.

The role of melanin‐concentrating hormone in conditioned reward learning

The orexigenic neuropeptide melanin-concentrating hormone (MCH) is well positioned to play a key role in connecting brain reward and homeostatic systems due to its synthesis in hypothalamic circuitry and receptor expression throughout the cortico-striatal reward circuit. Here we examined whether targeted-deletion of the MCH receptor (MCH-1R) in gene-targeted heterozygote and knockout mice (KO), or systemic treatment with pharmacological agents designed to antagonise MCH-1R in C57BL/6J mice would disrupt two putative consequences of reward learning that rely on different neural circuitries: conditioned reinforcement (CRf) and Pavlovian-instrumental transfer (PIT). Mice were trained to discriminate between presentations of a reward-paired cue (CS+) and an unpaired CS-. Following normal acquisition of the Pavlovian discrimination in all mice, we assessed the capacity for the CS+ to act as a reinforcer for new nose-poke learning (CRf). Pharmacological disruption in control mice and genetic deletion in KO mice impaired CRf test performance, suggesting MCH-1R is necessary for initiating and maintaining behaviors that are under the control of conditioned reinforcers. To examine a dissociable form of reward learning (PIT), a naïve group of mice were trained in separate Pavlovian and instrumental lever training sessions followed by the PIT test. For all mice the CS+ was capable of augmenting ongoing lever responding relative to CS- periods. These results suggest a role for MCH in guiding behavior based on the conditioned reinforcing value of a cue, but not on its incentive motivational value.

A glass full of optimism: Enrichment effects on cognitive bias in a rat model of depression

Investigations of cognitive biases in animals are conceptually and translationally valuable because they contribute to animal welfare research and help to extend and refine our understanding of human emotional disorders, where biased information processing is a critical causal and maintenance factor. We employed the "learned helplessness" genetic rat model of depression in studying cognitive bias and its modification by environmental manipulations. Using a spatial judgment task, responses to ambiguous spatial cues were assessed before and after environmental enrichment to test whether this manipulation would cause an optimistic shift in emotional state. Twenty-four congenitally helpless and nonhelpless male rats were trained to discriminate two different locations, "rewarded" versus "aversive." After successful acquisition of this spatial discrimination, cognitive bias was probed by measuring responses to three ambiguous locations. Latencies to "reach" and to actively "choose" a goal pot were recorded alongside exploratory behaviors. An overall strain difference was observed, with helpless rats displaying longer "reach" latencies than nonhelpless rats. This implies a "pessimistic" response bias in helpless rats, underscoring their depressive-like phenotype. No strain differences were observed regarding other behavioral measures. Half of the animals were then transferred to enriched cages and retested. Environmental enrichment resulted in reduced "choose" latencies in both rat strains, associating enrichment with more optimistic interpretations of ambiguous cues. Our results emphasize the suitability of cognitive bias measurement for animal emotion assessment. They extend the methodological repertoire for characterizing complex phenotypes and bear implications for animal welfare research and for the use of animal models in preclinical research.

New International Society of Pediatric Oncology Boston Ototoxicity Grading Scale for Pediatric Oncology: Still Room for Improvement

Best known for its remarkable effectiveness in successfully treating testicular cancer in adults, cisplatin is a platinum-based chemotherapeutic agent used in many multimodal pediatric cancer treatment regimens. Children with neuroblastoma, hepatoblastoma, retinoblastoma, germ cell tumors, osteosarcoma, medulloblastoma, and other brain tumors are routinely treated with cisplatin, and/or its newer and less toxic analog, carboplatin. The mechanism of action of these drugs involves covalent binding to purine DNA bases, leading to cellular apoptosis. The dose-limiting factors in the administration of platinum-based drugs are generally nephrotoxicity (cisplatin) or myelosuppression (carboplatin), but cisplatin in therapeutic doses is highly ototoxic. Carboplatin, although with substantially less ototoxic potential than cisplatin, is associated with a high risk for hearing loss when used in combination with cisplatin and when used in myeloablative doses as conditioning for hematopoietic stem-cell transplantation in children. Ototoxicity from cisplatin manifests initially as bilateral high frequency sensorineural hearing loss, progressing in severity to the speech ranges with increasing cumulative doses. The hearing loss is caused by sensory hair cell destruction that begins at the base of the cochlea, where high frequency sounds are processed, and continues toward the cochlear apex, where lower frequency sounds are affected. Hearing loss from cisplatin or carboplatin is permanent and may have a delayed onset, with progressive loss occurring many years after completion of therapy. Young children are particularly sensitive to this unfortunate adverse effect. Children treated for high-risk neuroblastoma, for example, are likely to sustain moderate to severe therapy-related hearing loss, with high potential for difficulties in speech discrimination and language acquisition, diminished academic achievement compared with peers with normal hearing, the potential for lifelong impairment of language and academic skills, and diminished quality of life. Although often underappreciated, even hearing loss restricted to high frequency ranges (4,000-8,000 Hz) can have a significant impact on language development, verbal abilities, and reasoning skills in young children. This is of particular concern with patients treated in early childhood for embryonal malignancies because the ototoxic effects are concurrent with the developmental period in which the process of acquiring speech and language skills is so critical. As described by Brock et al in this issue of Journal of Clinical Oncology, efforts to find a method to prevent or mitigate the ototoxic effect of therapeutic doses of platinum drugs in children without diminishing its effectiveness in killing cancer cells is ongoing but has yet to be realized in the clinical setting. One of the key issues in designing a clinical research study to evaluate preventative interventions is having a valid and reliable outcome measure that is standardized, practical, and widely accepted. Such a hearing loss measure needs to reflect the unique aspects of testing children of different ages and capabilities. Although in 1991 Brock et al published a pediatricspecific hearing loss scale for cisplatin exposure, the measure used to monitor and categorize severity of hearing loss in therapeutic trials has been the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 3.0, which requires a baseline evaluation before treatment initiation and then measures change in hearing level as treatment progresses. The NCI-CTCAE v3.0 scale was not specialized to children and has many inherent problems for clinical research purposes, including the fact that baseline measurements are often difficult to obtain in pediatric patients, particularly in very ill patients. In addition, obtaining true auditory thresholds (response to lowest intensity level) can be challenging in pediatric patients. Instead, only minimal response levels are often obtainable, which makes calculating a true decrease in hearing sensitivity difficult and potentially inaccurate. The NCI-CTCAE v3.0 also does not specify test frequencies. Greater emphasis should be placed on the higher frequencies than the lower frequencies when determining cisplatin-induced ototoxicity in children. NCI-CTCAE v3.0 toxicity grades 3 and 4, usually dose-limiting in clinical trials, are defined by subjective measures that are left to interpretation and may differ among audiologists. Although the most recent version of the NCICTCAE, version 4.03, significantly improves on the previous 3.0 version by identifying specific test frequencies for pediatric patients and defining more objective measures, problems with measuring change in hearing compared with baseline measurements and the somewhat subjective nature of defining grades 3 and 4 still remain. Several other hearing loss grading scales have been introduced over the years, as shown in Table 1, including a modification of the 1991 Brock et al scale by Chang and Chinosornvatana in 2010. In the new measure presented by Brock et al, a grading scale based on JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 19 JULY 1 2012

Lesions of the anterior thalamic nuclei and intralaminar thalamic nuclei: place and visual discrimination learning in the water maze

Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experimental animals. Both the anterior thalamic nuclei (ATN) and rostral intralaminar plus adjacent lateral thalamic nuclei (ILN/LT) have been implicated. Based on the differences in their main connections with other neural structures, we tested the prediction that ATN lesions would selectively impair acquisition of spatial location discrimination, reflecting a hippocampal system deficit, whereas ILN/LT lesions would impair acquisition of visual pattern discrimination, reflecting a striatal system deficit. Half the rats were first trained in a spatial task in a water maze before switching to a visual task in the same maze, while the remainder were tested with the reverse order of tasks. Compared with sham-operated controls, (1) rats with ATN lesions showed impaired place learning, but normal visual discrimination learning, (2) rats with ILN/LT lesions showed no deficit on either task. Rats with ATN lesions were also hyperactive when their home cage was placed in a novel room and remained more active than ILN/LT or SHAM rats for the subsequent 21h, especially during the nocturnal phase. These findings confirmed the influence of ATN lesions on spatial learning, but failed to support the view that ILN/LT lesions disrupt striatal-dependent memory.

Poster #144 BREAKING DOWN THINKING SPEED: COMPONENTS OF PROCESSING TIME AND THEIR RELATIONSHIP TO SYMPTOMS AND OTHER COGNITIVE DOMAINS IN SCHIZOPHRENIA

Increasingly precise molecular genetic tools are available to study in mice the cellular mechanisms underlying complex brain functions, but the behavioural paradigms to assess these functions often lack the required specificity. In this study, an attentional set-shifting paradigm to assess medial frontal cortex functions in rats was modified for use in mice and variation between two relevant mouse strains assessed. Male 129/SvEv and C57BL/6J mice and their F1 intercross (n=8 per genotype) were trained to dig in bowls for a food reward. On four consecutive days, mice performed a series of discriminations to criterion (six consecutive correct choices) between pairs of food bowls that differed along two dimensions (odour, digging medium), including a reversal, an intra-dimensional shift, and an extra-dimensional shift. Mice from the 129 strain performed significantly better than C57 mice in the initial acquisition of a simple discrimination and in the final extra-dimensional shift test, with no difference in the reversal and intra-dimensional shift. Performance of the F1 mice was intermediate or similar to that of the 129 mice. These results indicate a selective difference between these two strains in attentional selection processes that have been shown in humans, monkeys and rats to be mediated by prefrontal cortex.

Lateralized reward‐related visual discrimination in the avian entopallium

In humans and many other animals, the two cerebral hemispheres are partly specialized for different functions. However, knowledge about the neuronal basis of lateralization is mostly lacking. The visual system of birds is an excellent model in which to investigate hemispheric asymmetries as birds show a pronounced left hemispheric advantage in the discrimination of various visual objects. In addition, visual input crosses at the optic chiasm and thus testing of each hemisphere is easily accomplished. We aimed to find a neuronal correlate for three hallmarks of visual lateralization in pigeons: first, the animals learn faster with the right eye-left hemisphere; second, they reach higher performance levels under this condition; third, visually guided behavior is mostly under left hemisphere control. To this end, we recorded from the left and right forebrain entopallium while the animals performed a colour discrimination task. We found that, even before learning, left entopallial neurons were more responsive to visual stimulation. Subsequent discrimination acquisition recruited more neuronal responses in the left entopallium and these cells showed a higher degree of differentiation between the rewarded and the unrewarded stimulus. Thus, differential left-right responses are already present, albeit to a modest degree, before learning. As soon as some cues are associated with reward, however, this asymmetry increases substantially and the higher discrimination ratio of the left hemispheric tectofugal pathway would not only contribute to a higher performance of this hemisphere but could thereby also result in a left hemispheric dominance over downstream motor structures via reward-associated feedback systems.

AQUISIÇÃO DE REPERTÓRIO DISCRIMINATIVO AUDITIVO EM ESQUEMA MÚLTIPLO: EXPLORANDO PROCEDIMENTO PARA ESTUDO DA FORMAÇÃO DE CLASSES FUNCIONAIS EM RATOS

Estudos sobre a formação de classes de estímulos usualmente requerem o treino de discriminações de linha de base que incluem múltiplas discriminações simples e/ou condicionais inter-relacionadas. O objetivo do presente estudo foi replicar a fase de aquisição de discriminações de linha de base de um estudo anterior com ratos como sujeitos, com mudanças de procedimento objetivando tornar mais eficiente o treino de linha de base. Seis ratos albinos (Rattus norvegicus) foram submetidos a treino de discriminações simples sucessivas, com estímulos auditivos, em sessões de longa duração. Dois estímulos auditivos (A1 e B1) foram correlacionados a esquema de razão variável (VR) e dois outros estímulos (A2 e B2) foram correlacionados a esquema de reforço diferencial de taxas baixas (DRL). Cinco dos seis ratos demonstraram aquisição das discriminações, desenvolvendo dois padrões distintos de responder (taxas altas no esquema VR e taxas baixas no esquema DRL) sob controle dos estímulos auditivos. Este trabalho sugere que o emprego de esquemas múltiplos com estímulos auditivos em sessões de longa duração pode representar uma alternativa rápida e eficaz na formação de uma linha de base necessária aos estudos de formação de classes funcionais com estímulos auditivos e com ratos como sujeitos. Palavras-chave: razão variável, reforço diferencial de taxas baixas, estímulos auditivos, Rattus novergicus

Pavlovian biconditional discrimination learning in the C57BL/6J Mouse

Four experiments using mice examined acquisition of Pavlovian biconditional discriminations in which two stimulus compounds were paired with food (AX+ and BY+) and two were not (AY- and BX-). Temporally asynchronous compounds were generated by using contextual stimuli (Experiment 1) and 15-s discrete visual cues (Experiments 2A, 2B and 3) to disambiguate when embedded noise or tone stimuli would be paired with food. When food pellets followed both reinforced compounds, successful acquisition was obtained in Experiment 1 but not in Experiments 2A and 2B even though the order of trials was modeled after that used in Experiment 1. However, when differential outcomes followed the reinforced compounds in Experiment 3, acquisition was obtained with discrete cue stimulus compounds. The implications of these results for modulatory models of conditional discrimination learning in animals are discussed.

The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 min prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with an SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally biased response pattern or a learned choice pattern.

Conceptual Design, Development and Preliminary Tests of a Compact Neutron Spectrometer for the JET Experiment

A Compact Neutron Spectrometer (CNS) has been developed to measure the neutron emission spectra in Joint European Torus (JET) fusion plasma experiments. The spectrometer, based on a liquid scintillation detector (BC501A), is equipped with a Digital Pulse Shape Discrimination (DPSD) acquisition system for neutron (n) and gamma-ray (γ) separation. The CNS enables recording the n and γ pulse height spectra (PHS) up to total count rates of ~10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sup> s <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-1</sup> . Energy resolution, after PHS unfolding, will be <; 2% for 14 MeV neutrons and <; 4% for 2.5 MeV neutrons. The work done by ENEA-Frascati and Physikalisch-Technische Bundesanstalt (PTB) respectively in the assembly and test of DPSD and scintillation detector, along with the first results obtained by the spectrometer in JET plasma experiments are presented. The experience obtained with CNS in JET will contribute to the development of neutron spectrometers suitable for applications in the International Thermonuclear Experimental Reactor (ITER).

Behavioral effects of sub-acute inhalation of toluene in adult rats

Reports of behavioral effects of repeated inhalation of toluene in rats have yielded inconsistent findings. A recent study from this laboratory (Beasley et al., 2010) observed that after 13weeks of inhaled toluene (“subchronic” exposure scenario), rats showed mild but persistent changes in behavior, primarily involving acquisition of an autoshaped lever-press response. The present experiment sought to systematically replicate these findings, using a 4-week “sub-acute” exposure scenario. Adult male Long–Evans rats inhaled toluene vapor (0, 10, 100, or 1000ppm) for 6h/day, 5days/week for 4weeks. As in the subchronic study, toluene had no effect on motor activity, anxiety-related behavior in the elevated plus-maze, or acquisition of the visual discrimination. However, sub-acute toluene did not affect appetitively-motivated acquisition of the lever-press response, but did reduce accuracy of signal detection at the end of training. Analysis of the deficit in accuracy in the 1000ppm group by means of manipulations of different task parameters suggested a greater influence of attentional impairment than visual or motor dysfunction as a source for the deficit. These results confirm a pattern of subtle and inconsistent long-term effects of repeated daily exposure to concentrations of toluene vapor of 1000ppm and below, in contrast to robust and reliable effects of acute inhalation of the solvent at concentrations above 1000ppm.

Dissociable roles of the medial prefrontal cortex, the anterior cingulate cortex, and the hippocampus in behavioural flexibility revealed by serial reversal of three-choice discrimination in rats

Contributions of different limbic cortical areas to mediation of behavioural flexibility were examined using repeated acquisition of three-choice discrimination in operant chambers. Rats were trained on a series of positional discrimination tasks with three levers, where position of the correct lever remained the same within a task but shifted across tasks. Ibotenic acid lesions of the medial prefrontal cortex impaired acquisition of each discrimination task by increasing errors specifically in the early phase of each task. These errors were characterised by perseveration to the previously correct lever. By contrast, lesions of the anterior cingulate cortex resulted in the impairment of discrimination in general without inducing perseveration; the impairment was instead characterised by disruption of general error-correction processes. Hippocampal lesions severely impaired learning by increasing perseverative tendencies that were present throughout the learning stages in each task. These results extend our understanding of the contributions of the different nodes of the limbic cortico-striatal circuit to different aspects of behavioural flexibility.

Modulation of attention in discrimination learning: The roles of stimulus relevance and stimulus–outcome correlation

The advantage in learning after an intradimensional shift rather than an extradimensional shift has been widely used as a behavioural marker of attentional changes during discrimination learning in different fields of neuroscientific study. However, some of the factors assumed to guide these attentional changes have not been completely disentangled by previous research. In two predictive-learning experiments, we investigated the importance of stimulus relevance and of stimulus-outcome correlation for the modulation of attention. In each experiment, participants were trained on two discrimination problems given in successive order. Each problem required participants to differentiate stimuli varying on two dimensions. We found that acquisition of the second discrimination was influenced by whether its relevant dimension (Exp. 1) or its irrelevant dimension (Exp. 2) had previously been trained as relevant and uncorrelated or as irrelevant and uncorrelated. We also observed that acquisition of the second discrimination was independent of whether its relevant dimension (Exp. 1) or its irrelevant dimension (Exp. 2) had previously been trained as relevant and uncorrelated or as relevant and correlated. Our results indicated that the modulation of attention is guided by stimulus relevance and not by stimulus-outcome correlation.

Timing behavior in streptozotocin-induced diabetic rats

There is evidence of deterioration of spatial cognition in streptozotocin (STZ)-induced diabetic rats. Here, we evaluate a possible dissociation in the cognitive deficits due to diabetes by examining another crucial aspect of animal cognition: temporal perception. Timing behavior and temporal memory were evaluated in STZ-induced diabetic rats employing two timing tasks: the peak-interval procedure, with its Gap variant, and the interval bisection task. A spatial memory task, rewarded alternation in the T-maze, was also evaluated to explore spatial cognition. The two timing tasks employed coincide in the finding of a normal timing performance in STZ-induced diabetic rats. The peak-interval procedure provided results that suggest that the timing behavior is equally accurate and precise than in control subjects; in the Gap procedure, an equal change in peak time in both groups indicates that temporal working memory is also intact. In the interval bisection task, we analyzed the acquisition of a temporal discrimination and the sensitivity to changes in the duration of the stimulus; no differences were found in either the acquisition process or the sensitivity index. In contrast, in the rewarded alternation task, STZ-induced diabetic rats exhibited a significant deficit in spatial cognition. The cognitive processes involved in timing behavior and temporal memory are not deteriorated as a consequence of diabetes; the cognitive deficits associated to diabetes thus seem to be restricted to the spatial domain.

Disruptive effects of the prototypical cannabinoid Δ9-tetrahydrocannabinol and the fatty acid amide inhibitor URB-597 on go/no-go auditory discrimination performance and olfactory reversal learning in rats

The effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC; 0.3, 1, 3 and 10 mg/kg), and the fatty acid amide hydrolysis inhibitor URB-597 (0.1 and 0.3 mg/kg), on auditory and olfactory go/no-go discrimination tasks were examined in rats. The aims were to assess (i) whether simple olfactory and auditory discrimination tasks are sensitive to cannabinoid interference and (ii) whether manipulation of endogenous cannabinoid levels with URB-597 might have adverse effects on perceptual and cognitive functions. Thirsty rats were trained to nose poke at a 'sniff port', where odours were briefly presented. After one odour (S+, lemon), licks made at an adjacent tube were rewarded with water, whereas licks after a second odour (S-, strawberry) were unrewarded. In an analogous auditory task, nose pokes produced an auditory S+ (beep) or S- (white noise). Δ⁹-THC and URB-597 impaired performance on the auditory but not the olfactory discrimination task. Auditory performance was still affected on the day after Δ⁹-THC (3 and 10 mg/kg) and URB-597 (0.3 mg/kg) exposure. Δ⁹-THC and URB-597 markedly impaired olfactory discrimination reversals without disrupting acquisition of the original discrimination. Rimonabant (CB1 antagonist; 3 mg/kg) reversed all Δ⁹-THC and URB-597 effects on auditory discriminations and olfactory discrimination reversals. These results confirm impairment of cognitive flexibility (reversal learning) by cannabinoids and show remarkable sensitivity of auditory discrimination performance to Δ⁹-THC and the augmented endocannabinoid signalling produced by URB-597.

Intact Performance on Feature-Ambiguous Discriminations in Rats with Lesions of the Perirhinal Cortex

We developed a behavioral paradigm for the rat that made it possible to separate the evaluation of memory functions from the evaluation of perceptual functions. Animals were given extensive training on an automated two-choice discrimination task and then maintained their memory performance at a high level while interpolated probe trials tested visual perceptual ability. The probe trials systematically varied the degree of feature ambiguity between the stimuli, such that perceptual functions could be tested across 14 different levels of difficulty. As feature ambiguity increased, performance declined in an orderly, monotonic manner (from 87% correct to chance, 50% correct). Bilateral lesions of the perirhinal cortex fully spared the capacity to make feature-ambiguous discriminations and the performance of lesioned and intact animals was indistinguishable at every difficulty level. In contrast, the perirhinal lesions did impair recognition memory. The findings suggest that the perirhinal cortex is important for memory and not for perceptual functions.

Genetic Dissection of Behavioral Flexibility: Reversal Learning in Mice

Behavioral inflexibility is a feature of schizophrenia, attention-deficit/hyperactivity disorder, and behavior addictions that likely results from heritable deficits in the inhibitory control over behavior. Here, we investigate the genetic basis of individual differences in flexibility, measured using an operant reversal learning task. We quantified discrimination acquisition and subsequent reversal learning in a cohort of 51 BXD strains of mice (2-5 mice/strain, n = 176) for which we have matched data on sequence, gene expression in key central nervous system regions, and neuroreceptor levels. Strain variation in trials to criterion on acquisition and reversal was high, with moderate heritability (∼.3). Acquisition and reversal learning phenotypes did not covary at the strain level, suggesting that these traits are effectively under independent genetic control. Reversal performance did covary with dopamine D2 receptor levels in the ventral midbrain, consistent with a similar observed relationship between impulsivity and D2 receptors in humans. Reversal, but not acquisition, is linked to a locus on mouse chromosome 10 with a peak likelihood ratio statistic at 86.2 megabase (p < .05 genome-wide). Variance in messenger RNA levels of select transcripts expressed in neocortex, hippocampus, and striatum correlated with the reversal learning phenotype, including Syn3, Nt5dc3, and Hcfc2. This work demonstrates the clear trait independence between, and genetic control of, discrimination acquisition and reversal and illustrates how globally coherent data sets for a single panel of highly related strains can be interrogated and integrated to uncover genetic sources and molecular and neuropharmacological candidates of complex behavioral traits relevant to human psychopathology.