Two-choice Visual Discrimination Research Articles

Soluble and membrane-bound isoforms of fractalkine differentially regulate microglia activation and vascular damage in the diabetic retina

Abstract Diabetic retinopathy (DR) is the leading cause of blindness worldwide due to neuronal loss, microgliosis, and vascular damage. Inflammation caused by microglia exacerbates retinal damage, resulting in glial and neuronal cell dysfunction. Microglial-neuronal crosstalk mediated by CX3CR1/FKN signaling regulates microglial responses. CX3CR1 polymorphic variants present in 25% of the population decrease FKN binding affinity to CX3CR1, and their role in microglia function in the retina during diabetes is unknown. FKN exists as a membrane-bound (mFKN) adhesion molecule. When cleaved by proteases, the soluble (sFKN) form exerts chemoattractant properties. Previous studies show that disruption of CX3CR1/FKN signaling worsens retinal pathology and can be rescued by administration of recombinant FKN. Mechanisms by which mFKN and sFKN regulate retinal function are still unknown. We hypothesize that during diabetes, the over-expression of sFKN using recombinant adeno-associated viruses (rAAVs) will prevent vascular and neuronal damage, and improve visual function. To test this hypothesis, rAAVs expressing mFKN or sFKN were delivered to FKN-KO mouse retinas. We validated the expression of FKN levels in retinal protein extracts in mice that received rAAVs expressing mFKN or sFKN. Our findings revealed that rAAV-sFKN minimizes microglial activation, reduces fibrinogen deposition, and rescues neuronal loss, compared to rAAV-mFKN. rAAV-sFKN retinas of diabetic and non-diabetic mice improved visual function in a two-choice visual discrimination task. FKN appears to be neuroprotective, serving as an alternative therapeutic approach to minimize retinal pathology and improve visual function. Supported by NIH/NEI RO1 EY029913

Food and water restriction lead to differential learning behaviors in a head-fixed two-choice visual discrimination task for mice.

Head-fixed behavioral tasks can provide important insights into cognitive processes in rodents. Despite the widespread use of this experimental approach, there is only limited knowledge of how differences in task parameters, such as motivational incentives, affect overall task performance. Here, we provide a detailed methodological description of the setup and procedures for training mice efficiently on a two-choice lick left/lick right visual discrimination task. We characterize the effects of two distinct restriction regimens, i.e. food and water restriction, on animal wellbeing, activity patterns, task acquisition, and performance. While we observed reduced behavioral activity during the period of food and water restriction, the average animal discomfort scores remained in the ‘sub-threshold’ and ‘mild’ categories throughout the experiment, irrespective of the restriction regimen. We found that the type of restriction significantly influenced specific aspects of task acquisition and engagement, i.e. the number of sessions until the learning criterion was reached and the number of trials performed per session, but it did not affect maximum learning curve performance. These results indicate that the choice of restriction paradigm does not strongly affect animal wellbeing, but it can have a significant effect on how mice perform in a task.

Visual attention and cognitive performance in sheep

Cognitive probes are increasingly being used as an inferred measure of the emotional (and thus welfare) status of the animal. This reflects the bidirectional and interactive nature of emotional and cognitive systems. To date, cognitive paradigms have focused on how the emotional system biases expected outcome of prospective actions within goal-orientated scenarios. Evidence, however, suggests that negative affective state can also modulate attentional mechanisms. Measuring attention alongside other current tests of cognitive bias may provide greater resolution in the measurement of animal welfare. As a starting point for developing cognitive tasks of attentional control, we decided to assess the basic relationship between visual attention and cognitive performance in a farm animal species (sheep).Variation in visual attention and cognitive performance was sought through testing of four different breeds of upland and lowland sheep (Beulah, Bluefaced Leicester, Texel and Suffolk; n = 15/breed) on a visual attention task and a two-choice visual discrimination task (to measure cognitive performance).Cognitive performance and visual attention differed significantly between breeds (F 3,46 = 4.70, p = 0.006 and F3,5o = 6.05, p < 0.001 respectively). The least visually attentive breed of sheep (Blue face Leicester) had the lowest level of cognitive performance and the most visually attentive breed (Suffolk) had the highest level of cognitive performance. A weak but significant relationship between vigilance/fearfulness and visual attention was also observed (t44 = 3.91, p = <0.001; r2 = 0.23) that appeared to adhere to the Yerkes-Dodson law, with both high and low levels of vigilance/fearfulness having a negative effect on visual attention. These results demonstrate a discernible relationship between visual attention and cognitive performance. This provides a basis for further exploring attention systems in the context of changes in animal affective state and thus animal welfare.

Online LI-rTMS during a Visual Learning Task: Differential Impacts on Visual Circuit and Behavioral Plasticity in Adult Ephrin-A2A5-/- Mice.

Repetitive transcranial magnetic stimulation (rTMS) induces plasticity in normal and abnormal neural circuitries, an effect that may be influenced by intrinsic brain activity during treatment. Here, we study potential synergistic effects between low-intensity rTMS (LI-rTMS) and concurrent neural activity in promoting circuit reorganization and enhancing visual behavior. We used ephrin-A2A5–/– mice, which are known to possess visuotopic mapping errors that are ameliorated by LI-rTMS, and assessed the impact of stimulation when mice were engaged in a visual learning task. A detachable coil was affixed to each mouse, and animals underwent 2 wk of 10-min daily training in a two-choice visual discrimination task with concurrent LI-rTMS or sham stimulation. No-task controls (+LI-rTMS/sham) were placed in the task arena without visual task training. At the end of the experiment, visuomotor tracking behavior was assessed, and corticotectal and geniculocortical pathway organization was mapped by injections of fluorescent tracers into the primary visual cortex. Consistent with previous results, LI-rTMS alone improved geniculocortical and corticotectal topography, but combining LI-rTMS with the visual learning task prevented beneficial corticotectal reorganization and had no additional effect on geniculocortical topography or visuomotor tracking performance. Unexpectedly, there was a significant increase in the total number of trials completed by task + LI-rTMS mice in the visual learning task. Comparison with wild-type mice revealed that ephrin-A2A5–/– mice had reduced accuracy and response rates, suggesting a goal-directed behavioral deficit, which was improved by LI-rTMS. Our results suggest that concurrent brain activity during behavior interacts with LI-rTMS, altering behavior and different visual circuits in an abnormal system.

Relational concept learning in domestic dogs: Performance on a two-choice size discrimination task generalises to novel stimuli

One central issue in the study of animal cognition concerns conceptual behaviour, where an organism categorises objects, events, and relationships so as to transfer previously learned rules to novel contexts. In this study, we investigated whether or not dogs demonstrate conceptual behaviour in the form of simple relational class concept learning. A two-choice visual discrimination task was used to assess if dogs are capable of simple relational class concept learning by generalising the same rule (i.e. circle is larger or smaller than) to various novel shapes. Eight purebred Lagotto Romagnolos were included in the study. The results demonstrated that they were capable of generalising a previously learned size discrimination rule to novel stimuli; however, there were differences in dog’s generalization capabilities across certain shapes. Considering their unique relationship with humans, and their immediacy in everyday life, a better understanding of conceptual behaviour and generalising abilities in domestic dogs may have implications for training and management methods, as well as contributing to comparative psychology and applied ethology.

Selective Attention to Visual Stimuli Using Auditory Distractors Is Altered in Alpha-9 Nicotinic Receptor Subunit Knock-Out Mice.

During selective attention, subjects voluntarily focus their cognitive resources on a specific stimulus while ignoring others. Top-down filtering of peripheral sensory responses by higher structures of the brain has been proposed as one of the mechanisms responsible for selective attention. A prerequisite to accomplish top-down modulation of the activity of peripheral structures is the presence of corticofugal pathways. The mammalian auditory efferent system is a unique neural network that originates in the auditory cortex and projects to the cochlear receptor through the olivocochlear bundle, and it has been proposed to function as a top-down filter of peripheral auditory responses during attention to cross-modal stimuli. However, to date, there is no conclusive evidence of the involvement of olivocochlear neurons in selective attention paradigms. Here, we trained wild-type and α-9 nicotinic receptor subunit knock-out (KO) mice, which lack cholinergic transmission between medial olivocochlear neurons and outer hair cells, in a two-choice visual discrimination task and studied the behavioral consequences of adding different types of auditory distractors. In addition, we evaluated the effects of contralateral noise on auditory nerve responses as a measure of the individual strength of the olivocochlear reflex. We demonstrate that KO mice have a reduced olivocochlear reflex strength and perform poorly in a visual selective attention paradigm. These results confirm that an intact medial olivocochlear transmission aids in ignoring auditory distraction during selective attention to visual stimuli. The auditory efferent system is a neural network that originates in the auditory cortex and projects to the cochlear receptor through the olivocochlear system. It has been proposed to function as a top-down filter of peripheral auditory responses during attention to cross-modal stimuli. However, to date, there is no conclusive evidence of the involvement of olivocochlear neurons in selective attention paradigms. Here, we studied the behavioral consequences of adding different types of auditory distractors in a visual selective attention task in wild-type and α-9 nicotinic receptor knock-out (KO) mice. We demonstrate that KO mice perform poorly in the selective attention paradigm and that an intact medial olivocochlear transmission aids in ignoring auditory distractors during attention.

Cognitive Training at a Young Age Attenuates Deficits in the zQ175 Mouse Model of HD

Huntington's Disease (HD) is a progressive neurodegenerative disorder that causes motor, cognitive, and psychiatric symptoms. In these experiments, we tested if operant training at an early age affected adult cognitive deficits in the zQ175 KI Het (zQ175) mouse model of HD. In Experiment 1 we trained zQ175 mice in a fixed-ratio/progressive ratio (FR/PR) task to assay learning and motivational deficits. We found pronounced deficits in response rates and task engagement in naïve adult zQ175 mice (32–33 weeks age), while deficits in zQ175 mice trained from 6–7 weeks age were either absent or less severe. When those mice were re-tested as adults, FR/PR performance deficits were absent or otherwise less severe than deficits observed in naïve adult zQ175 relative to wild type (WT) mice. In Experiment 2, we used a Go/No-go operant task to assess the effects of early cognitive testing on response inhibition deficits in zQ175 mice. We found that zQ175 mice that began testing at 7–8 weeks did not exhibit deficits in Go/No-go testing, but when re-tested at 28–29 weeks age exhibited an initial impairment that diminished with training. These transient deficits were nonetheless mild relative to deficits observed among adult zQ175 mice without prior testing experience. In Experiment 3 we trained mice in a two-choice visual discrimination test to evaluate cognitive flexibility. As in prior experiments, we found performance deficits were mild or absent in mice that started training at 6–9 weeks of age, while deficits in naive mice exposed to training at 28–29 weeks were severe. Re-testing mice at 28–29 weeks age, were previously trained starting at 6–9 weeks, revealed that deficits in learning and cognitive flexibility were absent or reduced relative to effects observed in naive adults. In Experiment 4, we tested working memory deficits with a delayed non-match to position (DNMTP) test. Mice with prior experience exhibited mild working memory deficits, with males zQ175 exhibiting no deficits, and females performing significantly worse than WT mice at a single delay interval, whereas naive zQ175 exhibited severe delay-dependent deficits at all intervals exceeding 1 s. In sum, these experiments indicate that CAG-dependent impairments in motivation, motor control, cognitive flexibility, and working memory are sensitive to the environmental enrichment and experience. These findings are of clinical relevance, as HD carrier status can potentially be detected at an early age.

Mouse Ability to Perceive Subjective Contours.

In contrast to the previously held notion that mice have a weak visual system, it is now generally accepted that mice can perceive rather complicated figures in various contexts such as in cognitive experiments and in social settings. Here, we show that mice could even be capable of perceiving a visual illusion--subjective contours. This illusion requires the visual system to compensate for a lack of visual information in compressed 2D images on the retina. In this experiment, we trained mice to respond appropriately to a rectangle-shaped rewarded figure of specific orientation in a two-choice visual discrimination task with a touchscreen monitor. In Transfer Test 1, mice could discriminate illusory rectangle-shaped figures significantly as compared with a figure, which did not induce illusory figures. In Transfer Test 2, the choice rate of targets decreased with imperfect illusory figures, which produced weak perception of rotated or deficient inducers. Moreover, in Transfer Test 3, mice could not discriminate the low-resolution illusory figure, which also induced weak perception. These results demonstrated the possibility that mice might be useful for investigating fundamental properties of the neural visual system.

A mobile, high-throughput semi-automated system for testing cognition in large non-primate animal models of Huntington disease

BackgroundFor reasons of cost and ethical concerns, models of neurodegenerative disorders such as Huntington disease (HD) are currently being developed in farm animals, as an alternative to non-human primates. Developing reliable methods of testing cognitive function is essential to determining the usefulness of such models. Nevertheless, cognitive testing of farm animal species presents a unique set of challenges. The primary aims of this study were to develop and validate a mobile operant system suitable for high throughput cognitive testing of sheep. New methodWe designed a semi-automated testing system with the capability of presenting stimuli (visual, auditory) and reward at six spatial locations. Fourteen normal sheep were used to validate the system using a two-choice visual discrimination task. Four stages of training devised to acclimatise animals to the system are also presented. ResultsAll sheep progressed rapidly through the training stages, over eight sessions. All sheep learned the 2CVDT and performed at least one reversal stage. The mean number of trials the sheep took to reach criterion in the first acquisition learning was 13.9±1.5 and for the reversal learning was 19.1±1.8. Comparison with existing method(s)This is the first mobile semi-automated operant system developed for testing cognitive function in sheep. ConclusionsWe have designed and validated an automated operant behavioural testing system suitable for high throughput cognitive testing in sheep and other medium-sized quadrupeds, such as pigs and dogs. Sheep performance in the two-choice visual discrimination task was very similar to that reported for non-human primates and strongly supports the use of farm animals as pre-clinical models for the study of neurodegenerative diseases.

Cognitive Deficits in the R6/2 mouse model of Huntington’s disease and their Amelioration with Donepezil

The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies.

The effects of time, luminance, and high contrast targets: Revisiting grating acuity in the domestic cat

Based on optical clarity and retinal cone density, the cat has a potential acuity of 20–30 cycles per degree (cpd), yet most behavioral studies estimate feline acuity between 3 and 9 cpd. Those studies, however, were limited by restrictive experimental conditions that may have inadvertently lowered the estimated grating acuity. Two domestic cats previously trained on a two-choice visual discrimination task were retrained on a grating detection/discrimination task with unlimited time, high luminance, high contrast targets, and adequate space to prevent poor accommodation from affecting the results. Initially, vertical gratings of increasing cpd were tested until failure. Then, horizontal gratings of increasing cpd were tested until failure. Finally, the finest horizontal grating resolved was confirmed with a third test requiring 24 correct out of 36 consecutive trials, yielding a binomial probability less than 0.02 of non-random occurrence. M1, a 7-year-old male gray tabby with +2.00 OU refraction, tested for a grating detection acuity of 15 cpd for both vertical and horizontal gratings (binomial probability = 0.009). F1, a 2-year-old female gray tabby with +0.25 OU refraction, tested for a grating orientation discrimination acuity of 20 cpd for both vertical and horizontal gratings (binomial probability = 0.004). These results demonstrate that a young cat with good focus is capable of discriminating 20 cpd, in close agreement with the physiologic maximum. Uncorrected focusing errors appear to degrade visual performance. Optimum experimental conditions resulted in better grating acuity measurements than previously reported, emphasizing the importance of environmental factors in feline behavioral testing.

NMDA receptor antagonists distort visual grouping in rats performing a modified two-choice visual discrimination task

Visual perception is impaired during pathological psychosis, which can be mimicked by NMDA receptor antagonists. However, the underlying mechanisms are poorly understood, partly due to limits of current rodent models for visual integration. The objectives of the study are (1) to develop a rodent task that can differentiate between effects on perception and nonspecific effects on task performance and (2) to test whether NMDA receptor antagonists affect visual perception in rats. We used an adaptation of Glass patterns to assess visual grouping in rats using a two-choice visual discrimination task in an infrared touch screen conditioning chamber. After rats learned to discriminate between a radial and a concentric bipole pattern, the ability to discriminate between these patterns was tested at various levels of distortion and a psychometric function was fit to obtain the maximum task performance and signal level needed for half-maximum performance. NMDA receptor antagonists ketamine and phencyclidine at low doses increased the signal quality needed to discriminate between the visual patterns, without affecting the ability to discriminate between undistorted images. At higher doses, the ability to perform the task even with undistorted images was impaired, which was associated with stereotypic behaviour and increased impulsivity. The Glass pattern-based visual grouping task is able to differentiate the effect of psychotomimetic NMDA receptor antagonists on visual perception from the effects on motor and memory functions. The half-maximum performance signal level allows quantification of cognitive psychosis in rodents, which can be translated to human psychometric functions and can be used in the development of more effective treatments.

Different Levels of Food Restriction Reveal Genotype-Specific Differences in Learning a Visual Discrimination Task

In behavioural experiments, motivation to learn can be achieved using food rewards as positive reinforcement in food-restricted animals. Previous studies reduce animal weights to 80–90% of free-feeding body weight as the criterion for food restriction. However, effects of different degrees of food restriction on task performance have not been assessed. We compared learning task performance in mice food-restricted to 80 or 90% body weight (BW). We used adult wildtype (WT; C57Bl/6j) and knockout (ephrin-A2−/−) mice, previously shown to have a reverse learning deficit. Mice were trained in a two-choice visual discrimination task with food reward as positive reinforcement. When mice reached criterion for one visual stimulus (80% correct in three consecutive 10 trial sets) they began the reverse learning phase, where the rewarded stimulus was switched to the previously incorrect stimulus. For the initial learning and reverse phase of the task, mice at 90%BW took almost twice as many trials to reach criterion as mice at 80%BW. Furthermore, WT 80 and 90%BW groups significantly differed in percentage correct responses and learning strategy in the reverse learning phase, whereas no differences between weight restriction groups were observed in ephrin-A2−/− mice. Most importantly, genotype-specific differences in reverse learning strategy were only detected in the 80%BW groups. Our results indicate that increased food restriction not only results in better performance and a shorter training period, but may also be necessary for revealing behavioural differences between experimental groups. This has important ethical and animal welfare implications when deciding extent of diet restriction in behavioural studies.

Sensorimotor gating and vigilance-dependent choice accuracy: A within-subject correlative analysis in wild-type C57BL/6 mice

Deterioration in attention and related processes is an early sign in schizophrenia predictive of disease development. Amongst the various translational paradigms for assessing attention in rodents, it is not known if they are equivalent in detecting individual differences. Answers here are pertinent to their use in the general human population for identifying individuals at high risk of developing schizophrenia. The present study employed a within-subject approach to examine in mice two common paradigms for assessing attention that differ markedly in their implementation. An operant-based two-choice visual discrimination task (2-CVDT) that depends on effortful attention to brief visual cues was contrasted with prepulse inhibition (PPI) of the acoustic startle reflex, a well-established test of pre-attentive gating whereby processing of a startle-eliciting stimulus is inhibited by a preceding weak prepulse stimulus. Here, we revealed a correlation showing that individual mice with low PPI tended to perform poorly in the 2-CVDT in terms of choice accuracy but not response speed. This specific positive correlation suggests that the two readouts might be regulated via common attentional mechanisms, which might be critically dependent on normal muscarinic and N-methyl- d-asparate receptor functions. As demonstrated here, blockade of either receptor type by scopolamine or dizocilpine impaired 2-CVDT performance at doses that have been shown to disrupt PPI in mice. Further studies contrasting these two paradigms would be warranted to characterize the possible underlying psychological constructs that give rise to this correlation and to clarify whether the two paradigms may effectively capture schizophrenia-related cognitive deficits belonging to orthogonal domains.

Muscimol, AP5, or scopolamine infused into perirhinal cortex impairs two-choice visual discrimination learning in rats

The perirhinal cortex (PRh) has been strongly implicated in object recognition memory and visual stimulus representation. Studies of object recognition have revealed evidence for the involvement of several neurotransmitter subsystems, including those involving NMDA ( N-methyl- d-aspartic acid) and muscarinic cholinergic receptors. In the present study, we assessed the possible involvement of PRh and related receptor subsystems in two-choice visual discrimination learning by Lister Hooded rats tested in touchscreen-equipped operant boxes. In Experiment 1, daily pre-training inactivation of PRh with the GABA A receptor agonist muscimol (0.5 μg/hemisphere) significantly impaired acquisition of the two-choice visual discrimination. In Experiment 2, daily pre-training blockade of either NMDA or muscarinic receptors in PRh with AP5 (5.9 μg/hemisphere) or scopolamine (10 μg/hemisphere), respectively, impaired task acquisition. These results parallel the findings from object recognition studies and suggest a generality of neurotransmitter receptor involvement underlying the role of PRh in both object recognition memory and visual discrimination learning. The involvement of PRh in both types of tasks may be related to its role in complex visual stimulus representation.

Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin

The rod and cone cells of the mammalian retina are the principal photoreceptors for image-forming vision. They transmit information by means of a chain of intermediate cells to the retinal ganglion cells, which in turn send signals from the retina to the brain. Loss of photoreceptor cells, as happens in a number of human diseases, leads to irreversible blindness. In a mouse model (rd/rd) of photoreceptor degeneration, we used a viral vector to express in a large number of retinal ganglion cells the light sensitive protein melanopsin, normally present in only a specialized subset of the cells. Whole-cell patch-clamp recording showed photoresponses in these cells even after degeneration of the photoreceptors and additional pharmacological or Cd(2+) block of synaptic function. Interestingly, similar responses were observed across a wide variety of diverse types of ganglion cell of the retina. The newly melanopsin-expressing ganglion cells provided an enhancement of visual function in rd/rd mice: the pupillary light reflex (PLR) returned almost to normal; the mice showed behavioral avoidance of light in an open-field test, and they could discriminate a light stimulus from a dark one in a two-choice visual discrimination alley. Recovery of the PLR was stable for at least 11 months. It has recently been shown that ectopic retinal expression of a light sensitive bacterial protein, channelrhodopsin-2, can restore neuronal responsiveness and simple visual abilities in rd/rd mice. For therapy in human photodegenerations, channelrhodopsin-2 and melanopsin have different advantages and disadvantages; both proteins (or modifications of them) should be candidates.

Perirhinal cortex resolves feature ambiguity in configural object recognition and perceptual oddity tasks.

The perirhinal cortex (PRh) has a well-established role in object recognition memory. More recent studies suggest that PRh is also important for two-choice visual discrimination tasks. Specifically, it has been suggested that PRh contains conjunctive representations that help resolve feature ambiguity, which occurs when a task cannot easily be solved on the basis of features alone. However, no study has examined whether the ability of PRh to resolve configural feature ambiguity is related to its role in object recognition. Therefore, we examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus post-rhinal cortices) in the rat would cause deficits in a configural spontaneous object recognition task, and a configural simultaneous oddity discrimination task, in which the task could not be solved on the basis of features, but could only be solved using conjunctive representations. As predicted by simulations using a computational model, rats with PPRh lesions were impaired during a minimal-delay configural object recognition task. These same rats were impaired during a zero-delay configural object recognition task. Furthermore, rats with localized PRh lesions were impaired in a configural simultaneous oddity discrimination task. These findings support the idea that PRh contains conjunctive representations for the resolution of feature ambiguity and that these representations underlie a dual role for PRh in memory and perception.

Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington's disease.

Transgenic R6/2 mice carrying the Huntington's disease (HD) mutation show disrupted circadian rhythms that worsen as the disease progresses. By 15 weeks of age, their abnormal circadian behavior mirrors that seen in HD patients and is accompanied by dysregulated clock gene expression in the circadian pacemaker, the suprachiasmatic nucleus (SCN). We found, however, that the electrophysiological output of the SCN assayed in vitro was normal. Furthermore, the endogenous rhythm of circadian gene expression, monitored in vitro by luciferase imaging of organotypical SCN slices removed from mice with disintegrated behavioral rhythms, was also normal. We concluded that abnormal behavioral and molecular circadian rhythms observed in R6/2 mice in vivo arise from dysfunction of brain circuitry afferent to the SCN, rather than from a primary deficiency within the pacemaker itself. Because circadian sleep disruption is deleterious to cognitive function, and cognitive decline is pronounced in R6/2 mice, we tested whether circadian and cognitive disturbances could be reversed by using a sedative drug to impose a daily cycle of sleep in R6/2 mice. Daily treatment with Alprazolam reversed the dysregulated expression of Per2 and also Prok2, an output factor of the SCN that controls behavioral rhythms. It also markedly improved cognitive performance of R6/2 mice in a two-choice visual discrimination task. Together, our data show for the first time that treatments aimed at restoring circadian rhythms may not only slow the cognitive decline that is such a devastating feature of HD but may also improve other circadian gene-regulated functions that are impaired in this disease.

Location serves as a conditional cue when harp seals (Pagophilus groenlandicus) solve object discrimination reversal problems.

We examined the capacity of harp seals (Pagophilus groenlandicus) to use spatial context (i.e., their tank) as a conditional cue to solve a two-choice visual discrimination reversal task. Seals were trained to touch one of two 3D objects. Two of four seals experienced a context shift that coincided with each of five reversals in the reward value of the two stimuli (i.e., a reversal of S+ and S-); these seals solved the six discriminations in significantly fewer trials than did seals that did not experience a context shift with the contingency reversal. Thus, harp seals use contextual cues when encoding information. The findings are discussed in terms of harp seals' adaptations to the pack-ice environment, the constraints of the learning tasks, and the nature of the subjects that were raised in captivity.

A dynamic shift of neural network activity before and after learning-set formation.

Learning-set (LS) is a property of insight and hypothesis testing characterized by the ability to solve novel problems based on previous experiences with problem solving. However, the neural organization and mechanisms underlying LS remain unclear. To further characterize this process, positron emission tomography (PET) studies with [15O]H2O were performed to measure regional cerebral blood flow (rCBF) during the learning phase of the two-choice visual discrimination task under the LS paradigm in rhesus monkeys. When comparing studies before and after LS formation, the orbitofrontal and lateral prefrontal cortices were differentially activated, and functional connections between these structures and the striatum, which contributes to habit learning, were altered. We conclude that changes in the lateral prefrontal cortex during problem solving may contribute to the executive function of working memory and also inhibit control of a primitive learning system, thereby promoting LS formation.