No abstract

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in certain forms of synaptic plasticity and cognitive function. mGlu5 knockout (KO) mice and mGlu5 antagonists have been previously used to study the pathophysiology of schizophrenia as they have been shown respectively to display or induce endophenotypes relevant to schizophrenia. While schizophrenia presents with generalized cognitive impairments, the cognitive phenotype of mice lacking mGlu5 has so far only been explored using largely hippocampal-dependent spatial and contextual memory tasks. To address this, we used a touchscreen system to assess mGlu5 KO mice for pairwise visual discrimination, reversal learning, and extinction of an instrumental response requiring no discrimination. Furthermore, we tested the role of mGlu5 in working memory using the Trial-Unique Non-Matching to Location (TUNL) task utilizing pharmacological ablation. mGlu5 KO mice were impaired on discrimination learning, taking longer to reach criterion and requiring more correction learning trials. Performance on reversal learning was also impaired, with mGlu5 KO mice demonstrating a perseverative phenotype. The mGlu5 KO mice responded at a higher rate during extinction, consistent with this perseverative profile. In contrast, wildtype mice treated acutely with an mGlu5 antagonist (MTEP) showed no deficits in a touchscreen task assessing working memory. The present study demonstrates learning and memory deficits as well as an increased perseverative phenotype following constitutive loss of mGlu5 in this mouse model of schizophrenia. These findings will inform translational approaches using this preclinical model and the pursuit of mGlu5 as therapeutic target for schizophrenia and other brain disorders.

Clinical evidence indicates that serotonin-1A receptor (5-HT1AR) gene polymorphisms are associated with anxiety disorders and deficits in cognition. In animal models, exercise (Ex) and environmental enrichment (EE) can change emotionality-related behaviours, as well as enhance some aspects of cognition and hippocampal neurogenesis. We investigated the effects of Ex and EE (which does not include running wheels) on cognition and anxiety-like behaviours in wild-type (WT) and 5-HT1AR knock-out (KO) mice. Using an algorithm-based classification of search strategies in the Morris water maze, we report for we believe the first time that Ex increased the odds for mice to select more hippocampal-dependent strategies. In the retention probe test, Ex (but not EE) corrected long-term spatial memory deficits displayed by KO mice. In agreement with these findings, only Ex increased hippocampal cell survival and BDNF protein levels. However, only EE (but not Ex) modified anxiety-like behaviours, demonstrating dissociation between improvements in cognition and innate anxiety. EE enhanced hippocampal cell proliferation in WT mice only, suggesting a crucial role for intact serotonergic signalling in mediating this effect. Together, these results demonstrate differential effects of Ex vs EE in a mouse model of anxiety with cognitive impairment. Overall, the 5-HT1AR does not seem to be critical for those behavioural effects to occur. These findings will have implications for our understanding of how Ex and EE enhance experience-dependent plasticity, as well as their differential impacts on anxiety and cognition.

Cognitive decline appears as a core feature of dementia, of which the most prevalent form, Alzheimer’s disease (AD) affects more than 45 million people worldwide. There is no cure, and therapeutic options remain limited. A number of modifiable lifestyle factors have been identified that contribute to cognitive decline in dementia. Sedentary lifestyle has emerged as a major modifier and accordingly, boosting mental and physical activity may represent a method to prevent decline in dementia. Beneficial effects of increased physical activity on cognition have been reported in healthy adults, showing potential to harness exercise and cognitive stimulation as a therapy in dementia. ‘Brain training’ (cognitive stimulation) has also been investigated as an intervention protecting against cognitive decline with normal aging. Consequently, the utility of exercise regimes and/or cognitive stimulation to improve cognition in dementia in clinical populations has been a major area of study. However, these therapies are in their infancy and efficacy is unclear. Investigations utilising animal models, where dose and timing of treatment can be tightly controlled, have provided many mechanistic insights. Genetically engineered mouse models are powerful tools to investigate mechanisms underlying cognitive decline, and also how environmental manipulations can alter both cognitive outcomes and pathology. A myriad of effects following physical activity and housing in enriched environments have been reported in transgenic mice expressing Alzheimer’s disease-associated mutations. In this review, we comprehensively evaluate all studies applying environmental enrichment and/or increased physical exercise to transgenic mouse models of Alzheimer’s disease. It is unclear whether interventions must be applied before first onset of cognitive deficits to be effective. In order to determine the importance of timing of interventions, we specifically scrutinised studies exposing transgenic mice to exercise and environmental enrichment before and after first report of cognitive impairment. We discuss the strengths and weaknesses of these preclinical studies and suggest approaches for enhancing rigor and using mechanistic insights to inform future therapeutic interventions.

No abstract

A fundamental question in the study of consciousness is "To what extent are sensory experiences equivalent between individuals?'' One promising approach is to intersubjectively compare the similarity relationships of sensory experiences, named "qualia structures''. An issue with existing methods is the assumption that sensory experiences evoked by the same stimuli must be matched across participants, precluding the possibility that "my red'' might be "your blue''. To address this limitation, we present a novel method for assessing the degree of similarity between qualia structures without assuming any correspondence between experiences across individuals. Our approach, based on Gromov-Wasserstein optimal transport, aligns subjective experiences in a purely unsupervised manner, using only their subjective relationships. As a proof of concept, we applied our method to a large-scale dataset of color dissimilarity judgments and found that qualia structures can be aligned solely based on the subjective relationships between experiences. This method offers a new means of quantitatively investigating the structural properties of subjective experiences.

It seems obvious to lay people that neurotypical humans experience color equivalently across their entire visual field. To some neuroscientists, psychologists and philosophers though, this claim has been met with skepticism, as neurophysiological evidence indicates the mechanisms that support color perception degrade with eccentricity. However, the argument that this entails altered color experience in peripheral vision is not universally accepted. Here, we address whether color experience is essentially equivalent between central and peripheral vision. To assess this, we will obtain similarity relationships between color experiences across the visual field using both on-line and laboratory-based far-field displays, while removing the confounds of saccades, memory, and expectation about color experiences. Our experiment was designed to provide clear evidence that would favor either unchanged or altered color experience relationships in the periphery. Our results are consistent with lay people's phenomenological reports: Color experiences, as probed by similarity relationships in central vision and the far field (60°), are equivalent when elicited by large stimuli. These findings challenge the widespread view in philosophy and cognitive science that peripheral color experiences are illusory, and are discussed in the context of their related neurophysiological, psychophysical, and philosophical literature.

Background and Purpose Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5‐HT) transporter (SERT) in mediating these effects. Experimental Approach Hippocampal long‐term potentiation (LTP) and neurogenesis were measured in standard‐housed and exercising (wheel running) wild‐type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal‐dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task. Key Results SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard‐housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest. Conclusions and Implications Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise‐induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal‐dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5‐HT homeostasis.