The representation of space in the brain.

Spatially Periodic Activation Patterns of Retrosplenial Cortex Encode Route Sub-spaces and Distance Traveled.

Boundaries Shape Cognitive Representations of Spaces and Events

Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development.

/pdf/otud7a-regulates-neurodevelopmental-phenotypes-in-the-15q13-cn9sphx3fl.pdf

OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome

Concept cells in the human hippocampus encode the meaning conveyed by stimuli over their perceptual aspects. Here we investigate whether analogous cells in the macaque can form conceptual schemas of spatial environments. Each day, monkeys were presented with a familiar and a novel virtual maze, sharing a common schema but differing by surface features (landmarks). In both environments, animals searched for a hidden reward goal only defined in relation to landmarks. With learning, many neurons developed a firing map integrating goal-centered and task-related information of the novel maze that matched that for the familiar maze. Thus, these hippocampal cells abstract the spatial concepts from the superficial details of the environment and encode space into a schema-like representation.

https://science.sciencemag.org/content/sci/363/6427/635.full.pdf

Schema cells in the macaque hippocampus

Recent studies have shown that place cells in the hippocampus possess firing fields that repeat in physically similar, parallel environments. These results imply that it should be difficult for animals to distinguish parallel environments at a behavioral level. To test this, we trained rats on a novel odor-location task in an environment with four parallel compartments which had previously been shown to yield place field repetition. A second group of animals was trained on the same task, but with the compartments arranged in different directions, an arrangement we hypothesised would yield less place field repetition. Learning of the odor-location task in the parallel compartments was significantly impaired relative to learning in the radially arranged compartments. Fewer animals acquired the full discrimination in the parallel compartments compared to those trained in the radial compartments, and the former also required many more sessions to reach criterion compared to the latter. To confirm that the arrangement of compartments yielded differences in place cell repetition, in a separate group of animals we recorded from CA1 place cells in both environments. We found that CA1 place cells exhibited repeated fields across four parallel local compartments, but did not do so when the same compartments were arranged radially. To confirm that the differences in place field repetition across the parallel and radial compartments depended on their angular arrangement, and not incidental differences in access to an extra-maze visual landmark, we repeated the recordings in a second set of rats in the absence of the orientation landmark. We found, once again, that place fields showed repetition in parallel compartments, and did not do so in radially arranged compartments. Thus place field repetition, or lack thereof, in these compartments was not dependent on extra-maze cues. Together, these results imply that place field repetition constrains spatial learning.

/pdf/place-field-repetition-and-spatial-learning-in-a-14udhxe8r1.pdf

Place field repetition and spatial learning in a multicompartment environment

Adolescent neurodevelopment and substance use: Receptor expression and behavioral consequences

The role of acetylcholine and specific nicotinic receptors in sensorimotor gating and higher cognitive function has been controversial Here, we used a commercially available mouse with a null mutation in the Chrna7tm1Bay gene [α7-nicotinic acetylcholine receptor (nAChR) knockout (KO) mouse] in order to assess the role of the α7-nAChR in sensorimotor gating and spatial learning We examined prepulse inhibition (PPI) of startle and nicotine-induced enhancement of PPI We also tested short- and long-term habituation of the startle response as well as of locomotor behaviour in order to differentiate the role of this receptor in the habituation of evoked behaviour (startle) vs motivated behaviour (locomotion) To address higher cognition, mice were also tested in a spatial learning task Our results showed a mild but consistent PPI deficit in α7-nAChR KO mice Furthermore, they did not show nicotine-induced enhancement of startle or PPI Short- and long-term habituation was normal in KO mice for both types of behaviours, evoked or motivated, and they also showed normal learning and memory in the Barnes maze Thorough analysis of the behavioural data indicated a slightly higher degree of anxiety in α7-nAChR KO mice; however, this could only be partially confirmed in an elevated plus maze test In summary, our data suggest that α7-nAChRs play a minor role in PPI, but seem to mediate nicotine-induced PPI enhancement We found no evidence to suggest that they are important for habituation or spatial learning

https://onlinelibrary.wiley.com/doi/pdf/10.1111/gbb.12038

Sensorimotor gating and spatial learning in α7-nicotinic receptor knockout mice.

Patients with a serious mental illness often use cannabis at higher rates than the general population and are also often diagnosed with cannabis use disorder. Clinical studies reveal a strong association between the psychoactive effects of cannabis and the symptoms of serious mental illnesses. Although some studies purport that cannabis may treat mental illnesses, others have highlighted the negative consequences of use for patients with a mental illness and for otherwise healthy users. As epidemiological and clinical studies are unable to directly infer causality or examine neurobiology through circuit manipulation, preclinical animal models remain a valuable resource for examining the causal effects of cannabis. This is especially true considering the diversity of constituents in the cannabis plant contributing to its effects. In this mini-review, we provide an updated perspective on the preclinical evidence of shared neurobiological mechanisms underpinning the dual diagnosis of cannabis use disorder and a serious mental illness. We present studies of cannabinoid exposure in otherwise healthy rodents, as well as rodent models of schizophrenia, depression, and bipolar disorder, and the resulting impact on electrophysiological indices of neural circuit activity. We propose a consolidated neural circuit-based understanding of the preclinical evidence to generate new hypotheses and identify novel therapeutic targets.

/pdf/cannabis-use-and-mental-illness-understanding-circuit-7g45bycqeb.pdf

Cannabis Use and Mental Illness: Understanding Circuit Dysfunction Through Preclinical Models.

Introduction Over 14% of Canadians use cannabis, with nearly 60% of these individuals reporting daily or weekly use. Inhalation of cannabis vapour has recently gained popularity, but the effects of this exposure on neural activity remain unknown. In this study, we assessed the impact of acute exposure to vapourized Δ9-tetrahydrocannabinol (THC) on neural circuit dynamics in rats. Objectives We aimed to characterize the changes in neural activity in the dorsal striatum (dStr), orbitofrontal cortex (OFC), and prefrontal cortex (PFC), after acute exposure to THC vapour. Methods Rats were implanted with electrode arrays targeting the dStr, OFC, and PFC. Rats were administered THC (or vehicle) using a Volcano® vapourizer and local field potential recordings were performed in a plexiglass chamber in a cross-over design with a week-long washout period. Results Decreased spectral power was observed within the dStr, OFC, and PFC in the gamma range (>32-100 Hz) following vapourized THC administration. Most changes in gamma were still present 7 days after THC administration. Decreased gamma coherence was also observed between the OFC-PFC and dStr-PFC region-pairs. Conclusion A single exposure to vapourized THC suppresses cortical and dorsal striatal gamma power and coherence, effects that appear to last at least a week. Given the role of gamma hypofunction in schizophrenia, these findings may provide mechanistic insights into the known psychotomimetic effects of THC.

Bryan W. Jenkins

Papers

Place field repetition and spatial learning in a multicompartment environment

Adolescent neurodevelopment and substance use: Receptor expression and behavioral consequences

Sensorimotor gating and spatial learning in α7-nicotinic receptor knockout mice.

Cannabis Use and Mental Illness: Understanding Circuit Dysfunction Through Preclinical Models.

Extended attenuation of corticostriatal power and coherence after acute exposure to vapourized δ9 tetrahydrocannabinol in rats