Disrupting Jagged1-Notch signaling impairs spatial memory formation in adult mice.

It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1(+/-)) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1-Notch signaling is critical for memory formation in the adult brain.

Reprint of: disrupting Jagged1-Notch signaling impairs spatial memory formation in adult mice.

It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1(+/-)) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1-Notch signaling is critical for memory formation in the adult brain.

Impaired visual search in rats reveals cholinergic contributions to feature binding in visuospatial attention.

The visual search task established the feature integration theory of attention in humans and measures visuospatial attentional contributions to feature binding. We recently demonstrated that the neuromodulator acetylcholine (ACh), from the nucleus basalis magnocellularis (NBM), supports the attentional processes required for feature binding using a rat digging-based task. Additional research has demonstrated cholinergic contributions from the NBM to visuospatial attention in rats. Here, we combined these lines of evidence and employed visual search in rats to examine whether cortical cholinergic input supports visuospatial attention specifically for feature binding. We trained 18 male Long-Evans rats to perform visual search using touch screen-equipped operant chambers. Sessions comprised Feature Search (no feature binding required) and Conjunctive Search (feature binding required) trials using multiple stimulus set sizes. Following acquisition of visual search, 8 rats received bilateral NBM lesions using 192 IgG-saporin to selectively reduce cholinergic afferentation of the neocortex, which we hypothesized would selectively disrupt the visuospatial attentional processes needed for efficient conjunctive visual search. As expected, relative to sham-lesioned rats, ACh-NBM-lesioned rats took significantly longer to locate the target stimulus on Conjunctive Search, but not Feature Search trials, thus demonstrating that cholinergic contributions to visuospatial attention are important for feature binding in rats.

Voluntary Exercise Increases Neurogenesis and Mediates Forgetting of Complex Paired Associates Memories.

The hippocampus is a critical structure involved in many forms of learning and memory. It is also one of the only regions in the mammalian brain that continues to generate new neurons throughout adulthood. This process of adult neurogenesis may increase the plasticity of the hippocampus which could be beneficial for learning but has also been demonstrated to decrease the stability of previously acquired memories. Here we test whether exposure to voluntary running (which increases the production of new neurons) following the formation of a gradually acquired paired associates task will result in forgetting of this type of memory. We trained mice in a touchscreen-based object/location task and then increased neurogenesis using voluntary running. Our results indicate that running increased neurogenesis and resulted in poor recall of the previously established memory. When subsequently exposed to a reversal task we also show that running reduced the number of correction trials required to acquire the new task contingencies. This suggests that prior forgetting reduces perseveration on the now outdated memory. Together our results add to a growing body of literature which indicates the important role of adult neurogenesis in destabilizing previously acquired memories to allow for flexible encoding of new memories.

Cholinergic deafferentation of the neocortex using 192 IgG-saporin impairs feature binding in rats.

The binding problem refers to the fundamental challenge of the CNS to integrate sensory information registered by distinct brain regions to form a unified neural representation of a stimulus. Although the human cognitive literature has established that attentional processes in frontoparietal cortices support feature binding, the neurochemical and specific downstream neuroanatomical contributions to feature binding remain unknown. Using systemic pharmacology in rats, it has been shown that the neuromodulator acetylcholine is essential for feature binding at encoding, but the neural source of such critical cholinergic neurotransmission has yet to be identified. Cholinergic efferents from the nucleus basalis magnocellularis (NBM) of the basal forebrain provide the majority of the cholinergic input to the neocortex. Accordingly, it was hypothesized that the NBM is the neural source that provides the critical neuromodulatory support for feature binding. To test this hypothesis, rats received bilateral 192 IgG-saporin lesions of the NBM, and their feature binding performance was tested using a forced-choice digging paradigm. Relative to sham-lesioned rats, NBM-lesioned rats were significantly impaired at acquiring a crossmodal feature conjunction (FC) stimulus set that required feature binding, whereas their ability to retrieve an FC stimulus set and to acquire two crossmodal feature singleton stimulus sets, one of greater difficulty than the other but neither requiring feature binding, remained intact. These behavioral findings, along with histological analyses demonstrating positive relationships between feature-binding acquisition and markers of cholinergic activity in frontoparietal regions, reveal the importance of neocortical cholinergic input from the NBM to feature binding at encoding.

People With Lived Experience at the Centre of Canadian Stroke Best Practice Recommendations: A Model for Guideline Developers.

Actively engaging people with lived experience (PWLE) in stroke-related clinical practice guideline development has not been effectively implemented. This pilot project evaluated the feasibility, perceived value, and effectiveness of the Community Consultation and Review Panel (CCRP), a new model to engage PWLE in the writing and review of Canadian Stroke Best Practice Recommendations. Responses to a standardized evaluation tool indicated that participants perceived the CCRP as valued, impactful, effective, and beneficial to stroke care. This project successfully demonstrated that values, experiences, and recommendations of PWLE can be effectively incorporated into guideline content and is applicable to all guideline development processes.

Recent Trends in Hospitalizations for Cardiovascular Disease, Stroke, and Vascular Cognitive Impairment in Canada.

BACKGROUND: We analyzed hospitalization rates for a broad set of cardiovascular diseases, stroke, and vascular cognitive impairment (VCI) between 2007 and 2016 in Canada to characterize population-level trends and demographic and provincial/territorial variation in inpatient health care utilization. METHODS: Record-level administrative hospitalization data from April 1, 2007 to March 31, 2017 for individuals aged 0-105 years were obtained from the Canadian Institute for Health Information Discharge Abstract Database. Data were available for all provinces and territories, except Quebec. Using the International Classification of Diseases (10th Revision, Canada) diagnostic coding standards, we identified disease categories related to cardiovascular disease, stroke, or VCI. Hospitalizations, crude and standardized, for age and sex (direct method) were calculated using the 2011 Census as the standard population. RESULTS: Between 2007 and 2016, percent decreases in standardized hospitalization rates were relatively small for heart failure and stroke (-2.4% and -4.7%, respectively), whereas those for coronary artery and vascular disease and heart rhythm disorders were moderate (-27.4% and -16.8%, respectively). Percent increases were relatively small for congenital heart disease (+7.2%) and moderate for acquired valvular heart disease (+31.1%) and VCI (+23.4%). There were notable age- and sex-specific differences along with provincial/territorial variation. CONCLUSIONS: Between 2007 and 2016, there was an overall decrease in standardized hospitalization rates for coronary artery and vascular disease, heart failure, heart rhythm disorders, and stroke, and an increase in hospitalization rates for structural heart disease (congenital heart disease and acquired valvular heart disease) and VCI in Canada.

COVID-19 Pandemic: Global Impact and Potential Implications for Cardiovascular Disease in Canada.

BACKGROUND: The literature indicates that cardiovascular disease (CVD; including stroke), older age, and availability of health care resources affect COVID-19 case fatality rates (CFRs). The cumulative effect of COVID-19 CFRs in global CVD populations and the extrapolated effect on access to health care services in the CVD population in Canada are not fully known. In this study we explored the relationships of factors that might affect COVID-19 CFRs and estimated the potential indirect effects of COVID-19 on Canadian health care resources. METHODS: Country-level epidemiological data were analyzed to study the correlation, main effect, and interaction between COVID-19 CFRs and: (1) the proportion of the population with CVD; (2) the proportion of the population 65 years of age or older; and (3) the availability of essential health services as defined by the World Health Organization Universal Health Coverage index. For indirect implications on health care resources, estimates of the volume of postponed coronary artery bypass grafting, percutaneous coronary intervention, and valve surgeries in Ontario were calculated. RESULTS: Positive correlations were found between COVID-19 CFRs and: (1) the proportion of the population with CVD (ρ = 0.40; P = 0.001); (2) the proportion of the population 65 years of age or older (ρ = 0.43; P = 0.0005); and (3) Universal Health Coverage index (ρ = 0.27; P = 0.03). For every 1% increase in the proportion of the population 65 years of age or older or proportion of the population with CVD, the COVID-19 CFR was 9% and 19% higher, respectively. Approximately 1252 procedures would be postponed monthly in Ontario because of current public health measures. CONCLUSIONS: Countries with more prevalent CVD reported higher COVID-19 CFRs. Strain on health care resources is likely in Canada.

CONTEXTE: La littérature indique que les maladies cardiovasculaires (MCV, incluant les accidents vasculaires cérébraux), l'âge avancé et la facilité d'accès aux ressources de soins de santé ont une incidence sur les taux de létalité (TL) des cas de COVID-19. L'effet cumulatif du TL de la COVID-19 dans l'ensemble de la population atteinte de MCV et l'impact anticipé sur l'accès aux services de santé dans la population atteinte de MCV au Canada ne sont pas entièrement connus. Cette étude a exploré les liens entre les facteurs pouvant influencer le TL des cas de COVID-19 et a estimé le potentiel impact indirect de la COVID-19 sur les ressources de soins de santé au Canada. MÉTHODES: Les données épidémiologiques à l'échelle du pays ont été analysées pour étudier la corrélation, l'effet principal et l'interaction entre le TL de laCOVID-19 et : 1) la proportion de la population souffrant de MCV, 2) la proportion de la population ≥ 65 ans, et 3) l'accessibilité des services de santé essentiels tels que définis par l'indice de couverture sanitaire universelle (CSU) de l'Organisation Mondiale de la Santé. Pour les implications indirectes concernant les ressources de santé, des estimations du volume d'opération de pontages coronariens, d'interventions coronariennes percutanées et de chirurgies valvulaires reportées en Ontario ont été calculées. RÉSULTATS: Des corrélations positives ont été trouvées entre le TL de la COVID-19 et 1) la proportion de la population souffrant de MCV (ρ= 0,40, P = 0,001), 2) la proportion de la population ≥ 65 ans (ρ= 0,43, P = 0,0005), et 3) l'indice CSU (ρ= 0,27, P = 0,03). Pour chaque augmentation de 1 % de la proportion de la population ≥ 65 ans ou de la proportion de la population souffrant de MCV, le TL de la COVID-19 était respectivement supérieur de 9 % et 19 %. Environ 1 252 interventions seraient reportées chaque mois en Ontario en raison des mesures de santé publique actuelles. CONCLUSIONS: Les pays où les MCV sont plus répandues ont signalé un TL de la COVID-19 plus élevé. Il est probable que les ressources de soins de santé soient soumises à de fortes contraintes au Canada.

A cross-species investigation of acetylcholine, attention, and feature binding.

The binding problem is the brain's fundamental challenge to integrate sensory information to form a unified representation of a stimulus. A recent nonhuman animal model suggests that acetylcholine serves as the neuromodulatory substrate for feature binding. We hypothesized that this animal model of cholinergic contributions to feature binding may be an analogue of human attention. To test this hypothesis, we conducted a cross-species study in which rats and humans learned comparable intramodal feature-conjunction (FC) and feature-singleton (FS) tasks. We challenged the cholinergic system of rats using the muscarinic antagonist scopolamine (0.2 mg/kg) and challenged the attentional system of humans by dividing attention. The two manipulations yielded strikingly similar patterns of behavior, impairing FC acquisition, while sparing FS acquisition and FC retrieval. These cross-species findings support the hypothesis that cholinergically driven attentional processes are essential to feature binding at encoding, but are not required for retrieval of neural representations of bound stimuli.

Characterization of methylphenidate self-administration and reinstatement in the rat.

RATIONALE: Methylphenidate, which is used to treat attention deficit/hyperactivity disorder, increases extracellular dopamine by inhibiting the dopamine transporter. Methylphenidate has an abuse potential, and there are increasing reports of recreational use of methylphenidate. Little work has examined methylphenidate self-administration in rodent models. OBJECTIVES: This work characterized intravenous methylphenidate self-administration in rats, determined whether dopamine mediates its reinforcing effects and examined the influence of route of administration on the ability of methylphenidate to reinstate extinguished drug-seeking behaviour. MATERIALS AND METHODS: Rats were trained to self-administer methylphenidate (0.25 mg per infusion) via an intravenous catheter according to a fixed ratio 1 (FR1) or progressive ratio (PR) schedule. The effects of manipulating the dose of methylphenidate and of treatment with the dopamine D1 receptor antagonist SCH23390 or the dopamine D2 receptor antagonist eticlopride (both at 0.01 and 0.03 mg/kg) were examined. Finally, the ability of noncontingent administrations of methylphenidate (intraperitoneal [IP] or gavage) to reinstate extinguished drug-seeking behaviour was examined. RESULTS: Rats readily self-administered methylphenidate dose dependently on FR1 and PR schedules. Treatment with SCH23390 or eticlopride increased the number methylphenidate infusions taken by rats on the FR1 schedule and reduced breaking points on the PR schedule. Following extinction of drug-seeking behaviour, methylphenidate reinstated responding and was more effective at doing so when administered IP. CONCLUSION: These results demonstrate that intravenous methylphenidate is a reinforcer and that its reinforcing efficacy is related to increased dopamine activity at D1 and D2 receptors. Methylphenidate reinstates drug-seeking behaviour; the route of administration modifies this response suggesting that pharmacokinetic factors are important in determining methylphenidate-induced reinstatement.

Cholinergic influences on feature binding.

The binding problem refers to the fundamental challenge of the central nervous system to integrate sensory information registered by multiple brain regions to form a unified neural representation of a stimulus. Human behavioral, neuropsychological, and functional neuroimaging evidence suggests a fundamental role for attention in feature binding; however, its neurochemical basis is currently unknown. This study examined whether acetylcholine (ACh), a neuromodulator that has been implicated in attentional processes, plays a critical role in feature binding. Using a within-subjects pharmacological design and the cholinergic muscarinic antagonist scopolamine, the present experiments demonstrate, in a rat model, a critical role for the cortical muscarinic cholinergic system in feature binding. Specifically, ACh and the attentional resources that it supports are essential for the initial feature binding process but are not required to maintain neural representations of bound stimuli.

The nucleus basalis magnocellularis contributes to feature binding in the rat.

The binding problem refers to the fundamental challenge of the central nervous system to integrate sensory information registered by multiple brain regions to form a unified neural representation of a stimulus. Although the human cognitive literature has yielded substantial insights into the attention-dependent nature and general cortical networks involved in feature binding, the specific downstream neuroanatomical modulatory contributions to feature binding remain unknown. We hypothesized that the nucleus basalis magnocellularis (NBM) of the basal forebrain would be critical for feature binding given the NBM's widespread neuromodulatory projections to regions of the neocortex important for attentional processing, such as the frontal and parietal cortices. Accordingly, we tested the ability of rats with bilateral excitotoxic (quisqualic acid) lesions of the NBM to acquire a crossmodal Feature-Conjunction (FC) task that required feature binding and a Feature-Singleton (FS) task that did not require feature binding. Additionally, rats retrieved a FC stimulus set they had acquired prior to surgery. Relative to sham-lesioned controls, NBM-lesioned rats were significantly impaired at acquiring and retrieving the FC task, while their ability to acquire the FS task remained intact. These findings provide insight into the functional role of the NBM and establish the importance of this basal forebrain structure to the fundamental cognitive process of feature binding.

Fatigue and shift work.

Shift work is a ubiquitous phenomenon and its adverse effects on workers' physical and mental health have been documented. In the sleep literature, differentiating between the symptoms of fatigue and sleepiness, and developing appropriate objective and subjective measures, have become very important endeavors. From such research, fatigue and sleepiness have been shown to be distinct and independent phenomena. However, it is not known whether shift work differentially affects fatigue and sleepiness. In an attempt to answer this question, 489 workers from a major Ontario employer completed a series of subjective, self-report questionnaires, including the Fatigue Severity Scale (FSS) and the Epworth Sleepiness Scale. Workers were separated into four groups based on the frequency with which they are engaged in shift work (never, fewer than four times per month, 1-2 days per week, 3 days or more per week). The frequency of shift work was found to have a significant effect on subjective fatigue, but not on subjective sleepiness. Compared with the subjects who never had a shift schedule, those who worked in a shift for 3 days or more had significantly higher mean score of the FSS. In agreement with previous results, a low correlation was found between workers' subjective fatigue and sleepiness scores, providing further support for the concept of fatigue and sleepiness as distinct and independent phenomena. Future research should address the possibility of using the FSS as an indicator when the frequency of shift work has become high enough to adversely affect work performance or cause health problems.

The geometric module in the rat: independence of shape and feature learning in a food finding task.

Rats found food in a rectangular enclosure in three experiments testing how learning about a distinctive feature near a goal interacts with learning based on the geometry of an enclosure. Rats trained to follow a feature in square and triangular enclosures and to use geometry in the rectangle followed the feature when it was in the rectangle (Experiment 1). Rats trained with the feature in a geometrically consistent corner of the rectangle learned about both geometry and the feature (Experiment 2). Training with the feature in the square did not block learning of geometry when both predicted the location of food in the rectangle (Experiment 3). The "geometric module" (Cheng, 1986) may have a special status in spatial learning.