Canada

Current hypotheses propose that sleep/wake regulation depends on both the circadian clock and a homeostatic process. The glycogen synthase kinase-3 beta (GSK3b) regulates the activity of key circadian transcription factors (e.g., BMAL1, CLOCK). GSK3b is also involved in long-term depression and metaplasticity. Moreover, FXR1, a GSK3b substrate, has recently been shown to affect both cell-autonomous homeostatic plasticity and system-level response to sleep loss in a GSK3b-dependent manner. This project thus aims to investigate a potential role of GSK3b in circadian and homeostatic sleep/wake regulation by verifying how its knockdown (KD) in cortical neurons impacts vigilance states under normal (baseline: BL) and sleep-deprived (SD) conditions. A neuron-specific KD of Gsk3b was achieved in adult male mice via dual adeno-associated virus delivery of a CRISPR/Cas9 system. Cortical viral injections and electrocorticography (ECoG)/electromyography (EMG) electrodes implantation surgeries were done simultaneously 3 weeks prior to ECoG/EMG recording, which comprises 24 h of BL, 6 h of SD, and 18 h of recovery. Analyses notably include vigilance state duration/distribution and ECoG spectral activity. Gsk3b KD did not affect the time spent in wakefulness and sleep states nor the alternation between states. However, the KD of Gsk3b in the motor cortex decreased gamma (30-50 Hz) activity during wakefulness and alpha (8-10 Hz) activity during slow-wave sleep (SWS). Moreover, a SD-induced increase in beta/gamma (20-50 Hz) activity during SWS was found in the visual cortex only under Gsk3b KD. These results support a role for GSK3b in the regulation of ECoG activity during wakefulness and sleep, and bring a deeper insight on molecular mechanisms controlling vigilance state quality.

CAN-ACN 2021

Knocking down glycogen synthase kinase-3 beta (GSK3b) in cortical neurons affects the mouse electrocorticogram across vigilance states

electrocorticography

sleep/wake regulation

gsk3-beta

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Colleagues and Friends:

I am very happy to welcome you to the 14th annual Canadian Neuroscience Meeting, and to the first virtual edition of our meeting. I want to highlight the important work the CAN meeting chair, **Roger Thompson** and co-chair, **Alyson Fournier**, did to put together the great program we are offering this year. Moving to a virtual format required a complete re-design of the program, and both Roger and Alyson did a splendid job in providing us with an appealing and well adapted program for our first virtual event. I wish to thank them for this very important effort.

Highlights of this year’s scientific meeting include invited speakers **Michael Hausser, Franck Polleux, Gwyneth Card, Magdalena Götz**and Brain Prize winner **Huda Zoghbi**. Plenary and parallel symposia, proposed by our members complete our diverse [scientific program.](https://can-acn.org/meeting-2021/program-2021/)

The 2021 Advocacy session, chaired and organized by CAN advocacy committee chair **Karun Singh**, will feature a special lecture and question period with Member of Parliament and past Science Minister **Kirsty Duncan**. This will be followed by a short overview of CAN’s advocacy activities over the last year. We invite you to participate in this session for insight from Dr. Duncan on the workings of Parliament Hill, and to learn more about what CAN has been doing to promote neuroscience research in Canada.

We are also excited to host **Lisa Willis** in the Equity Diversity and Inclusion session, organized by EDI committee chair **Jibran Khokhar**.

A special highlight of our meeting will be the lectures by award-winning young neuroscientists. We are please to host the CAN 2020 Young Investigator Award winner **Mihaela Iordanova**, and CAN 2021 Young Investigator Award winners **Aaron Phillips** and **Tabrez Siddiqui**. Highlights will also include presentation by the top three winners of the CAN-CIHR-INMHA Brain Star Award winners, **Claire Gizowski, Nuria Daviu Abant** and **Lukas Tamayo-Orrego**.

Independently organized satellite symposia complement and complete this exciting program, check them out here: https://can-acn.org/meeting-2021/2021-satellite-symposia/

Some of the most engaging sessions are always the poster sessions featuring the work of our trainees, so make sure to log in to Gather Town during the poster sessions to chat with the presenters.
We hope you enjoy this program, and look forward to welcoming you, virtually.

Shernaz Bamji

President of the Canadian Association for Neuroscience

![](https://assets.underline.io/uploads/markdown_image/1/image/b9aea25343a87d5aac3b9367dc780974.jpg)



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14th Canadian Neuroscience Meeting from August 23rd-25th

Early life stress (ELS) increases vulnerability to psychiatric disorders associated with emotional dysregulation. The corticolimbic circuit is important for fear conditioning and is highly sensitive to environmental stressors during early development. Using the limited bedding paradigm (LB) between postnatal days (PND)1-10 as a model of ELS, we examined the functional consequences of ELS on glutamatergic tone in the infralimbic (IL) and prelimbic (PL) medial prefrontal cortex (mPFC) during the juvenile period, a time of peak GABAergic inhibitory tone. We measured glutamate concentrations during fear conditioning using in vivo microdialysis in behaving juvenile (PND28-32) rats. We report that while LB conditions enhanced behavioral fear expression in juvenile males but not females, fear-induced glutamate response in the right PL, but not IL mPFC was diminished in male LB offspring compared to controls. To estimate ELS effects on parvalbumin (PV) interneurons and their maturational state, we determined PV neuronal density and the proportion of PV neurons expressing perineuronal nets (PNNs). Formation of PNNs is associated with the closure of periods of plasticity and stabilizes GABAergic output of PV neurons. Total PV population in PL mPFC was not altered by ELS in male juveniles, but fewer PV neurons expressed PNNs. These results suggest that ELS differentially affects glutamatergic neurotransmission in the PL and IL mPFC during fear conditioning in juveniles and might delay the maturation of PNNs around PV interneurons and maintain a higher inhibitory tone in the PL mPFC.

Early life stress modifies fear-induced glutamate release and parvalbumin interneuron maturation in the medial prefrontal cortex of juvenile rats.

AIM: The co-occurrence of electronic cigarette (e-cigarette) use and alcohol consumption during adolescence is frequent and well documented. However, little is known about their long-term effects on subsequent behavioural outcomes in adulthood. This highlights the importance in elucidating the consequences of concurrent alcohol and nicotine vapour exposure during such a vulnerable developmental period. METHODS: Male and female Sprague-Dawley rats (n=8-11/group/sex) received either nicotine (JUUL 5% nicotine) or vehicle (30:70 propylene glycol to glycerol) vapour daily from post-natal day (PND) 30-46 and had continuous voluntary access to ethanol (10% v/v) or water in adolescence. Upon adulthood, rats began Pavlovian conditioned approach (PCA) testing, where they learned that a lever presentation predicted a non-contingent reward delivery. Preference toward the reward receptacle indicated goal-tracking behaviour. Preference toward the lever indicated sign-tracking behaviour, demonstrating that the lever had acquired incentive salience. RESULTS: Males co-exposed to alcohol and nicotine vapour during adolescence exhibited significantly higher levels of sign-tracking behaviours in adulthood compared to male controls. No significant effects were observed in females. CONCLUSION: Our results support the notion that adolescent co-exposure to alcohol and nicotine vapour produces marked changes in behaviours in adulthood. Delineating the long-term ramifications of alcohol and nicotine vapour will be vital for understanding their interactions when concurrently used in adolescence.

Long-term behavioural effects of concurrent alcohol and nicotine vapour exposure during adolescence in adult male and female Sprague-Dawley rats

Age-related decline in episodic memory for contextual details (context memory) arises in early midlife, and is associated with altered brain activity in the medial temporal lobes (MTL). Previous work has observed that cognitive decline and structural integrity of the hippocampus appear to be tightly coupled across the adult lifespan, and that MTL structure appears to influence memory performance. However, it remains unclear if age-related atrophy within the MTL mediates age-related decline in context memory. Thus, the goal of this project was to investigate the intersection between age-related declines in MTL volume and context memory. We tested 132 participants across the adult lifespan on spatial and temporal context memory tasks. We employed a semi-automated segmentation protocol to segment the perirhinal, entorhinal and parahippocampal cortices, and the anterior and posterior segments of the hippocampus. We then computed multiple mediator models to investigate how MTL volumes mediated age-related declines in context memory. These analyses revealed that age-related atrophy of the posterior hippocampus, but not any other MTL structure, fully mediated the association between age and spatial context memory performance (βab = -0.17, 95% CI [-0.28, -0.07]). Further, we are currently investigating investigating structure-function interactions to assess whether there is a relationship between age-related declines in MTL volume and task-related functional activation in aging.

Age-related declines in context memory and medial temporal lobe volume

Although attention-deficit/hyperactivity disorder (ADHD) is associated with the atypical development of large-scale brain networks, network organization in those with different ADHD-traits (inattention/hyperactivity) is not well understood. Here, we examine the relationship between ADHD traits and EEG functional networks during an attentional control task. To do so, 128-channel EEG was recorded while 62 non-clinical participants (ages 18-24) underwent a Go/No-Go task. Networks were created using EEG sensors as nodes and across-trial phase-lag index values as edges (10% threshold, binarized). Using cross-validated LASSO regression, we examined whether dynamic graph-theory metrics of integration, segregation and modularity predict inattention and/or hyperactivity. In the gamma-band (30-90Hz), and no other frequency bands, a three feature model accounted for a substantial amount of variance in hyperactivity (R2 = .28). This showed that throughout processing (0-500ms, 2ms intervals), networks of those with low hyperactivity: (1) have nodes which tend to remain in the same module (r = -.44, p = .0004), (2) consistently share connections with the same neighbours (r = -.34, p = .007), and (3) take more time to transfer information globally (r = .36, p = .004; all powers > .85). Thus, the well-reported developmental process whereby task-specific systems of brain regions become increasingly specialized might be protracted in the ADHD Hyperactive-Impulsive subtype. Understanding which developmental processes might be altered in ADHD has implications for diagnosis and intervention.

The segregation of task-based EEG networks into functionally specialized systems is reduced in those with hyperactive traits

Recognition memory explores the what, where and when components of episodic memory. Using the animal's natural tendency towards novelty, spontaneous recognition memory tasks allow for the study of the neural underpinnings of learning and memory. Spontaneous recognition memory deficits are common in rodent models of neurodevelopmental disorders, and yet very little is known about the expression of spontaneous recognition memory in young rodents. To address this, we sought to establish the ontogeny of three types of spontaneous recognition memory in mice: object location (OL), novel object recognition (NOR) and temporal order recognition (TOR). In OL, animals must recognize a change in location of a familiar object (where). In NOR, they are presented with a novel object (what). In TOR, animals must distinguish between two objects based on how recently they interacted with them (when). We found that C57/129J mice first displayed recognition memory for OL, at postnatal day (P)21, followed by NOR expression at P25, and lastly expressed TOR memory at P28. No correlation was found between memory performance and total object exploration for any age or task, suggesting that this time of onset is not a result of age-dependent changes in object exploration time. Determining the onset of spontaneous recognition memory tasks in mice is an important first step towards a better understanding of the maturation of episodic memory, and will provide the necessary foundation for the use of these tasks in clinically relevant time points in animal models of disease.

Developmental onset distinguishes three types of spontaneous recognition memory in mice

Behavioural flexibility, the ability to adapt behaviour in response to environmental changes, is regulated by the mesocorticolimbic system. In strategy set shifting, subjects initially learn to use one rule to receive a reward (e.g. select the lever denoted by a cue light, known as cue rule), but then must switch to a new rule (e.g. select the left/right lever, known as response rule). Treatment with androgens, such as testosterone, impairs set shifting. Moreover, we previously showed that decreasing androgens with an androgen synthesis inhibitor (abiraterone) facilitates behavioural flexibility (shift from cue rule to response rule). The effect size of abiraterone treatment, however, was small. To increase the effect size of abiraterone, we modified the set shifting task to be more difficult. Here, we manipulated the order of the shift, the minimum number of learning trials during the initial discrimination, and the presence of reminder trials immediately prior to the set shift. Rats were assigned to one of six different set shifting tasks, which required them to perform either the cue-response shift or response-cue shift with variable numbers of minimum learning trials and with or without reminder trials. Rats performing the response-cue shift made significantly more errors to criterion compared to rats performing the cue-response shift. There were no effects of minimum number of learning trials or reminder trials. Ongoing work will examine the effects of abiraterone on the two types of shift.

Effects of androgens on behavioural flexibility in male rats

Laboratory rodent housing conditions vary significantly across laboratories and facilities. Variation in housing is implicated in animal stress leading to study variability and subsequently the ability to replicate experimental findings. Optimization and standardization of animal housing conditions are necessary to improve animal welfare and data consistency, thereby reducing the number of animals necessary to detect treatment effects. While interest in environmental enrichment is increasing, many studies do not examine the behavior of animals within the home cage, neglecting important aspects of enrichment. To determine the impact of increased vertical home cage area on animal welfare, double-decker cages (enriched), which allow animals to rear (stand on hind legs), were compared to single-level cages (standard), which impede the ability to rear. Home cage welfare was assessed by analyzing ultrasonic vocalizations, fecal corticosterone, rearing and agonistic behavior. Ultrasonic vocalization content was further explored by analyses of call type as defined by a 14 call-type schematic. Contrary to our expectations, rats housed in enriched cages spent more time fighting, produced less 50 kHz calls and had higher levels of fecal corticosterone. Standard caged animals attempted to rear more, but reared for a shorter amount of time due to the height limitation imposed by standard cages. Standard cages restrict some naturalistic behaviors such as rearing, but reduce agonistic behavior which may be attributable to their single-tier organization. Increased home cage height is beneficial, as it permits rats to engage in normal ethological behavior. However, the inclusion of a continuous "upper deck" appears to increase dominance/aggressivebehavior among cage mates.

Ultrasonic vocalization analysis as a novel metric to assess home cage welfare in rats

Exposure to emotional conditioned stimuli (CS) enhance memory consolidation, a process of memory stabilization that involves noradrenergic (NA) activity. However, these CSs not only generate conditioned fear, but they also serve as predictors that a US is about to occur, and this function appears dependent on mesolimbic dopamine (DA) activity. Therefore, this study explored whether both NA and DA are involved in the memory enhancing action of an avoidance CS. Male Sprague-Dawley rats trained on a signalled active avoidance task (8 days; 30 trials/day; 0.8 mA) were exposed to the avoidance CS immediately following the sample phase of the Object Recognition task. Different groups were pre-treated with the ß-noradrenergic receptor antagonist propranolol (0, 10, 20 mg/kg) or the DA D2 antagonist pimozide (0, 0.2, 0.6 mg/kg). All groups were tested for object memory 72h later, in drug free conditions. It was found that immediate post-sample exposure to the avoidance CS in the absence of shock enhanced object memory, and that this effect was dose-dependently blocked by both propranolol and pimozide. Overall, these results indicate that the memory-enhancing effect of an avoidance CS requires both NA and DA neurotransmission.

Analysis of memory modulation by an avoidance cue: role of noradrenaline and dopamine

Ghrelin stimulates food intake in part by increasing motivated behaviours through its receptor (GHSR) in the ventral tegmental area (VTA). Recent data suggest that ghrelin may interact with the endocannabinoid system in the VTA to produce these effects. It is hypothesized that ghrelin may influence this system by stimulating the release of endocannabinoids from dopamine cells through its action on the GHSR, via increased synthesis and accumulation of membrane bound cannabinoid enzymes. Previous data from our lab show peripheral ghrelin injections increases 2AG in the VTA. To examine if ghrelin alters the expression of enzymes that synthesize or degrade 2AG, male and female WT and GHSR KO rats were given an i.p. injection of saline or ghrelin (1 mg/kg). Western blot analysis showed lower VTA MAGL of GHSR KO rats compared to WT. Ghrelin also increased MAGL in the VTA of WT females. Next, we examined the behavioural effects of blocking MAGL/FAAH on ghrelin induced reward seeking behaviour using an exponential operant conditioning paradigm. Rats received a unilateral VTA infusion of endocannabinoid degrading enzymes inhibitor (MJN110/PF-00457845) cocktail (5μg and 3μg/0.5μl, respectively), followed by an infusion of ghrelin (0.5μg/0.5μl). Pre-treatment with the inhibitor cocktail enhanced the effects of ghrelin in the VTA. This suggests that ghrelin may act on the VTA to increase reward seeking behaviours via 2AG regulating mechanisms. Moreover, our data suggest that ghrelin stimulates the production of MAGL as a feedforward regulatory process to regulate 2AG. Funded by NSERC.

Ghrelin, cannabinoids, and motivation: increased food motivation on progressive ratio conditioning through MAGL/FAAH inhibition in a rat model

Memory reactivation (RA) can facilitate trace destabilization, enabling memory updating. Some memories, however, are resistant to modification. Specifically, elderly individuals display deficits in declarative memory updating. There is currently no treatment to target this cognitive impairment, likely because factors mediating RA-based memory updating remain unclear. We propose that cholinergic signalling supports RA-based memory changes. Recent findings in our lab suggest that M1-muscarinic acetylcholine receptor (mAChR) signalling within perirhinal cortex supports object memory destabilization and RA-based updating. Correspondingly, aging research indicates a decline in cholinergic transmission across the lifespan. Therefore, we hypothesize that age-related cholinergic system dysfunction underlies memory updating deficits in elderly individuals. To test this, we used a post-RA object memory modification (PROMM) task--where a reactivated object memory is updated with new contextual information--to assess object memory updating in 3-, 6-, and 12-month-old male mice. 3-month-old mice showed intact PROMM task performance, 6-month-old mice showed a mild impairment, while 12-month-old mice were severely impaired. Subsequently, we administered the M1-selective agonist CDD-0102A prior to object memory RA in the PROMM task in the 12-month-old male mice; remarkably, pre-RA systemic M1-mAChR agonism enhanced PROMM task performance. These results therefore suggest a promising neural target for promoting the modification of inflexible memories in aged populations.

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Early life stress modifies fear-induced glutamate release and parvalbumin interneuron maturation in the medial prefrontal cortex of juvenile rats.

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