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Ancient medicine drugs containing the alkaloid rhynchophylline (RHY) increase sleep duration and quality in humans. Although treatment with RHY alone has not been tested in humans, rodent studies suggest that it modulates cellular pathways involved in sleep/wake regulation by targeting ion channels and kinases. Interestingly, RHY can inhibit EphA4, and EphA4-/- mice have sleep alterations. We thus studied effects of RHY on sleep and related molecular mechanisms. The electrocorticogram was recorded in male and female mice receiving 50 or 100 mg/kg of RHY (or saline) at light onset and 1h before light offset. Sleep architecture and spectral activity were examined. Additional groups had their brains sampled 3h after each injection to assess changes in the transcriptome with a high spatial resolution. In both sexes, RHY decreases wake and increases NREM sleep during the dark period, and reduces REM sleep during the light period. Moreover, RHY shortens individual bouts of wake and NREM sleep. RHY also enhances activity in low frequencies in wake and modifies the time-course of NREM sleep delta and sigma activity. Preliminary results in females suggest that Rhy affects the expression of genes such as Sgk1 similarly at the beginning of the light and dark periods, while its impact on mitochondrial genes and genes expressed in the hypothalamus appears time-dependent. RHY modifies sleep in manners similar to EphA4-/- mice, but additional effects may suggest EphA4-independent mechanisms. The transcriptomic approach will help defining how RHY impacts wake/sleep regulatory circuits.

CAN-ACN 2021

The traditional Chinese medicine component Rhynchophylline modifies sleep and the brain spatial transcriptome in mice

sex-differences

rhynchophylline

transcriptomics

sleep

electroencephalogram

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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

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.

Systemic M1 muscarinic acetylcholine receptor activation can restore aging-related object memory updating deficits in mice

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.

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

Bipolar disorder (BD) is associated with language disturbances such as speech pressure and poverty of speech. However, little is known about the neurophysiology underlying language deficits in BD. In a previous study, we extracted three functional brain networks (i.e., a linguistic processing network - LPN, default mode network - DMN, and motor response network - RESP) involved in the lexical decision (LD) task by manipulating the "word-likeness" of LD stimuli combined with a multivariate functional connectivity analysis in healthy adults. Here, we applied the same techniques to determine if these three networks could be extracted in people with BD. The BD patients (n = 25) were also compared to controls (n = 21) to assess possible difficulties in LD task performance and abnormal activity in the three functional networks in BD. There were no differences between BD patients and controls in their accuracy or reaction times in the LD task. We replicated our previous work in healthy subjects as we were able to separate the LPN from the DMN and RESP. LPN activity did not differ between the groups, which is in line with the lack of significant differences in LD task performance between BD and control. BD was associated with sustained activity in the RESP, which involves activations in left-dominant pre- and post-central gyri and juxtapositional lobule cortex, as well as bilateral activations in superior and inferior lateral occipital cortex, superior parietal lobule, and occipital fusiform gyrus. Impairment in RESP may be observed in any task and could potentially be a biomarker for BD.

Altered activity in functional brain networks involved in lexical decision in bipolar disorder

It has been proposed that a context paired with ketamine (KET) can elicit an antidepressant response through principles of Pavlovian conditioning. This raises the question as to whether this conditioned antidepressant response is unique to KET, or whether it can be generalized to other antidepressant drugs with known pharmacological mechanisms like the serotonin reuptake inhibitor, escitalopram (ESC), or the norepinephrine-dopamine reuptake inhibitor, bupropion (BUP). Thus, the current study investigated whether a context paired with KET, ESC, or BUP could influence the immobility response to forced swimming stress (FSS; 10 mins/session, 3 sessions total), which is a preclinical tool used to assess the antidepressant efficacy of drugs. To do this, male Sprague-Dawley rats were injected with 0.9% saline (w/v; SAL) and placed in a vehicle-paired context (CS-) and injected with SAL, KET (10 or 20 mg/kg, IP), ESC (10 mg/kg, IP), or BUP (10 mg/kg, IP) and placed in a drug-paired context (CS+) on alternating days (10 days total, 5 pairings each in the CS- and CS+). One week later, rats were exposed to 3 sessions of FSS over 3 consecutive days (FSS1-3; exposure to CS- and CS+ prior to FSS2 and FSS3, respectively). Exposure to a KET-paired context prior to FSS3 significantly reduced immobility without affecting general locomotor activity in comparison to contexts paired with SAL or BUP, but not ESC. These findings support the notion that a KET-paired context elicits a conditioned antidepressant response, and that this response may partially involve serotonergic mechanisms.

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