Canada

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.

CAN-ACN 2021

Effects of androgens on behavioural flexibility in male rats

testosterone

behavioural flexibility

set-shifting

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)



Please head to https://can-acn.org/meeting-2021/registration-2021/ to register. 

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

poster

Neurons of the hypothalamic arcuate nucleus (ARC) integrate nutritional signals to modulate energy balance. Evidences suggest that the underlying mechanisms involve the release of fatty acids (FA) from intracellular lipid droplets (LD). This model is supported by data from our lab showing that neurons can form and accumulate triglycerides in LD. In addition, our data and single-cell RNAseq studies show that Adipose Triglyceride Lipase (ATGL) is expressed in ARC pro-opiomelanocortin (POMC) neurons that play a crucial role in energy balance. Thus, we propose that ATGL in ARC POMC neurons is involved in energy balance control by regulating LD lipolysis. To test this, we quantified LD and oxidation of FA in hypothalamic neurons (cell lines and primary cultures) treated with oleate, forskolin (ATGL activator in adipose tissues), or Atglistatin (ATGL inhibitor). Also, we generated POMC specific ATGL KO mice (Cre-Lox) which were subjected to metabolic phenotyping. Our results show that hypothalamic neurons accumulate LD in response to Atglistatin/oleate, forskolin decreases LDs via ATGL and Atglistatin decreases the oxidation rate of LD-derived FA. Our lipidomics data show that palmitate and oleate are the major FA in neuronal LD. In our mouse model, ATGL KO in POMC neurons does not affect body weight or food intake in chow-fed males. These animals will be subjected to metabolic challenges (high fat diet) to assess the role of ATGL in adaptive metabolic responses. Our data show for the first time that hypothalamic neurons can accumulate LD and that ATGL activates LD lipolysis.

Feeling hungry? The role of fat stores in hypothalamic neurons on energy balance

Social defeat is a preclinical model to study the effects of chronic psychosocial stress in rodents, as it recapitulates many stress-induced pathologies observed in humans, including metabolic changes. This model, however, is based off male territorial aggression that is not applicable to female rodents. To investigate how females respond to psychosocial stress, we tested two adaptations to the social defeat paradigm to study the effect of chronic stress on metabolism in females. In the first paradigm, fighting females, a female and castrated male CD-1 are cohoused for several days, priming the CD-1 female to display territorial behaviors towards an intruding C57 female mouse. In the second paradigm, non-discriminatory social defeat, we introduced a C57 male and female simultaneously to a CD-1 male mouse. The intruding male provokes territorial aggression towards both the male and female mice. We tested both paradigms for 21-days and gave mice access to chow and a high fat diet, ad lib. Females in the non-discriminatory model displayed changes to hormone levels and metabolism commonly associated with chronic stress. These mice increased their consumption of the standard chow diet, high in carbohydrates, when stressed and had elevated ghrelin and corticosterone levels. Females from the fighting female's paradigm, however, did not display the same markers of chronic stress. Our results highlight discrepancies in the magnitude of stress elicited by each paradigm, with the second paradigm inducing metabolic changes in females commonly observed in males following social defeat.

Chronic stress & metabolism in females: evaluating two novel models of female social defeat stress

Circadian rhythms, 24-hour oscillations within an organism generated by biological clocks, keep temporal order of molecular, physiological, and behavioral processes with respect to daily changes in the environment, thus enabling systemic homeostasis and proper function of the biological system. A multi-oscillatory network of circadian pacemakers, comprising a central clock in the suprachiasmatic nucleus of the hypothalamus, and peripheral clocks located in other brain regions and tissues throughout the body, sustains tissue-specific rhythms, such as in the striatum. The striatum, a region of the basal ganglia that receives dopaminergic input from the midbrain, controls motor functions and behavioral processes related to mood and reward. Proper function of the striatum is presumably maintained by a mutual interaction of components of the circadian clock and the dopamine signalling pathway. Using a conditional knockout of the core clock gene Bmal1 within medium spiny neurons (MSNs) of the striatum, we assessed the molecular, physiological, and behavioural consequences of striatal clock malfunction. Male and female knockout mice showed deficits in motor coordination and control, but were less affected in mood-related tests. Daily rhythms of gene expression, primarily targeting the circadian clockwork and cell signalling pathways, were also studied, in addition to measurements of mitochondrial respiration in MSNs. Preliminary results indicate changes in molecular and physiological processes in MSNs of knockout animals, that may contribute to the observed behavioural phenotypes.

Molecular and behavioural consequences of a striatal bmal1 knockout in mice

Gonadal and adrenal steroids play a fundamental homeostatic role in the brain, maintaining the hippocampal-neocortical circuitry, which is important for learning, memory and mood regulation. Previous work in our laboratory has demonstrated changes in hippocampal dendritic morphology in males, but not females, following gonadectomy. Acute glucocorticoid exposure in male rats mirrored this effect, suggesting that surgical stress results in pruning of the hippocampal CA3 apical dendrites. The consequences of short-term stress in females have not been as well characterized. We investigated the effects of acute glucocorticoid exposure in cycling female Sprague-Dawley rats by treatment with the synthetic glucocorticoid Dexamethasone (DEX) in the drinking water for 16h, at a dose designed to mimic the effects of acute stress. The animals were sacrificed during proestrus, when circulating estradiol (E) levels are at a maximum. DEX significantly decreased apical dendritic spine density in CA1 and CA3 at 1 and 5 days following treatment. The dendritic branching patterns and length were significantly increased in CA3 dendrites at 1 day. These effects were accompanied by increased phosphorylation of the MAPK signaling proteins, ERK and JNK, as well as increased levels of the ERK-specific phosphatase, DUSP6. These results indicate differences between the sexes in the effects of brief glucocorticoid exposure on hippocampal neuronal structure, possibly as a result of E-induced increases in the activity of the MAP kinase pathways involved in dendrite growth, in females but not in males.

Effects of short-term glucocorticoid exposure on hippocampal neuronal structure and signaling pathways in female rats

Advancements in Ultrasound techniques such as Transcranial ultrasound or TCS, led us to detect Structural disturbances such as echogenicity changes of the brain raphe, as well as the assessment of the diameter of the third ventricle, in many psychiatric disorders such as type 2 bipolar mood disorders, major unipolar depression, psychosis as well as organic - neurodegenerative disorders, etc. Various similar studies indicated that tissue degeneration involved in functional neurons of the serotonergic and dopaminergic systems in the limbic system, brainstem networks. There is a lack of consensus among researchers in previous studies on type 1 bipolar mood disorder, which guided us to conduct our research. In this observational case-control study,80 samples, including 27 patients with confirmed nonpsychotic type 1 bipolar disorder, hospitalized at the psychiatric ward and 53 subjects in the correlated healthy control group, were randomly selected. Respectively Transcranial ultrasound or TCS was performed in order to find out the disturbances of brain stem Raphe Echogenicity and also determining the 3rd ventricular diameter. Considering the disappearance of the structure as abnormal structure, 9 (33.3%) of patients and in comparison with the control group, 5 subjects (9%) showed a significant depletion in RN echogenicity. Also, 7 patients and 3 controlled subjects showed a significant third ventricular diameter elevation. In this study, we concluded that the echogenicity of brain stem Raphe was significantly reduced (p-value: 0.008) and the Diameter of the third ventricular significantly increased (p-value: 0.01) among the nonpsychotic type 1 bipolar patients comparing to the healthy correlated control group.

Mesencephalic transcranial ultrasound in patients with type 1 bipolar mood disorder showed Raphe nucleus hypoechogenicity and 3rd ventricle diameter elevation in comparison with the control group.

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.

Effects of androgens on behavioural flexibility in male rats

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