Canada

Dopamine (DA) connectivity in the prefrontal cortex (PFC) continues to unfold until early adulthood, with dramatic organizational and functional changes occurring during adolescence. This delayed development involves long-distance axonal growth of midbrain DA neurons across the adolescent period and is mediated by the Netrin-1/DCC guidance cue pathway. We examined whether repeated social stress in adolescence dysregulates the Netrin-1/DCC pathway, disrupting PFC DA innervation and cognitive control in adulthood. We used a modified accelerated social defeat stress (ASD) model and segregated mice into resilient (RES) and susceptible (SUS) groups by measuring social avoidance in a social interaction test (SIT) 24h after ASD exposure. ASD in adolescence downregulates DCC expression in DA neurons in SUS and RES groups, but its effects on PFC DA development and behavior differ between phenotypes. ASD-induced molecular, cellular and behavioral changes are not observed following ASD exposure in adulthood. While most (~60%) mice exposed to adolescent ASD show RES, most adult mice show stress SUS. Alterations in dopamine development in adolescence may mediate the established link between genetic variance within the Netrin-1/DCC pathway and psychiatric disorders of neurodevelopmental origin.

CAN-ACN 2021

Stress in adolescence alters guidance cue pathways and impacts dopamine development

netrin-1

impulse control

prefrontal cortex

social stress

sex differences

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

technical paper

Bisphenol A (BPA) is an industrial chemical extensively used in the production of polycarbonate plastics and epoxy resins, resulting in sustained low levels of human environmental exposure. BPA has been a particular focus of concern, due to its endocrine disrupting properties, including effects on metabolic processes, as well as on the central nervous, reproductive and immune systems. Low dose BPA exposure attenuates spatial and non-spatial memory performance, while also reducing the neuroplastic effects of sex steroids in the brain. These effects have prompted replacement of BPA with structurally-related chemicals, such as bisphenol S (BPS). However, whether BPS is actually safer is an open question because its biological effects have not yet been fully explored. In this study, we directly compared the effects of BPA and BPS exposure on spatial memory in mice. Adult male and female CD-1 mice were exposed to BPA or BPS via voluntary, oral administration in a small quantity of peanut butter for 10 days. Both bisphenols were administered at the US Food and Drug Administration "safe daily limit" for human BPA exposure (50ug/kg b.wt./d). Mice were then tested in a home cage object-placement paradigm, followed 24h later by brain tissue and serum collection for neuronal morphological and hormone analyses, respectively. Both BPA and BPS reduced memory performance, in a non sex-specific manner. Thus, the most widely used BPA replacement, BPS, may not be a "safer" alternative than BPA, at least as far as effects on cognitive function are concerned.

The effects of bisphenol S exposure on memory in gonadally intact male and female mice

Why do we make bad choices? A behavioral economist might look for algorithmic or psychological bounds on rational decision-making. However, decision-making can also be bounded by hardware: by constraints on how well our brains can represent the offers in front of us. Fortunately, emerging mathematical tools mean that we can now directly examine how information is represented in neuronal populations. Here, we applied these tools to neuronal recordings from the ventromedial prefrontal cortex (vmPFC, area 14), a part of the prefrontal cortex implicated in economic decision-making. In contrast to what we expected from single-neuron studies, offer values were not represented linearly in the vmPFC population. Instead, value traced a predictable, but curvilinear manifold through neuron-dimensional space. This curvilinear geometry predicted a surprising violation of rational choice theory: a violation of the axiom that terrible offers--offers that will never be chosen--should not affect preferences between better offers. Indeed, we found that monkeys were more likely to confuse two good options when a third, irrelevant offer was worse, compared to when the third offer was better (when the set should have been harder to discriminate, not easier). Past theoretical work showed that linear representations of value could permit neural circuits to generate rational economic decisions. However, our results suggest that the neural representation of value is nonlinear. This nonlinearity could contribute to the systematic patterns of irrational choice highlighted in behavioral economics.

Irrational choice via curvilinear value geometry in ventromedial prefrontal cortex

Second order conditioning (SOC) of fear forms when a previously shock-paired conditioned stimulus (CS1) is associated with a new neutral stimulus (CS2).CS2 acquires the same negative valence as CS1, indicated by freezing behaviour in rats. SOC has been shown to engage transcriptional and epigenetic mechanisms in the basolateral amygdala (BLA). However, whether other sensory areas are involved in SOC is not known. Here we conducted cFos and epigenetic marker mapping in rat brains after fear memory retrieval upon CS2 presentation. Odor, context, and tone may be used interchangeably as conditioned stimuli to produce SOC in rats. We first compared cFos activation across multiple brain regions upon presentation of a shock-paired odor CS1, or an odor CS2, CS1 being a tone or context. Following conditioning, shock-paired odor CS1 presentation enhances cFos expression in the anterior BLA, piriform cortex, and dorsal and ventral CA1. Similar patterns of cFos are observed if an odor CS2 has been associated with a context CS1. However, when a tone serves as CS1, odor CS2 enhances cFos expression in the auditory cortex. We then mapped changes in epigenetic markers for histone acetylation (H3Ac, H4ac) and DNA methylation (5MC) following tone CS1 + odor CS2 conditioning. A CS1/CS2 unpaired group was used as a control. The conditioned group showed elevated H3Ac and H4Ac expression in the BLA and piriform cortex. Moreover, the elevated H4Ac in the dorsal hippocampus of conditioned group was observed. Our data suggests that primary sensory cortices and the hippocampus are involved in SOC.

Brain regions and epigenetic mechanisms involved in second order fear conditioning

Interoceptive stimuli elicited by drugs of abuse form associations with exteroceptive cues. Feature positive (FP) and feature negative (FN) occasion setters disambiguate associations of exteroceptive conditioned stimuli and appetitive unconditioned stimuli. Here we investigate whether morphine can act as an occasion setter, and also determine the effect of this learning history on morphine reward. Male and female rats were assigned to FP or FN training, and received daily intermixed morphine or saline injections before each training session. On morphine sessions, FP rats received white noise (WN) presentations that were followed by access to sucrose, but withheld on saline sessions. FN rats learned the reverse contingency. After conditioning, rats underwent place conditioning, and morphine was paired with a distinctive context of a 2-sided chamber. In pairing sessions, rats received alternating morphine or saline injections and access was restricted to the appropriate side. When rats were tested for preference, they had access to both sides of the chamber following no injections. Training with morphine as an occasion setter resolved the ambiguity of reward-predictive exteroceptive cues. In male rats, regardless of learning history, rats spent more time on the morphine-paired side of the chamber. In female rats, however, a history of FP learning increased the rewarding value of morphine compared to FN learning. These data indicate that a history of learning affects the rewarding value of morphine differently in male and female rats.

Morphine as an interoceptive discriminative stimulus alters morphine reward in female rats

Interoceptive sensations elicited by drugs of abuse can form associations with surrounding stimuli in a manner similar to externally perceived (i.e., exteroceptive) cues. A wide range of interoceptive stimuli have been established to guide behaviour in male rats. Here we extend that research to an opioid agonist stimulus, in both males and females. We predicted that when paired with an appetitive outcome, morphine could imbue that drug state with increasing appetitive value. Male and female rats were assigned to a feature positive (FP) or feature negative (FN) group and received daily intermixed morphine or saline sessions. For FP rats, on morphine sessions, each white noise (WN) presentation was followed by access to sucrose; on saline sessions, WN was still presented, but sucrose was withheld. FN rats learned the reverse contingency. After conditioning, rats learned to lever-press for intravenous access to morphine to assess motivation for the interoceptive stimulus. Indeed, morphine can resolve the ambiguity of reward-predictive cues in male and female rats. In males, an appetitive learning history with morphine imbued the interoceptive stimulus with conditioned reinforcing properties such that FP males showed greater morphine self-administration compared to FN counterparts. In contrast, there were no differences in morphine self-administration between FP and FN-assigned female rats. These data indicate that the valence of a learning history with an internally-perceived stimulus can alter its subsequent reinforcement value in a sex-dependent manner.

Investigating the conditioned enhancing properties of a morphine interceptive discriminative stimulus in male and female rats

Physical activity and healthy eating are vital elements for establishing metabolic and mental health. We recently showed that unhealthy snacking is a strategy used to cope with stress during the coronavirus disease 2019 (COVID-19) pandemic. Here, we implemented a longitudinal survey with 319 participants in May (Phase P1) and October 2020 (P2) to assess whether physical activity can improve mood and mental health outcomes over time. There was a decrease in leisure-time physical activity, but not on-the-job activity, from P1 to P2. Lower leisure-time physical activity in P1 was associated with appraisals of uncontrollability in P2. These appraisals predicted worsened mood, and increased feelings of depression, anxiety, or stress in P2. We then conducted mediation models to determine if uncontrollability underlies the relationship between P1 leisure-time physical activity and subsequent mood and mental health outcomes in P2. Interestingly, we found that when situations were appraised as uncontrollable in P2, the level of leisure-time physical activity in P1 was predictive of worsened mood and mental health outcomes in P2. In aggregate, we surmised that physical activity at the onset of the pandemic indirectly predicted mood and mental health outcomes 4 months later. This suggests that physical activity may protect against the widespread stress and lifestyle changes inflicted by COVID-19.

Impact of physical activity at the onset of the COVID-19 pandemic on mood and mental health over time

The set of behavioral strategies we develop to manage stress stems from social interactions. Similarly, chronic stress models in rich environments in mice models, simplify the analysis of environmental and social factors using an automated assessment and tracking system. In a large group, mice are so influenced by pressures from other members of the group that over time, the evolutionary structure is formed by the social hierarchy in the group. For example, in this evolutionary structure, in rich and complex environments, group members interact with each other, sometimes play, and sometimes fight with each other to prove their dominance to the group. The behavioral ability that each mouse exhibits during daily life to control stress determines its status in the colony. The goal of this project is to develop an automated behavioral platform using machine-based units and a radio-frequency identification system (RFID) to evaluate the behaviors resulting from chronic variable stress (CVS) in male and female mice in groups ethically. To achieve our goals, we have developed two smart vivariums (1m x1m) equipped with high-quality cameras including various components such as beddings, enrichments, food, nesting material, games and toys, bridges, and ropes for each group of male and female. We control the behavioral characteristics of different groups up to a maximum of 10 people for 6 weeks by these smart vivariums at the same time for both mice groups and finally archive them in cloud data storage. To that end, we created an extensive library of several thousand images of different mice to automatically detect these individual or group behavioral characteristics by tracking them through a hybrid machine system consisting of DeepLabCut and YOLO with an RFID system.

The smart vivarium v1.0: implementation and validation

AIM: Opioid withdrawal can be associated to environmental cues through classical conditioning to produce conditioned withdrawal. Recent preclinical evidence suggests that exposure to these cues can have profound cognitive effects and can play a role in the addiction by enhancing memory consolidation. To further understand the neurobiological mechanism by which cues influence memory, this study investigated the roles of two stress neuromodulators: noradrenaline and corticotrophin-releasing factor. METHODS: In Experiment 1, 0-3 mg/kg naloxone, 0.1 - 0.6 mg/kg lofexidine (alpha-2 adrenergic agonist) and 10 - 20 mg/kg antalarmin (CRF1 antagonist) were co-administered shortly after training on the object recognition task to heroin-dependent rats (via subcutaneous osmotic mini-pumps; 3.5 mg/kg/day). In Experiment 2, heroin-dependent rats were confined for 2 hours in a context (CS ) following naloxone injections and in another context (CS-) following vehicle injections. The effects of immediate post-training exposure to the CS (or CS-) and co-administration of lofexidine and antalarmin were tested 7 days after removal pumps. RESULTS: It was found both lofexidine and antalarmin dose-dependently blocked the enhancement of object memory consolidation by post-training naloxone precipitated withdrawal and by conditioned withdrawal. CONCLUSIONS: These experiments suggest that pharmacological and psychological withdrawal have significant effects on memory storage by activating noradrenergic and CRF stress systems.

Antagonists of noradrenergic and corticotrophin-releasing factor receptors block enhancement of memory consolidation by heroin withdrawal and conditioned heroin withdrawal

Major psychiatric diseases (MPDs), including schizophrenia, are diagnosed very late, due to the lack of effective biomarkers. Post-mortem analyzes show that the lipid composition of neuronal membranes differs in people with schizophrenia. This difference is also reflected in several types of cells, including red blood cells (RBCs). RBCs are known to exhibit spectacular biomechanical properties (BPs) resulting in unique deformability capacity and spontaneous membrane vibrations at the nanoscale . It has been reported that the lipid composition of the RBC membranes affects these BPs. An accurate biomechanical characterization of RBCs could thus reveal MPD-related phenotypes. Quantitative Phase Digital Holography Microscopy (QP-DHM), providing images with a nonmetric axial sensitivity, represents a highly relevant technique to quantitatively study the RBC biomechanics. As a first step to identify MPD-related RBC phenotypes, we have started to develop a methodology based on QP-DHM to characterize RBC biomechanics. Studies are conducted in different conditions known to specifically impact RBC BPs. Concretely membrane vibrations and RBC deformations are monitored in environments controlled for temperature, ph, O2 and CO2 partial pressures. We are also going to start a biomechanical study of RBCs obtained from mice, having benefited from a strict diet allowing a control of their membrane lipid composition. Then, aiming at identifying MPD-related RBC phenotypes, we will apply this methodology on our clinical data set, composed or RBC samples collected from patients suffering for MPDs.

Exploration of the red blood cell biomechanics with digital holographic microscopy: Towards a methodology to identify cellular phenotypes related to major psychiatric disorders

The atypical spectrum of mood disorders includes a variety of phenotypes characterized by unusually high sensitivity to environmental factors as well as increased eating behaviour and weight gain. In the case of Seasonal Affective Disorder, the environmental sensitivity relates to highly predictable photoperiodic phenomena tied to the seasons of the year. In the case of DSM-defined atypical depression, the environmental sensitivity relates to the social realm as reflected in the construct of rejection sensitivity. Patients with various forms of binge eating are highly sensitive to both appetitive and non-appetitive stimuli over time. Our group has been interested in identifying gene-environment interactions that might explain why certain individuals are more prone to develop these disorders characterized by environmental sensitivity and overeating/weight gain. Our primary genetic focus has been on the seven-repeat allele (7R) of the DRD4 gene because it is a hypo-functional variant that is likely to influence dopamine system functioning over the lifespan. There is also significant evidence that the 7R allele moderates phenotypic development in the face of various environmental signals. The current talk will review various findings linking the 7R allele to increased environmental sensitivity in patients with Seasonal Affective Disorder, bulimia nervosa and to young children exposed to various levels of maternal sensitivity in the early postnatal period. The possible evolutionary and clinical significance of these findings will also be discussed.

Stress in adolescence alters guidance cue pathways and impacts dopamine development

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