Canada

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.

CAN-ACN 2021

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

morphine

conditioned place preference

occasion setting

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

To successfully navigate uncertain environments, we need an algorithm for exploration: a way to ensure that we sample policies whose value is uncertain. We also need a mechanism to reliably follow rewarding policies we discover: a system for exploitation. Understanding how exploration and exploitation are implemented in the brain is a major topic of research in decision-making neuroscience, with several studies pointing to pupil-linked mechanisms. However, these studies relied on ad hoc applications of reinforcement learning models that were not designed to identify exploration. As a result, it is still not clear whether pupil-linked mechanisms predict exploratory behavior per se, much less its neural signatures. Here we applied a novel approach that models exploration and exploitation as latent goal states generating decisions. This allowed us to contrast model-labelled explore and exploit decisions in terms of both (1) pupil size and (2) neural activity recorded in the frontal eye fields (FEF), a part of the prefrontal cortex implicated in sensorimotor decision-making. We found that pupil size was larger during exploration and ramped up in anticipation of exploration. Then, it abruptly decreased below baseline levels at the start of exploitation. Concurrently, pupil size predicted neural signatures of exploration in FEF neurons and neuronal populations. In sum, we found that pupil-linked processes anticipate exploration via disruption of neuronal tuning. Further research will be necessary to identify how exactly pupil-linked mechanism influence exploration.

Pupil size anticipates exploration and predicts disorganization in prefrontal cortex

Objective: The purpose of our study was to determine whether indirect social stress could affect brain areas important for spatial learning and memory in adult rats. Methods: Each week for 10 consecutive weeks, 4 male and 4 female Sprague-Dawley rats were randomly assigned to same-sex pairs. Next, twice daily for 5 consecutive days, one male and one female rat were placed on an elevated platform for 30 min (Platform Stress, PS). The cage-mates of PS animals were considered members of the Bystander Stress (ByS) group (i.e., those receiving indirect stress). As well, Platform Control (PC) animals were simply moved to another room twice daily for 30 min, and the cage-mate of each PC animal was considered to be a Bystander Control (ByC). Spatial learning and memory were then assessed over 5 days using standard training and probe trials in the Morris water maze. The animals were then sacrificed and brain tissue harvested to allow for the assessment of differences in synaptic proteins. Results: Regardless of sex, there were no statistically significant differences among the ByC and ByS animals in either spatial learning [training day four: F (3, 72) = 1.4; p = .24], or memory [F (3, 72) = 1; p = .17]. Conclusion: Our results suggest that ByS may not dramatically affect spatial learning and memory in either male, or female rats. As our next step, we will analyse the synaptic expression and phosphorylation level of several plasticity-related proteins (e.g., GluN1, GluA2, PSD-95) in the hippocampus across the treatment groups.

Would short-term, indirect social stress affect spatial learning and memory in either male, or female rats?

Theta rhythms (4-12 Hz) are crucial for hippocampal network coordination and functions, including memory and anxiety. Lesion and pharmacological studies have shown that the median raphe nucleus (MR) exerts a strong modulation over theta rhythms. However, the MR is composed of mixed neuronal populations, including serotonergic neurons (5-HT) and glutamatergic neurons expressing the vesicular glutamate transporter type 3 (VGLUT3). In this study, we aim to evaluate the contribution of these two largely distinct median raphe neuronal populations to theta rhythm properties. We used optogenetics to activate either 5HT or VGLUT3 neurons in the median raphe (MR) of freely behaving mice. To do so, we injected CRE-dependent AAV vectors in the MR of either SERT-CRE or VGLUT3-CRE mice, to selectively transfect 5-HT or VGLUT3 MR neurons with the excitatory opsin ChETAET/TC. An optic fiber implanted above the MR allowed light delivery and activation of 5-HT or VGLUT3 neurons, while simultaneously recording theta rhythms in the hippocampus during REM sleep and awake locomotion. Our results show that 5HT and VGLUT3 neurons participate in the modulation of hippocampal theta frequency and power. These results suggest a potential role for MR 5-HT and VGLUT3 neurons in the modulation of hippocampal functions such as memory and anxiety.

3Hippocampal theta rhythm modulation by the glutamatergic and serotonergic raphe

Variations in gene expression patterns and cortico-striatal circuit morphology have been linked to sex differences in depression. We investigated gene-by-environment (G*E) interactions between dopamine gene expression in these brain regions and the social environment on depressive symptomatology (CESD-10 scale) in 45-75 y.o. CLSA participants. We computed two biologically-informed genetic scores related to the D4 dopamine receptor (DRD4): 1. predicted prefrontal (PFC) expression using PrediXcan machine learning; 2. expression-based polygenic risk scores for the co-expression gene network in the striatum (STR-ePRS). Using latent profile analysis, we classified individuals based on social network size, support, cohesion, and participation in 3 distinct profiles: low-, medium-, and high-social network support (18/40/42%). In the full sample, G*E interactions were significant for STR-ePRS--with effects driven by men--but not for PFC expression. Analyses by sex revealed significant G*E effects for both DRD4 scores in men (n=7217) but not in women (n=6733). Lower STR-ePRS scores were associated with worse depressive symptomatology for men in the low-support profile. Higher PFC DRD4 expression was associated with worse depressive symptoms for men in the low-support profile but milder symptoms in the medium- and high-support groups. The DRD4 gene network overlapped with gene sets related to cardiometabolic health (blood pressure, BMI, diabetes), suggesting common pathways for physical and mental well-being. Our findings implicate DRD4 and related gene networks as potential moderators of social environmental influences in depression, particularly for male seniors with low social support, consistent with previously reported sex differences in reward sensitivity and decision-making.

Tracing molecular and social pathways to sex differences in depression: An empirical analysis of the Canadian Longitudinal Study on Aging (CLSA)

Tobacco smoking is the main cause of preventable disease in Western Europe and North America. Nicotine is the principal psychoactive agent in tobacco, underlying tobacco's addictive properties. Most preclinical studies on the effects of voluntary nicotine use have used self-administration procedures that provide continuous nicotine access during each self-administration session (Long-access or LgA). However, many smokers consume cigarettes intermittently, rather than continuously throughout each day. Here we gave female and male rats LgA (6 h/day) or intermittent access (IntA; 12 min ON, 60 min OFF, for 6 h/day) to intravenous nicotine (15 µg/kg/infusion), for 12 daily sessions. We then compared the groups on intake, responding for nicotine under a progressive ratio schedule of reinforcement, as well as cue- and nicotine-induced reinstatement of nicotine-seeking behavior after abstinence (measures of relapse). Nicotine self-administration behavior was similar across the sexes and so they were pooled for analysis. LgA rats took more nicotine than IntA rats did. However, the two groups later showed similar responding for nicotine under progressive ratio, and similar cue- and nicotine-induced reinstatement. Thus, intermittent nicotine use is just as effective as continuous use in producing addiction-relevant behaviors, despite significantly less nicotine exposure. Our findings have implications for modeling in rats nicotine-induced changes in brain and behavior at different stages of the addiction process.

Nicotine self-administration behavior under continuous versus intermittent access conditions in male and female rats

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

BACKGROUND AND AIM: Microglia are the principal immune cells of the brain. The consensus today is that once activated microglia/macrophages can acquire a wide repertoire of profiles ranging from the classical pro-inflammatory to alternative and more protective phenotypes. Over the past decade, we and others have shown that optimal and timely activation of microglial cells and innate immunity is instrumental in the control of the inflammation-induced damage to CNS. To add to complexity, increasing evidence suggests a marked sexual dimorphism in the processes associated with microglial activation following different types of brain injuries. At present, the in vivo molecular mechanisms involved in the control of microglia and/or macrophage immune profiles remain elusive METHODS: To decipher the molecular mechanisms underlying microglial activation in vivo, we created a transgenic model in which Flag/EGFP was fused to the N-terminus of the large subunit ribosomal protein L10a and expressed under the transcriptional control of a myeloid specific gene promoter Thus, a simple high affinity immunoprecipitation assay from brain homogenates allows a pull down of the transcriptome and/or proteome from the targeted cell type. By isolating both ribosome-attached mRNAs and peptides, we obtained a snapshot of the dynamic translational state of microglial ribosomes with mRNAs as input and newly synthesized peptides as output. Using this strategy, we identified mRNA and protein signatures associated with microglial activation. RESULTS: By using in vivo model-system for analysis of dynamic translational state of microglia ribosomes with mRNAs as input and newly synthesized peptides as an output, we discovered a marked dissociation of microglia mRNA and protein networks following innate immune challenge. We found that the highly up-regulated and polysome- associated mRNAs are not translated resulting in two distinct and rather divergent microglia molecular signatures: i) a highly specialized immune and pro-inflammatory mRNA signature and ii) a more immunomodulatory and homeostatic protein signature. As molecular mechanism, we discovered a selective 3'UTR-mediated translational suppression of highly expressed immune mRNAs. Furthermore, we identified a novel and previously unknown role for RNA binding protein Serine/Arginine-Rich Splicing Factor 3 SRSF3 as a master suppressor/regulator of innate immune genes translation in activated microglia. CONCLUSIONS: Our recent work suggests involvement of SRSF3 -mediated mechanisms in the modulation of immune profiles of activated microglia in different type of brain injuries and/or pathologies. Better understanding of SRFS3- mediated immunomodulation may open new avenues for therapeutic modulation of innate immune response following brain injuries.

Microglial cells after brain injuries: sexually dimorphic and lost in translation

Microglia are the resident immune cells in the central nervous system (CNS). Originally thought to be primarily responsible for disposing of cellular debris and responding to neural insults, emerging research now shows that microglia are highly dynamic cells involved in a variety of neural processes, including development. The hypothalamus is a brain region critical for maintaining homeostatic processes such as energy balance, thirst, food intake, reproduction, and circadian rhythms. Given that microglia colonize the embryonic brain alongside key steps of hypothalamic development and that the loss of microglia causes obesity in newborn pups, consistent with a defect in neuroendocrine signaling, we explored how microglia influence these nearby hypothalamic progenitors. We found that embryonic microglia directly and indirectly interact with hypothalamic radial glial cells by both touching and clipping of their projections and also by releasing signaling cues, respectively. These interactions were increased following maternal stress, suggesting that fetal microglia might be sensors to the external environment. Combined, these data demonstrate that microglia can influence overall development of this important brain region, which might contribute to diseases later in life.

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

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Pupil size anticipates exploration and predicts disorganization in prefrontal cortex

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