Conference Agenda

Symposium Chair

Chair Name:
Ina Anreiter

Co-Chair Name (Optional):
Rebekah Jolicoeur Alfaro

Email:
Preferred
r.jolicoeur@mail.utoronto.ca

Email:
ina.anreiter@utoronto.ca

Organization:
University of Toronto

Department:
Cell and Systems Biology

Position:
Assistant Professor

Species:
Drosophila melanogaster

Description

Title:
Gene Expression and Behavioral Regulation: A Cross-Species Exploration

Abstract (500 word limit):
Behavior, as a complex and plastic phenotype, arises from a dynamic interplay of genetic and environmental factors. Genes and their intricate regulatory networks play a fundamental role in determining the structure and function of neural circuits and pathways that underpin various behaviors. This symposium explores the relationship between gene expression and behavioral regulation, shedding light on the complex and nuanced ways in which gene expression actively contributes to the modulation of brain activity and behavioral outcomes. The four talks will center on the dynamic nature of this relationship in a variety of species, emphasizing how gene expression both influences and is influenced by behavioral outcomes. Furthermore, the symposium seeks to emphasize the variety of ways gene expression can be altered, consequently affecting the regulation of different behavioral phenotypes. This symposium will serve as a platform for speakers from a variety of fields, career stages, and institutions in order to encourage cross-disciplinary discussions. The chairs, Dr. Ina Anreiter and Rebekah Jolicoeur Alfaro, will introduce the symposium and speakers and moderate the discussion. In the first talk, titled “Determining the Molecular Mechanisms of Substance Use Disorders through Single-Cell Regulatory Genomics “,Dr. Brad Balderson, Postdoctoral Researcher at the Salk Institute for Biological Studies, will discuss cell type-specific molecular mechanisms that contribute to the susceptibility of substance use in rats, using single-cell transcriptomics/chromatin accessibility combined with genotype data. His presentation will focus on cell type-specific genetic and transcriptomic changes in rodent brains that predict propensity for oxycodon addiction. . In the second talk, titled “Developmental logic informs the cellular and sexual identities of the nervous system”, Dr. Aaron Allen, postdoctoral researcher at University of Oxford, will speak about the the connection between sex, gene expression, and the properties of cells in the Drosophila melanogaster brain. Using a sexed single-cell transcriptomic atlas of the adult Drosophila melanogaster central brain, he will explore the emergence of coherent sexual behavior which depends on the genetically controlled developmental programs. Dr. Charles Nichols, Professor of Pharmacology at Louisiana State University, will speak about the mechanism of action behind the therapeutic effects of psychedelics, which are re-emerging as a promising new tool to treat various neuropsychiatric diseases. His talk, titled “Behavioral pharmacology and genetics of psychedelics”, will focus on the acute and long-term behavioral changes in both mammalian and Drosophila systems in response to psychedelic administration, as well as the observed alterations to gene expression and synapses after administration. Finally, Dr. Andrew Gordus, Assistant Professor of Biology at Johns Hopkins University, will speak on the neural and genetic basis for the behavioral repertoire used in spider orb-weaving in his talk titled “Untangling the web of behaviors used in spider orb-weaving”. The elegant geometry of the orb webs of Uloborus diversus are a physical record of carefully coordinated behavioral states and his talk will uncover the biological basis of this behavioral algorithm through neuronal, chemical, and genetic manipulations. All four speakers have agreed to participate in-person.

Speaker 1

Name:
Brad Balderson

Email:
bbalderson@salk.edu

Organization:
Salk Institutes

Department:
Biological Studie

Position:
Postdoctoral Researcher

Species:
Rattus norvegicus

Speaker 2

Name:
Aaron Allen

Email:
aaron.allen@dpag.ox.ac.uk

Organization:
University of Oxford

Department:
Physiology, Anatomy, and Genetics

Position:
Postdoctoral researcher

Species:
Drosophila melanogaster

Speaker 3

Name:
Charles Nichols

Email:
cnich1@lsuhsc.edu

Organization:
Louisiana State University

Department:
Pharmacology

Position:
Professor

Species:
Drosophila melanogaster, Rattus norvegicus

Speaker 4

Name:
Andrew Gordus

Email:
agordus@jhu.edu

Organization:
Johns Hopkins

Department:
Biology

Position:
Assistant Professor

Species:
Uloborus diversus (spider)

Brad Balderson1 , Narayan Pokhrel2 , Yanning Zuo2 , Benjamin Johnson2 , Olivier George2, Abraham A. Palmer2,3 , Graham McVicker1 , Francesca Telese2

The nucleus accumbens (NAc) is a key subcortical brain structure that regulates reward and is involved in addiction. However, the specific cell types, cell-cell interactions, and genetic variants that contribute to addiction phenotypes are unknown. To dissect the molecular basis of oxycodone addiction, we used outbred Heterogenous Stock (HS) rats that were characterized for their oxycodone addiction-like behaviors, measured by an addiction index (AI), and for which we had genotype data. Using the NAc tissues collected after 5 weeks of abstinence from oxycodone self-administration, we measured gene expression and chromatin accessibility in ~500,000 single-cell nuclei across 100 HS rats with variable oxycodone AI. Differential expression analysis revealed several genes specifically expressed in either high or low AI individuals compared with drug-naive individuals. We identified a subset of genes specifically expressed in high AI rats and a subset of drug-naive rats, suggesting pre-existing gene expression markers of oxycodone AI. Utilising these observations, we trained a probabilistic machine learning model to impute AI phenotypes for drug-naive rats, as a novel gene expression-based oxycodone risk score method. We will also map gene expression quantitative trait loci (eQTLs) to identify genetic variants associated with oxycodon AI genes, and perform differential cell-cell interaction analysis to illuminate neural circuits within the NAc that regulate oxycodone addiction-like behaviors. Overall, we will present evidence of cell type-specific NAc differential gene expression, cell-cell communications, and eQTLs, that are associated with vulnerability to oxycodone addiction-like behaviors.

1 Salk Institute for Biological Studies, Integrative Biology Laboratory, La Jolla, CA 2 Department of Psychiatry, University of California San Diego, La Jolla, CA, USA 3 Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA

Psychedelic drugs target serotonin 2A receptors for their behavioral effects and have recently shown promise in multiple clinical trials for the treatment of depression, substance use disorders, and OCD, among other disorders. Remarkable, a single treatment with psychedelics can have therapeutic efficacy lasting from months to years. We have developed experimental models recapitulating persistent antidepressant-like effects for mechanistic study in both rat and Drosophila. In rat brain, acute psychedelic administration influences immediate early genes involved in synaptic plasticity, among others. Interestingly, gene expression changes differ between cortical cell type and cortical region. Several weeks after a single administration of psychedelic, there is increased synaptic function, but without accompanying increases in synaptic structural gene expression. We hypothesize that epigenetic mechanisms are at play that lead to persistent expression of higher conducting ion channels at synapses in certain brain circuits. When given chronically to rats, LSD produces profound behavioral changes that include hyperactivity and aggression that begin at about six weeks and stabilize by three months, and persist long after discontinuation of LSD. Gene expression analysis of mPFC in rat brains 30 days after drug discontinuation shows many hundred genes are affected that group into several sets, and are significantly enriched for those found by others to be involved in psychosis and bipolar disease. In summary, psychedelics produce complex changes in gene expression and epigenetic factors that likely contribute to their behavioral effects.

1. Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA USA

Funding Support: NIMH R01 083689, NIDA R21 DA039462, 2A Biosciences, Eleusis Therapeutics

Andrew Gordus

Many innate behaviors are the result of several coordinated sensorimotor programs to produce higher-order behaviors. Knowing the underlying cognitive states that encode how these programs are coordinated is often difficult since we simply can’t ask the animal their objective. However, extended phenotypes such as architecture provide us with a window into the mind because the structure itself is a physical record of behavioral intent. A particularly elegant and easily quantifiable structure is the spider orb-web. We have developed a novel assay enabling high-resolution behavioral quantification of web-building by the hackled orb-weaver Uloborus diversus. With a brain the size of a fly’s, the spider U. diversus offers a tractable organism for the study of complex behaviors. Using machine vision algorithms for limb tracking, and unsupervised behavioral clustering methods, we have developed an atlas of stereotyped movements used in orb-web construction. The rules for how these movements are coordinated change during different phases of web construction, and we find that we can predict web-building stages based on these rules alone. Thus, the physical structures of the web explicitly represent distinct phases of behavior. To uncover how this sophisticated algorithm is encoded in the brain, we have assembled a genome, and developed biological assays to understand which neurons and genes are critical to encoding web-building behavior.

Johns Hopkins University

Allen, A. M.¹, Neville, M. C. ¹, Nojima, T. ¹, Agarwal, D. ², Sims, D. ², and Goodwin, S. F¹.

The nervous systems of females and males display anatomical and functional differences across many taxa, and the emergence of coherent sexual behaviour critically depends on the genetically controlled developmental programs that generate these sexually dimorphic circuits. To discover new insights into the single-cell basis of how sex informs the relationships between transcriptomic signatures and specific anatomical, physiological, and functional properties of cells in the brain, we generated a sexed single-cell transcriptomic atlas of the adult central brain using single-cell RNA sequencing. We next generated the first detailed single-cell transcriptomic atlas of fru+ and dsx+ cell types in the adult central brain by performing a sub-clustering meta-analysis, gaining exclusive genetic access to these sexually dimorphic cell types. Through a detailed analysis of the dsx⁺ pC1 neuronal cluster, a crucial site in the central brain driving a persistent behavioural state of social arousal in both males and females, we show the coupling of developmental timing with sexual identity. pC1 cells are developmentally distinct between the sexes – female pC1 cells are born early in development, and male pC1 cells are born late in development. When we looked at all fru+ and dsx+ cells, we saw a similar trend, with females having an over-representation of early-born cells and males having an over-representation of late-born cells. These data suggest that a sexually dimorphic nervous system is built by differential cell death, resulting in "paralogous" and not "orthologous" neurons between the sexes. Our sexed single-cell atlas of the adult central brain, along with the fru- and dsx-specific atlases, provides a comprehensive resource that can facilitate a systematic insight into the single-cell basis of sexual dimorphism and an understanding of the circuit architecture and information processing underlying sexual behaviours in the adult.

¹ Centre for Neural Circuits and Behaviour, The University of Oxford, Oxford, United Kingdom

² MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom