Program

To study the neural circuitry, the action of one cells under the context of others, one would precisely measure and perturb specific neuronal populations and molecules in behaving animals who are specifically engaged in performing the computation or function of interest. The dataset of millions of neurons firing together underlying a behavior are required to develop and refine theories (hypotheses) explaining animal behavior in terms of brain physiology. The focus of lab is to develop novel genetically encoded indicators based on fluorescence proteins, especially focusing on direct and specific measurement of myriad input signals with needed spatial and temporal resolutions. In this talk, I will discuss our recent progress into develop and apply a new suite of genetically encoded indicators of neural activity. I will discuss the design, characterization and applications of these genetically encoded indicators. We also validate our sensor design platform, which could also be applied to developing sensors for a broad range of neuromodulators, including norepinephrine, serotonin, melatonin, and opioid neuropeptides. In combination with calcium imaging and optogenetics, these sensors are well poised to permit direct functional analysis of how the spatiotemporal coding of neural input signaling mediates the plasticity and function of target circuits.

Stephan Lammel¹, Markita Landry¹, Tianyi Mao³, Benoit Girard², Johannes de Jong¹

¹University of California Berkeley, ²University of Geneva, ³Vollum Institute

Great strides have been made towards understanding the diversity of midbrain dopamine neurons. Recent studies suggest that rather than a single functional unit, dopamine neurons form distinct groups at anatomical, molecular and functional levels contributing to the signaling of reward, aversion, salience, novelty and locomotion. This panel will highlight the development of novel optical tools and imaging approaches, as well as the application of cutting-edge tools to add important information to the rapidly progressing dissection of heterogeneous dopamine signaling in health and disease. Markita Landry (UC Berkeley) will discuss the development of a near-infrared nanosensor (nIRCats) that can measure dopamine transmission in acute brain slices and detect dopamine efflux in the extracellular space driven by electrical or optogenetic stimulation. Tianyi Mao (Vollum Institute) will present the development of novel PKA and cAMP fluorescence sensors, which combined with modern microscopy can image intracellular responses to endogenous dopamine release at single-cell and subcellular resolutions in brain slices and behaving animals. Benoit Girard (University of Geneva) will discuss the role of the nucleus accumbens (NAc) in evaluating social appetitive and aversive information, how the NAc integrates information about conspecifics and how it incorporates learned associations to initiate conspecific approach or avoidance. Stephan Lammel (UC Berkeley) will discuss how developing a detailed understanding of subregion-specific dopamine signaling in the NAc contributes to the anatomical and functional diversity of dopamine neurons and may represent an important step towards the identification of clinically-relevant targets for treating impulse control disorders. Taken together, this panel will cover technology development and biological applications that allow exciting progress in understanding the structural and functional heterogeneity of the dopamine system.

Clifford Cassidy¹, Luigi Zecca², Jason Smucny³, Fumihiko Ueno⁴

¹The University of Ottawa, ²Institute of Biomedical Technology, ³University of California Davis, ⁴CAMH

Establishing new methods to interrogate the status of the dopamine and noradrenaline systems in the human brain in vivo is needed to promote research and treatment in neuropsychiatric illness. Over recent years, diverse applications have been developed for a novel family of MRI sequences, known as neuromelanin-sensitive MRI. In this symposium, the biology of neuromelanin will be reviewed to indicate the relevance of neuromelanin content to the health and function of catecholamine neurons. The well-established use of this method as a marker of neurodegeneration in the substantia nigra in Parkinson’s disease will be reviewed as well as more recent applications of this technique as an assay of dopamine function and marker of dopamine dysregulation in psychotic illness. Finally, measurement of NM-MRI signal in the locus coeruleus to probe the integrity of the noradrenergic system will be reviewed.

Kim Neve¹, Jonathan Javitch², Chris Ford³, Jean Martin Beaulieu⁴

¹VA Portland Health Care System, ²Columbia University/New York State Psychiatric Institute, ³University of Colorado School of Medicine, ⁴University of Toronto

Recent technological advances have greatly enhanced our ability to move rapidly from molecular-level studies of protein function and signal transduction to behavioral and translational studies. The speakers in this session will present work on the dopamine D2 receptor that extends the full range of that spectrum. Chris Ford has characterized synaptic activation of D2 receptors on medium spiny neurons in the murine striatum and nucleus accumbens. He will describe differences in kinetics and sensitivity of the receptors between these two regions and how exposure to cocaine leads to region-specific alterations in D2 receptor sensitivity. Jonathan Javitch will describe the design and characterization of D2 receptors biased towards interactions with arrestin or G proteins and will show data elucidating the relationship between this signaling bias and D2 receptor-mediated behaviors. Kim Neve will discuss the in vitro and in vivo functional consequences of splice and allelic variation of the D2 receptor. Martin Beaulieu has used high-precision intersectional approaches to characterize cerebral cortical neurons that express the D2 receptor and modify gene expression in these cells. He will discuss the relationship of cortical D2 receptor signaling to emotional and cognitive functions that may be involved in mental illnesses.

Vincent Seutin¹, Josef Shin², Jean-Marc Goaillard⁴, Paul Kramer³

¹Liège University, ²Goethe University, NINDS/NIH, ⁴Université of Aix Marseille

Vincent Seutin will describe experiments suggesting a hereto unknown mechanism for the characteristic slow pacemaking of these neurons. Josef Shin will talk about how Cav1.3 calcium channels act as amplifiers of firing excitability selectively in lateral DA SN neurons. Jean Marc Goaillard will describe the voltage- and calcium-gated ion currents underlying the electrophysiological phenotype of DA neurons, focusing on the functional influence of cell-to-cell variability in channel properties. With Paul Kramer we will move to the axon. He will describe experiments showing the properties of DA axons and their modulation by acetylcholine.

Hui Zhang¹, Quyen Hoang², Mark Cookson³, Wanli Smith⁴

¹Thomas Jefferson Univ., ²Indiana University School of Medicine, ³NIH, ⁴Johns Hopkins University School of Medicine

Mutations in LRRK2 are the most common known genetic causes of Parkinson’s disease (PD). Given its strong genetic links, LRRK2 represents a compelling therapeutic target for PD. However, the mechanisms that regulate LRRK2 function and the pathogenic effects of mutations remain unclear. While studies have focused largely on LRRK2 kinase activity, attention on the GTPase activity is limited. In this symposium, we will discuss the importance of the GTPase domain for LRRK2-Linked PD Pathogenesis.

Louis-Eric Trudeau¹, Pascal Kaeser², Ulrik Gether³, Zachary Freyberg⁴

¹Université de Montréal, ²Harvard University, ³University of Copenhagen, ⁴University of Pittsburgh

Compared to neurons using classical fast synapses, we presently know very little about the connectivity mediated by neurons releasing modulatory neurotransmitters such as dopamine, which signal through release sites that do not conform to the classical synaptic model. In this session, the four speakers will present new discoveries on the structure and function of dopaminergic axon terminals.

Marco Leyton¹, Isabelle Boileau², David Zald³, Eleanor Simpson⁴

¹McGill University, ²CAMH, University of Toronto, ³Vanderbilt University, ⁴Columbia University

What is the role of D2/3 receptors in reward-related behaviors? The answer has proven to be more complex than previously envisaged. The present speakers’ combination of correlational studies in humans and causality testing in rodents extends our understanding of the influence of temporal factors, spatial factors and receptor subtypes, indicates that both increases and decreases in DR2/3 transmission can be disruptive, and clarifies previously reported superficially contradictory findings.

Nina Karalija¹, Alireza Salami², Goran Papenberg³, Jarkko Johansson¹

¹Umeå university, ²Umeå university and Aging Research Center, Karolinska Institute and Stockholm University, ³Aging Research Center, Karolinska Institute and Stockholm University

This symposium will address interindividual differences and decline of dopamine receptor systems during normal (non-pathological) aging. The presentations will demonstrate interrelations between D1 and D2-receptor availability, their contributions to various cognitive domains in old age, their associations to brain structure and function, and their interactions with lifestyle and genetic variations.

Kauê M. Costa ¹, Angela Langdon², Thorsten Kahnt³, Peter Shizgal⁴

¹National Institute on Drug Abuse Intramural Research Program, ²National Institute on Mental Health Intramural Research Program, ³National Institute on Drug Abuse Intramural Research Program, ⁴Concordia University

Recent data poses challenges to model-free approaches of dopamine signaling. The present symposium will address the constrains of the model-free hypothesis and how can they be resolved.

Heinz Steiner¹, Carlos Bolanos², Panayotis Thanos³, Micky Marinelli⁴

¹RFUMS/Chicago Medical School, ²Texas A&M University, ³University at Buffalo, ⁴University of Texas at Austin

Psychostimulant plus antidepressant co-exposure occurs in treatment of ADHD/depression comorbidity (~40% of ADHD) and with psychostimulant abuse in patients on antidepressants. We will discuss how SSRI antidepressants potentiate neuronal and behavioral effects of psychostimulants, including effects on gene regulation, functional brain connectivity, reward and cocaine self-administration, in rats. Our findings indicate that psychostimulant+SSRI co-exposure may increase addiction liability.

Dysfunctional dopamine (DA) signaling has been associated with a broad spectrum of neuropsychiatric disorders, prompting investigations into how midbrain DA neuron heterogeneity may underpin this variety of behavioral symptoms. Recognizing the need for a systematic classification scheme, we and others have catalogued DA neurons based on their gene expression profiles. Here I will synthesize points of congruence, but also highlight key differences, between these molecular classification schemes. In doing so, I hope to provide an initial framework that will facilitate investigations into the functions of these putative DAergic subtypes. Next, I will discuss recent studies on the developmental basis of DA neuron diversity. Our lab has previously described the floor plate origin of DA neurons. Here I will discuss recent studies that suggest that molecular subdivisions in the floor plate, at least in part, underpin DA neuron diversity.

Please note this session is in french

There is a strange disconnect in how we typically think about dopamine. On the one hand, there is broad consensus that dopamine is a critical modulator of motivation. On the other, our predominant theory – that dopamine signals reward prediction errors – is not about motivation at all, but rather learning. In recent years we have attempted to bridge this gap, demonstrating that dopamine fluctuations can track convey motivational signals in specific forebrain subregions, even when midbrain dopamine cell firing does not. Yet this has proven controversial, with some continuing to interpret all dopamine fluctuations as reward prediction errors. I will present our latest contributions to this debate, including new results on how dopamine signals are regulated to drive motivated behavior.

Jeremy Day¹, Colleen McClung², Ian Maze³, Erin Calipari⁴

¹University of Alabama at Birmingham, ²University of Pittsburgh, ³Mt. Sinai School of Medicine, ⁴Vanderbilt University

Genetic and epigenetic regulatory mechanisms exert tremendous control over nearly all aspects of dopamine neurotransmission, and alterations in these processes have been linked to numerous neuropsychiatric disorders. The goal of this session is to communicate cutting-edge research into our understanding of how these mechanisms influence reward circuit function and drug-seeking behaviors.

Véronique Deroche-Gamonet¹, Ana Clara Bobadilla², Anna Samaha³, Marco Venniro⁴

¹Université de Bordeaux, ²University of Wyoming, ³Université de Montréal, ⁴University of Maryland

Addiction research relies heavily on preclinical models, where animals self-administer drugs voluntarily. Animal research has made great contributions to our current understanding of addiction, but it has not yet met the urgent need for new treatment approaches. This may be because present preclinical approaches do not adequately reflect the human situation. Here we present novel approaches that might help remedy this.

Katlin Silm¹, Nic Tritsch², Susana Mingote³, Shelley Warlow⁴

¹Cedars-Sinai Medical Center, ²New York University, ³Advance Science Research Center/City University of New York, ⁴University of California San Diego

It is now well established that subsets of midbrain dopamine neurons can store and co-release the major excitatory and inhibitory neurotransmitters, glutamate and GABA. However, basic physiological and functional roles of these signals are only just beginning to come into focus. This symposium will explore recent findings on the physiological mechanisms that regulate the synaptic release of co-transmitters, their effects on defined post-synaptic cells, as well as their roles in shaping behavior.

Felix Meyer¹, Sara Jones², Aurelio Galli³, Ali Salahpour⁴

¹FAU Brain Institute, ²Wake Forest, ³University of Alabama in Birmingham, ⁴University of Toronto

This symposium is focused on dopamine transporter. Presenters will discuss published and unpublished data using a variety of approaches to interrogate how drugs, interacting proteins and disease causing mutants impair/affect transporter function. Each presenter will also discuss different pharmacological interventions that can be used to rectify the various DAT impairments described in their presentations. 

Martin Parent¹, Philippe Huot², Christopher Bishop³, Véronique Sgambato⁴

¹Université Laval, ²McGill University, ³Binghamton University, ⁴CNRS

This session will revolve around the interactions between DA and 5-HT systems involved in the expression of motor and non-motor symptoms that are experienced by PD patients, and will address the growing interest in the fate of 5-hydroxytryptamine (serotonin or 5-HT) neurons in Parkinson’s disease (PD).

Nao Chuhma¹, Naoshige Uchida², Jochen Roeper³, Mark Howe⁴

¹Columbia University, ²Harvard University, ³Goethe University Frankfurt, ⁴Boston University

The functional diversity of midbrain DA neurons ranges across multiple scales. Speakers will address distinct biophysical features of projection-defined DA neuron subpopulations, diversity of encoding of reward prediction error signals underpinning improvement in reinforcement learning, heterogeneity in DA neuron synaptic actions in the striatum, and how spatiotemporal variations in DA axonal signals contribute to spontaneous movements and unpredicted rewards across striatal territories.

Rebekah Evans¹, Jill Crittenden², Fumino Fujiyama³, Nadine Gut⁴

¹Georgetown University, ²Massachusetts Institute of Technology, ³Doshisha University, ⁴Rutgers University

Inhibition of DA activity has been associated with reduced motor performance and encoding of negative reward prediction error, but how different sources of inhibition contribute to DA activity in the SNc and how they shape behavior is not well understood. We will address the different components of the inhibitory afferent circuitry using a variety of tools to describe the connectivity of GABAergic afferents and their effects on DA neurons, and the behavioral consequences of this inhibition.

Tom Hnasko¹, Jasper Heinsbroek², Mary Kay Lobo³, Steve Mahler⁴

¹Univeristy of California San Diego, ²University of Colorado Denver – Anschutz Medical Campus, ³University of Maryland, School of Medecine, ⁴University of California, Irvine

The ventral pallidum has recently emerged as an underappreciated, but critical player in the regulation of physiological and pathological dopamine signaling. This panel brings new light on how heterogeneous VP neurons, as well as their inputs and outputs, impact motivated behaviors, and contribute to maladaptive behaviors related to abnormal dopamine signaling.

Jeroen Pasterkamp¹, Sandra Blaess², Martin Levesque³, Sarah Nickels⁴

¹University Medical Center Utrecht, ²University of Bonn, ³Université Laval, ⁴University of Luxembourg

It is becoming clear that the midbrain dopamine system is rather heterogeneous. How this heterogeneity is established and how different dopamine neuron subtypes function remains incompletely understood.

Patricia Silveira¹, Cecilia Flores¹, Zisis Bimpisidis², Catherine Peña³

¹McGill University, ²Istituto Italiano di Tecnologia, ³Princeton

In this symposium, we will present multidisciplinary and translational data from different labs demonstrating that dopamine neurotransmission is a key modulator of the effects of early life adversity on neurodevelopment and risk for psychopathology.

Since the 1990s, thinking about the role of dopamine (DA) in the regulation of basal ganglia circuitry and movement has focused on the striatum. This single-mindedness is particularly evident in models of movement disorders, like Parkinson’s disease (PD). However, DA signaling takes place throughout the basal ganglia. Indeed, new progressive models of PD suggest that while striatal DA release is critical for associative learning and action sequences, it is not necessary for simple ambulation. This recognition has implications not only for how we think about DA control of movement, but how we approach treating movement disorders, like PD.

Inter-individual variability refers to differences in the expression of behaviors between members of a population. For instance, some individuals take greater risks, are more attracted to immediate gains or are more susceptible to drugs of abuse than others. To probe the neural bases of inter-individual variability and personality traits, we study exploration and decision-making in mice, and dissect the specific role of dopamine in the modulation of these behaviors. Using a spatial version of the multi-armed bandit task, in which mice are faced with consecutive binary choices, we linked modifications of midbrain dopamine cell dynamics with modulation of exploratory behaviors, a major component of individual characteristics in mice. By analyzing mouse behaviors in semi-naturalistic environments, we then explored the role of social relationships in the shaping of dopamine activity and associated beahviors. I will present recent data from the laboratory suggesting that changes in the activity of dopaminergic networks link social influences with variations in the expression of non-social behaviors: by acting on the dopamine system, the social context may indeed affect the capacity of individuals to make decisions, as well as their vulnerability to nicotine.

Lauren Burgeno², Val Collins¹, Larry Zweifel³, Marta Blanco-Pozo²

¹University of California,San Francisco, ²University of Oxford, ³University of Washington,

Dopamine function is shaped by anatomical organization and connectivity. Dopamine cell-cluster and projection-target sub-systems, as well as axonal regulation of dopamine neurons, have diverse behavioral implications. This panel will present novel insights on the behavioral impact of such systems – detailing and integrating the cellular and regional specificity of dopamine signaling by applying an array of cutting-edge in vivo techniques supporting high temporal and spatial resolution.

James Daniel⁴, Joe Lebowitz¹, Margaret Rice², Dalibor Sames³

¹Vollum Institute, ²New York University, ³Columbia University, ⁴Max Planck Institute of Experimental Medicine

Given the importance of dopamine in brain function and behavior, it is essential to understand the molecular regulation of dopamine secretion and its dysfunction in disease. Recently, several innovative approaches to studying dopamine release have been developed, allowing deeper insight into dopaminergic transmission. This symposium focuses on recent breakthroughs in deciphering the molecular regulation of dopamine based on innovative methodologies to detect released dopamine.

Mattias Rickhag¹, Pierre Vincent², Vikram Gadagkar³, Katherine Brimblecombe⁴, Cecile Ladouceur⁵

 ¹Copenhagen University Hospital and University of Copenhagen, ²CNRS – Sorbonne Université, ³Columbia University, ⁴University of Oxford, ⁵University of Pittsburgh

Understanding the function of dopamine in the brain is critical to identifying neural mechanisms of disease and potential targets for treatment. Dopamine is implicated in many behaviours, including motor control, goal-directed behaviours and signalling reward-prediction errors – yet, the lack of specificity in the function of dopamine signalling in these behaviours remains an important problem. Moreover, although alterations in dopamine function has been reported in movement disorders such as Parkinson’s disease and psychiatric disorders such as addiction and anhedonia, the specific mechanisms contributing to these alterations remain unknown.

In this session, speakers will discuss data from studies using wide-ranging dopamine detection methods including fMRI, biosensors and fast-scan cyclic voltammetry to explore the mechanisms and consequences of dopamine release in a range of model systems spanning songbirds, rodents and humans. Rickhag will demonstrate how G protein-coupled receptors (GPCRs) in spiny projection neurons modulate striatal signaling. Dr. Vincent will then highlight how striatal spiny neurons, with a specific set of signaling proteins, are able to detect dopamine transients. Dr. Gadagkar will use a songbird model to show that reward and performance prediction error signals can be gated by social context. Dr. Brimblecome will present data, which speaks to the roles of L-type voltage-gated calcium channels in controlling striatal dopamine release, exploring the potential of negative regulators of L-type channels as neuroprotective strategies in Parkinson’s disease. Using fMRI with adolescents with depression, Dr. Ladouceur will discuss the role of striatal dopamine neurophysiology and function in symptoms of anhedonia.

The breadth of this session offers a rare opportunity to address the roles and consequences of dopamine signalling across species utilising different methods to highlight emerging insights into the intracellular pathways underlying the mechanisms and consequences of dopamine signalling and their potential role in movement and psychiatric disorders.

Ashley Kopec¹, Caroline Smith², Kristen Delevich³, Nicola Grissom⁴

¹Albany Medical College, ²Duke University, ³Washington State University, ⁴University of Minnesota Twin Cities

Behaviors supported by the dopaminergic ‘reward’ circuitry of the brain have broad relevance to many mental health disorders in humans. Neurological disorders often present in sex-specific ways, but how sex differences manifest is an active area of research. This symposium will focus on the sex-specific development and utilization of dopaminergic systems at cellular, molecular, genetic, circuit, and behavioral levels, with implications for behavioral outcomes in health and disease.

Catharine Winstanely¹, Melissa Sharpe², Erin Calipary⁴, Mihaela Iordanova³

¹University of British Columbia, ²University of California Los Angeles, ³Concordia University, ⁴Vanderbilt University

The hypothesis that mesolimbic dopamine signals reward prediction error has fascinated the field of neuroscience. This symposium will delve deeper into the conditions that define this signal and its influence over learning and motivated behaviour. The studies presented will explore circuit dynamics within and beyond the realm of reward.

Freja Herborg¹, David Sulzer², Robert Edwards³, Anne Bassett⁴

¹University of Copenhagen, ²Columbia University, ³UCSF School of Medicine, ⁴University of Toronto

Dopamine plays an essential role in neuropsychiatric and neurodegenerative diseases but classically these two groups of diseases have been viewed as distinct pathologies. This session will present novel insights into shared pathobiological mechanisms with focus on results from new genetic mouse models, large-scale exome sequencing data, mechanisms of altered dopamine release patterns, role of alpha-synuclein in exocytotic monoamine release, and phenotypic spectrum of 22q11.2 deletion syndrome.

Pierre Trifilieff¹, Marco Niello², Nathalie Ginovart³, Matthaeus Willeit², Harald Sitte²

¹INRA, ²Medical University of Vienna, ³University of Geneva

Altered reward processing is a key element in the pathogenesis of psychiatric disorders. Assembling scientists engaged in molecular, behavioral, and clinical studies, this symposium will focus on alterations in dopamine (DA) signalling affecting the physiological functions of DA in dopaminergic and dopaminoceptive neurons.

Leveraging CRISPR/Cas9 gene editing technologies to determine the regulators of dopamine physiology and behavior

Barbara Juarez¹

¹University of Washington- Seattle

Chronic administration of D2/3 agonist ropinirole enhances the ability of win-paired cues to drive development of long-lasting preference for risky choice in a rat gambling task

Leili Mortazavi¹, Tristan Hynes², Catharine Winstanley²

¹Stanford University, ²University of British Columbia

Role of D2 receptor-positive ventral tegmental area dopamine neurons in effort-related motivation for food-seeking

Yoshio Iguchi¹, Shigeki Kato¹, Kazuto Kobayashi¹

¹Fukushima Medical University

Dopaminergic circuit for compulsive eating behaviorBokyeong Kim¹, Ja-Hyun Baik¹¹Korea University

A mosaic of dopamine dynamics: assessing the role of dopamine neuromodulation in habit learning

Oren Princz-Lebel¹, Miguel Skirzewski¹, Claire Lemieux², Daniel Palmer¹, Marco Prado¹, Vania Prado¹, Penny MacDonald¹, Lisa Saksida¹, Timothy Bussey¹

¹Western University, ²McMaster University

A reaction diffusion model of dopaminergic and cholinergic traveling waves in the striatum

Joshua Goldberg¹, Jeffery Wickens²

¹The Hebrew University of Jerusalem, ²Okinawa Institute of Science and Technology

Ingo Willuhn¹, Talia Lerner², Scott Bolkan³, Benjamin Saunders⁴

¹The Netherlands Institute for Neuroscience, ²Northwestern Feinberg School of Medicine, ³Princeton University, ⁴University of Minnesota

Dopamine is well known both for its roles in reward processing and in action selection, but these roles are often studied in isolation. This symposium will go in depth to explore how interactions between heterogeneous populations of dopamine neurons translate motivational states into motor patterns, bridging two areas of study and providing unique insights into the dopaminergic coordination of motivated behavior.

Dopamine (DA) in the mammalian striatum plays critical roles in motivation, action and reinforcement learning, and DA dysregulation underlies psychomotor disorders that include Parkinson’s disease and addictions. DA neurons in substantia nigra and ventral tegmental area generate action potentials at a range of instantaneous frequencies, but it is becoming evident that a mechanisms operating on the colossal branched arbours of DA axons govern whether dynamic activity in DA neurons is relayed into DA release. Our work in mouse striatum shows that a diverse range of mechanisms gate DA output, and these include other striatal circuits such as cholinergic interneurons, GABA tone and their regulators, as well as intrinsic regulators of short-term presynaptic plasticity including the DA transporter, and proteins associated with Parkinson’s. I will highlight our recent findings to illustrate how processes operating on DA axons powerfully filter DA output.

Dan Covey¹, Giovanni Hernandez², Natalie Zlebnik¹, Miriam Melis³

¹University of Maryland School of Medicine, ²McGill University, ³University of Cagliari

Chair: Joseph Cheer, University of Maryland School of Medicine. The endocannabinoid (eCB) system is an evolutionarily conserved signaling network that acts throughout the brain and periphery to regulate numerous homoeostatic processes. We will present recent work demonstrating that, by modulating dopamine function, eCB signaling controls various neural adaptations critical to normal learning and development. This work is timely and relevant given the spreading legalization of cannabis in North America and rising interest in cannabinoid-based therapies for neuropsychiatric disorders. A large body of work demonstrates that eCB manipulations potently alter reward-directed behavior. Dr. Covey will present findings showing that eCB signaling in the ventral tegmental area shapes neural circuit control of dopamine neurons and allows them to function as the canonical neural substrate of reward prediction during the pursuit of reward. Adolescence is a critical period for refinement and organization of dopamine neural circuitry. Dr. Hernandez will show that adolescent cannabinoid exposure increases susceptibility to depression and alters mesolimbic dopamine pathways later in life. Specifically, CB1 receptor agonist administration in adolescent mice disrupts responding to chronic social defeat stress in adulthood and alters levels of the microRNA miR-218 as well as those of Dcc receptors in the prefrontal cortex. Similarly, Dr. Zlebnik will present findings demonstrating that adolescent cannabinoid exposure dysregulates genes that orchestrate mesolimbic dopamine system development and induces aberrant addiction-related behaviors in adulthood, including potentiated cocaine-seeking behavior and its dopaminergic correlates. Finally, the work Dr. Melis will describe how prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders. Her findings establish that PCE promotes molecular, cellular and synaptic changes resulting in a hyperdopaminergic phenotype in juvenile rat offspring.

Rodrigo Pachego⁴, Jennifer Felger³, Peter Gaskill², Habibeh Khoshbouei¹,

¹University of Florida, ²Drexel University, ³Emory University, ⁴Fundacion Ciencia & Vida

Although dopamine is widely studied for its role in CNS mediated neurological and neuropsychiatric diseases such as drug addiction, reward, learning and Parkinson’s diseases, a growing body of literature has demonstrated the importance of dopamine as an immunomodulatory factor and a neuro-immune mediator. Immune cells involved in both adaptive and innate immune responses, such as dendritic cells, T cells, B cells, and macrophages are capable of synthesizing and releasing dopamine into the extracellular compartment, thus enabling communications with different cell types in the periphery. These interactions not only suggest that dopamine can mediate communication between immune cells, but also may be involved in a bidirectional cross-talk between the immune and the nervous system. Indeed, the immunologic effects of dopamine has shown a substantial impact on immune cell function, and on the pathogenesis of several diseases. These include HIV infection, autoimmune diseases such as inflammatory bowel disease, Parkinson’s disease and cancer. However, the mechanisms regulating the impact of dopamine on these distinct pathologies remain unclear, as to the specific signaling pathways and neuro-immune interactions mediating these effects. This symposium will examine the disparate and common mechanisms involved in dopamine-mediated pathogeneses, bringing the immunologic impact of dopamine into wider focus. This will provide the conference with a novel perspective on the immunologic role of dopamine and potentially spur new insight and collaborations focused on targeting these pathways to amplify or ameliorate the positive and negative effects of dopamine on the etiology of disease.

Kuei Tseng¹, Joshua Gross², Amy Newman³, Lauren Slosky²

¹College of Medicine – University of Illinois at Chicago (UIC), ²Duke University, ³NIDA-IRP, NIH

Chair: Amy Neuman. Dopamine (DA) is a major modulator of brain function that regulates executive function, motor control, motivation, arousal, reinforcement, and reward. This Parallel Session will demonstrate how using recently developed tools based of functional selectivity/ biased signaling at dopamine receptors can be used for potential therapeutic benefits.

Bruno Giros¹, Sebastian Haesler², Daniela Neuhofer³, Alban de Kerchove d’Exaerde⁴

¹McGill University, ²KU Leuven & Neuroelectronics Research Flanders, ³Medical University of South Carolina, ⁴Université Libre de Bruxelles (ULB)

Chairs: Bruno Giros, Alban de Kerchove d’Exaerde

Dopaminergic and dopaminoceptive systems are among the most studied because of their central roles in locomotion, the reward system, learning and many neuropsychiatric and cognition disorders. Despite these intensive studies, new roles and new circuits are constantly being discovered within the frame of the canonical direct (D1-MSNs) and indirect (D2-MSNs) striatal output and their complex regulation of the thalamo-cortico-striatal loop.

Illuminating dopamine dynamics in Huntington’s disease

Sarah Yang¹, Markita Landry¹, David Schaffer¹

¹University of California, Berkeley

A novel target for neuroprotection: The small GTPase Rin inhibits LRRK2 to promote autophagy and reduce alpha-synuclein pathology

Anne-Marie Castonguay¹, Julia Obergasteiger¹, Mattia Volta², Martin Lévesque¹

¹Laval University, ²Eurac Research

Early activation of dopaminergic system alters behavior and neural branching of prepubertal mice in a sexually dimorphic manner

Laila Arabe¹, Muiara Moraes¹, Ana Luiza L. Reis¹, Bruna Resende¹, Sofia Avritzer¹, Paula Valverde¹, Bruno Souza¹

¹Universidade Federal de Minad Gerais

Axon-derived netrin-1 regulates midbrain GABAergic migration and substantia nigra development

Divya Darwin Arulseeli¹, Sara Brignani¹, Ewoud Schmidt¹, Ozge Dudukcu¹, Laurens Grossouw¹, Youri Adolfs¹, Juan Moreno-Bravo², Alain Chedotal², Jeroen Pasterkamp¹

¹Utrecht University, ²Sorbonne Université

Dopamine spatiotemporal dynamics comparison between members of the dLight sensors family

Julie Chouinard¹, Akash Pal², Sakiko Takahashi¹, Kiyoto Kurima¹, Nobuyoshi Kitamura¹, Lin Tian², Jeffery Wickens¹

¹Okinawa Institute of Science and Technology, ²University of California Davis

Cardio-Metabolic and Psychiatric Comorbidities: Early Adversity- Mesocorticolimbic Dopamine Gene Network Interactions

Barbara Barth¹, Danusa Mar Arcego¹, Euclides De Mendonça Filho², Randriely Merscher Sobreira de Lima², Irina Pokhvisneva³, Zihan Wang¹, Michael Meaney¹, Patricia Pelufo Silveira¹

¹McGill University, ²Universidade Federal do Rio Grande do Sul, ³Ludmere Centre

Adele Stewart¹, Jennifer Zachry², Oscar Solis³, and Roberta Marongiu⁴

¹Florida Atlantic University, ²Vanderbilt University, ³National Institute of Drug Abuse, ⁴Cornell University

Historically, female subjects have been excluded from preclinical research, with the ratio of male-only to female-only studies in neuroscience at 5.5:1, a discrepancy attributed concern over the impact of estrus cycling on population homogeneity or the assumption that sexual dimorphism is absent. However, accumulating evidence demonstrates that genetic sex and sex hormones influence critical brain functions including dopamine (DA) release, reuptake, and signaling. This symposium will provide critical evidence demonstrating that genetic sex and sex hormones determine key elements of the dopamine system from dynamic neurotransmission to behavior and, ultimately, disease susceptibility. Dr. Stewart will describe sex-dependent phenotypic divergence observed in mice expressing the disease associated DAT Val559 variant, which derives from region-specific D2AR-DAT coupling. Dr. Solis will present data describing interactions between sex, Zn²⁺, and DAT in the context of cocaine exposure. Ms. Zachry will present her work investigating the dopaminergic neural circuits driving sex-based differences in reward seeking and avoidance. Dr. Marongiu will end by presenting new data outlining a critical role for sex in determining vulnerability to dopamine neurodegeneration in Parkinson’s disease. Given the NIH mandate requiring consideration of sex as a biological variable is a key part of the NIH initiative to enhance reproducibility, an in-depth discussion of the behavioral ramifications of sexually dimorphic DA neurotransmission is both timely and imperative.

Christoph Kellendonk¹, Eduardo Gallo², Ana Rodrigues³, Veronica Alveraz⁵

¹Columbia University, ²Fordham University, ³University of Minho, ⁴University of California Berkeley, ⁵NIAAA

Extensive research has associated ventral striatal dopamine to reward-driven behavior. However, the underlying neurobiological mechanisms are still being explored. Newly developed tools in the mouse allow for cell type-specific circuit approaches that can help unravel these mechanisms in vivo.

Maria Concetta Miniaci¹, Paolo Calabresi², Elvira De Leonibus³, Sathya Puthanveettil⁴

¹University of Naples Federico II, ²Gemelli University Hospital, ³Institute of Neurobiology and Cellular Biology, ⁴The Scripps Research Institute

Neuromodulators, such as norepinephrine, serotonin, and dopamine have been implicated in the regulation of neuronal activity, synaptic plasticity, cognition and behavior across the lifespan. How these neurotransmitters shape neural activity during behavioral tasks and how they regulate synaptic transmission during memory formation is poorly understood. Understanding the mechanisms of monoamine synaptic modulation is of high clinical relevance since the neuromodulatory systems have been identified as a target of many pharmacological treatments for psychiatric and neurological conditions such as dementia, depression, anxiety, schizophrenia, and drug abuse.

Orexin (ox, also known as hypocretin) neurons of the lateral hypothalamus (LH) project widely through out the brain, including to the ventral tegmental area (VTA). Orexin signalling has been linked to many different behavioural phenotypes, but a recent hypothesis suggests that, across all domains, orexin plays a critical role in driving motivational activation. Orexin neurons are activated by internal, homeostatic or external, motivationally relevant signals and coordinate both psychological and physiological processes to facilitate adaptive behaviours. This presentation will focus on how orexin modulates drug-induced synaptic transmission in the VTA and related behavioural outcomes. Orexin is co-expressed with dynorphin, a kappa-opioid receptor agonist. These co-released peptides have opposing action on VTA dopamine firing and drug seeking behaviour. This presentation will also discuss potential consequences of co-release of these neuromodulators to dopamine neuronal activity and related behaviours.