Laboratory on Neurobiology of Compulsive Behaviors (LNCB)

Our research is aimed at uncovering the circuits and synaptic mechanisms mediating reward motivated behaviors and compulsive drug use. Specifically, the goal is to better understand how cocaine and ethanol affect synapses and neuronal connectivity to drive the development of compulsive seeking that characterizes individuals suffering from cocaine abuse or alcohol use disorder. Our research focuses on drug actions in the cortico-mesolimbic circuit, with an emphasis on the nucleus accumbens. We combine physiological with behavioral analysis and use cutting-edge approaches, such as in vivo and in vitro optogenetic and chemico-genetic tools, to manipulate the activity of targeted neuronal populations and dissect their role in ethanol and cocaine related behaviors. Our overarching hypothesis is that cocaine and ethanol induce different adaptations on the two distinct subpopulations of medium spiny neurons in the striatum, direct- and indirect-pathway neurons, and that both pathways contribute differently to the psychomotor, rewarding and addictive properties of these drugs of abuse.

We are addressing three specific questions:

• How does chronic exposure to cocaine and ethanol affect the structure and function of neurons and synapses?
• Is there a difference in synaptic function and morphology between animals that display addictive-like behaviors and animals that do not after they all have been chronically exposed to cocaine or ethanol?
• Are there differences in the function and morphology of synapses in animals with higher predisposition to become addicted to cocaine?

To answer these questions, we use a combination of techniques: electrophysiology, 2-photon laser scanning microscopy, biochemistry and behavior. The lab employs two models of drug exposure: a passive non-contigent administration (such as intraperitoneal injections of cocaine) and models of ethanol and cocaine self-administration in mice (see models of drug administration ).

Electrophysiological recordings (whole cell voltage clamp) from medium spiny neurons (MSN) of the nucleus accumbens and the striatum are performed in order to determine the functional properties of the synaptic inputs onto D2-positive neurons and D1-positive neurons.

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We are also studying the morphological changes associated with chronic cocaine and with the development of addictive behaviors by fluorescently labeling MSN using ballistic methods and imaging spine morpholgy with confocal and 2-photon microscopes.

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Findings from these studies will provide information about the short-term and long-term effects of drug of abuse, such as cocaine and alcohol, on synapses. In addition, we hope they will lead to the identification of neuronal markers associated with higher vulnerability to addiction and they will aid in the development of new therapies.

Models of drug administration in mice:

Cocaine intraperitoneal injections: Cocaine is a psychostimulant drug that acts by blocking the reuptake of monoamines, such as dopamine, from the synaptic cleft. One of the acute actions of cocaine on mouse behavior is to increase their locomotor activity. In the lab, mice receive single or repetitive cocaine injections and their locomotor activity is measured using infrared beams and detectors located across the sides of the cage (see schematic below). Horizontal locomotion is measured daily for 20—60 min after injection of either saline or cocaine (5—30 mg/kg) in the intraperitoneal cavity. An example of this response is shown in the graph below where an acute response to cocaine is observed on day 1 and subsequent injections increase the psychomotor response furthermore. The enhancement of the locomotor activity with repeated injections is what has been called locomotor sensitization.

Graph 1: Locomotor sensitization to cocaine:

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Cocaine drug self-administration: The lab uses models of intravenous (IV) cocaine self-administration in mice to investigate the development of addictive-like behaviors in rodents. Mice undergo surgical implantation of a catheter in the jugular vein and, after recovery, are trained to poke their noses in a hole to gain an intravenous infusion of cocaine through this catheter (see a video of a mouse performing the task ). We analyze the number of rewards gained per daily session and track the progression of drug intake during consecutive days and weeks. In one of our models, daily sessions are intermingled with two time-out periods during which the drug is unavailable and nose pokes do not lead to infusions. (Graph below, gray area). We measure the perserverance of nose poking during the time-out periods as one determinant of the development of compulsive drug seeking behavior. The other two parameters are a breakpoint value obtained in sessions of progressive response ratio to test the motivation and one punishment session in which reward is paired to a mild foot shock to determine the perserverance of drug seeking despite aversive consequences (model based on Derroche-Gamonet et al. 2004).
Interestingly, different patterns of drug taking behavior are observed among different mice. The plot below shows an example of a regular (right side) and a more clustered or binging (left side) self-administration pattern.

Graph 2: Different patterns of cocaine self-administration:

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Ethanol self-administration: In collaboration with the laboratory of Dr. Kathleen A. Grant ( Oregon National Primate Center and OHSU ) and Dr. Todd Thiele (University of North Carolina at Chapel Hill) we are studying the morphological changes at synapses that occur after chronic ethanol self-administration in non-human primates and rodents, respectively.

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Collaborators

present

• Dr Jose A. Moron-Concepcion
  • Washington University School of Medicine in St Louis - Washington University Pain Center Missouri, USA
• Dr. Michael R. Bruchas
  • Washington University School of Medicine in St Louis - Department of Anesthesiology Missouri, USA
• Dr. Christoph Kellendonk
  • Columbia University Irving Medical Center New York, USA
• Dr. Dorit Ron
  • University of California San Francisco San Francisco, California, USA
• Dr. Alexxai Kravitz
  • National Institute on Diabetes and Digestive and Kidney Diseases (NIDDK) / National Institutes of Health (NIH),
    Maryland, USA

past

• Dr. Marcelo Rubinstein
  • Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires (UBA) Buenos Aires, Argentina
• Dr. Kathleen A. Grant
  • Oregon National Primate Center and OHSU, Oregon, USA
• Dr. Todd Thiele
  • University of North Carolina at Chapel Hill, North Carolina, USA
• Dr. David Sibley
  • National Institute of Neurological Disorders and Stroke (NINDS) / National Institutes of Health (NIH), Maryland, USA

Alumni

Image Tanisha London, BSc Postbaccalaureate IRTA Fall 2017 — Summer 2018 currently graduate student University of Southern California (USC)	Image Sannidhi Shashikiran Volunteer Sommer 2017 — Sommer 2018 currently college student at Georgetown University	Image Julia Lemos, PhD Postdoctoral Fellow, IRTA Summer 2012 — Winter 2017 currently Assistant Professor in the Medical Discovery Team Addiction at the MDT University of Minnesota
Image Martin Adrover, PhD Postdoctoral Visiting Fellow Winter 2010 — Fall 2017 currently faculty at INGEBI - CONICET in Buenos Aires, Argentina	Image Elizabeth Kirby Lab Secretary	Image Mariah Blegen, BS Postbaccalaureate IRTA Summer 2013 — Summer 2015 currently a medical student at School of Medicine & Dentistry University of Rochester
Image He, PhD Postdoctoral Visiting Fellow Winter 2014 — Summer 2014 currently a industry researcher in Shanghai, China.	Image Alanna Kaplan, BS Postbaccalaureate IRTA Summer 2011 — Summer 2013 currently a graduate student (MD/PhD) at Yale School of Medicine	Image Jilian Iafrati, PhD Visting Fellow IRTA Fall 2012 — Spring 2013 currently a post-doctoral fellow a University of California, San Francisco.
Image Katie Holroyd, BS Postbaccalaureate IRTA Spring 2012 — Spring 2013 currently a neurology resident at the Brigham and Women's Hospital & Massachusetts General Hospital	Image Alice Dobi (Yue Wu), PhD Postdoctoral Fellow Summer 2008 — Summer 2012 currently a pathology resident at the PennState Health Milton S. Hershey Medical Center	Image Mark Wilcox, BS Postbaccalaureate IRTA Summer 2011 — Summer 2012 currently a Ob/Gyn resident at the University of California, San Francisco and Co-founder and Director of MERIT (Medical Education Resources Initiative for Teens)
Image Robert Fuino, BS Postbaccalaureate IRTA Fall 2010 — Winter 2011 currently a neurology resident at the University of Vermont Medical Center	Image Nyssa Sherazee, BA Postbaccalaureate IRTA Spring 2010 — Summer 2011 currently a junior architect in New York	Image Paul Kramer, BA Postbaccalaureate IRTA Summer 2009 — Summer 2011 currently a post-doctoral fellow with Zayd Khaliq at NINDS
Image Eric Markey, BA Postbaccalaureate IRTA Summer 2009 — Fall 2010	Image Gail Seabold, PhD Postdoctoral Fellow, IRTA Summer 2007 — Winter 2009 currently a Scientific Skill Coach at the Office of Intramural Training and Education (OITE) - seaboldg@mail.nih.gov	Image Christine Christensen, BS Postbaccalaureate IRTA Summer 2008 — 2009 currently a graduate student of nursing at the University of Alabama

Summer Students