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Using an integrated research program, the McLean Conte Center for the Neurobiology of Approach-Avoidance Decision Making aims to advance the understanding of brain mechanisms behind depression and anxiety. Funded through a five-year Silvio O. Conte Center for Translational Mental Health Research grant from the National Institute of Mental Health, researchers from laboratories at McLean Hospital, Massachusetts General Hospital, Massachusetts Institute of Technology, the University of Washington, and Brown University will collaborate on this important work.
Depression and anxiety disorders are major public health problems. Despite more than half a century of research, our understanding of and treatment for these prevalent disorders remains lacking.
The disorders are characterized by blunted approach-related behaviors and increased avoidance, which predict worse disease trajectories, increased suicide risk, and poor treatment response. However, little is known about the neurobiological mechanisms underlying abnormal approach-avoidance behavior in these disorders.
Treatment of these disorders remains stubbornly challenging and no new antidepressant treatments have been approved for decades. Currently available antidepressants (around 99% of which target the neurotransmitter serotonin) have shown themselves to be ineffective for a substantial portion of patients (up to 50% of those who try them) and are not particularly effective at preventing future depressive episodes.
This exciting opportunity will allow us to learn more about the brain and develop more effective treatments for anxiety and depression. Read McLean’s announcement of the hospital’s second Conte Center.
Newly discovered neurochemical pathways in the brain—such as those offered by nociceptin receptors—could provide clues to help develop novel antidepressant and anti-anxiety treatments with completely different modes of action and better rates of success. Nociceptin receptors have been implicated in pain, reward, learning, and stress responses—phenomena that are highly relevant to major depressive disorder (MDD) and anxiety disorders. Most importantly, depression has been associated with increased levels of nociceptin receptors in both animal models and postmortem studies of individuals who died by suicide.
To address unmet needs, this Conte Center will investigate the role of corticostriatal-midbrain and nociceptin circuitry in approach-avoidance behaviors. The center aims to identify novel treatment targets and markers that map disease course. These goals will be achieved by bringing together a highly interdisciplinary team with complementary expertise and an established record of successful collaboration.
The team will tackle pivotal questions through a highly coordinated approach that will entail numerous conceptual and technological innovations. Guided by a large amount of preliminary data, the proposed approach spans different species (mice, non-human primates, humans), approaches (non-invasive neuroimaging, intracortical recordings, and deep brain stimulation in humans; optogenetics, chemogenetics techniques, and CRISPR-cas9 knockdown in non-human animals), and units of analyses (genes, molecules, cells, circuits, physiology, behavior, self-report).
Critically, to increase translational impact, functionally identical tasks will be used, and identical molecular targets will be probed across three species.
The center’s unifying hypotheses are that:
These innovative hypotheses will be pursued through four closely intertwined projects supported by an administrative core and a computational modeling core. The significance and impact of the knowledge generated by the center will be substantial, as we aim to transform our understanding of the pathophysiology of two disorders that affect more than 35% of the U.S. population, which is a necessary step toward more effective treatments.
Diego A. Pizzagalli, PhD, Overall Center Director, Project 1 Director, Administrative Core Director
Dr. Pizzagalli is director of the McLean Imaging Center, the Center for Depression, Anxiety and Stress Research, and the Laboratory for Affective and Translational Neuroscience at McLean Hospital and director of research for McLean’s Center of Excellence in Depression and Anxiety Disorders. He is a professor of Psychiatry at Harvard Medical School.
Using a multimodal approach spanning different levels of analyses (e.g., environment, genes, brain, behavior), lab members in the Laboratory for Affective and Translational Neuroscience and the Center for Depression, Anxiety and Stress Research are working toward a better understanding of the causes, consequences, and pathophysiology of depression. One of the labs’ main goals is to improve the understanding of functional, structural, and neurochemical brain abnormalities in depression. This information will be critical for developing better treatments, identifying individuals at increased risk for depression, and uncovering markers that could be used to guide treatment selection.
Darin Dougherty, MD, MMSc, Project 2 Director/Principal Investigator
Dr. Dougherty is director of the Division of Neurotherapeutics at Massachusetts General Hospital and an associate professor of Psychiatry at Harvard Medical School.
The Division of Neurotherapeutics at Massachusetts General Hospital focuses on neurotherapeutic interventions for severe, treatment-resistant psychiatric illnesses. Their emphasis is on major depressive disorder and obsessive compulsive disorder. The research spans mechanistic studies, clinical trials, and device-based interventions employing a variety of techniques, including neuroimaging and electrophysiology. The team utilizes functional and structural magnetic resonance imaging (fMRI), positron emission tomography (PET), electroencephalography (EEG), magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS) and deep brain stimulation (DBS) to further understanding of psychiatric illness and treatment. They also provide clinical services and surgical treatments for psychiatric illness.
Ann Graybiel, PhD, Project 3 Director/Principal Investigator
Dr. Graybiel is an Institute Professor at the Massachusetts Institute of Technology and investigator at the McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences at MIT.
The goal of the Graybiel Laboratory is to gain an understanding of basal ganglia circuits sufficiently to provide clear potential avenues for therapeutic intervention in neurologic and neuropsychiatric disorders as well as fundamental insights into brain function. The lab focuses on discovering neural mechanisms underlying habit learning, motivation, motivationally based decision-making, and how these networks translate their signals to the action systems of the brain to build up behaviors. These studies are paralleled by work on the related issue of how behaviors can be driven first consciously by particular goals and outcomes and then be transformed into habitual behaviors hardly requiring conscious attention: in essence, how the brain decides which behaviors are successful enough to repeat and eventually make into habits.
Michael Bruchas, PhD, Project 4 Director/Principal Investigator
Dr. Bruchas is director of the Bruchas Laboratory, professor in the Department of Anesthesiology and Pain Medicine, and the Center for Neurobiology of Addiction, Pain, and Emotion in the Department of Pharmacology, and an adjunct professor in Bioengineering at the University of Washington.
Stress and pain-induced behavior is controlled by specific neurotransmitters and their signaling partners in the central and peripheral nervous systems. Many of these signals are conveyed through the activation of neuropeptide and monoamine receptor systems. These receptors are seven transmembrane spanning G-protein coupled receptors (GPCR, also called 7 transmembrane receptors) and they engage a variety of signaling cascades following neurotransmitter release and receptor binding. To expand the knowledge of the inner workings of the brain and to identify treatments for psychiatric diseases, the Bruchas Laboratory at the University of Washington aims to dissect how GPCR systems function in the contexts of stress, depression, addiction, and pain. The lab strives for a greater understanding of these receptors in real time, within intact systems, and biologically relevant models of behavior. Bruchas’ team utilizes pharmacological, optogenetic, genetic, viral, imaging, behavioral, and cutting-edge engineering approaches to uncover the specific role of GPCRs and their endogenous transmitters within in vivo neural circuits that modulate affective behavior.
Michael Frank, PhD, Computational Modeling Core Director/Principal Investigator
Dr. Frank is the Edgar L. Marston Professor of Cognitive, Linguistic and Psychological Sciences and director of the Carney Center for Computational Brain Science and the Laboratory of Neural Computation and Cognition at the Carney Institute for Brain Science at Brown University.
Research in Frank’s Laboratory of Neural Computation and Cognition at Brown University combines multiple levels of computational modeling and experimental work to understand the neural mechanisms underlying reinforcement learning, decision-making, and cognitive control. The lab develops neural circuit and algorithmic models that simulate systems-level interactions between multiple brain areas (primarily prefrontal cortex and basal ganglia and their modulation by dopamine). They test theoretical predictions of the models using various neuropsychological, pharmacological, genetic, and imaging (primarily EEG) techniques.
The overarching hypotheses of the current Conte Center are that MDD and anxiety disorders are characterized by negative biases in approach-avoidance behaviors due to dysregulation within corticostriatal-midbrain circuitry and nociceptin/orphanin FQ peptide and the nociceptin receptor (NOPR).
Project 1 will directly contribute to this goal by using functional magnetic resonance imaging (fMRI) while unmedicated individuals with current MDD or anxiety or individuals with past MDD perform an approach-avoidance decision-making task the team has adapted from non-human primates (Project 3).
The goal of Project 2 is to causally probe the role of corticostriatal circuits in approach-avoidance conflict using invasive recording and neurostimulation in awake, behaving humans.
Noninvasive human functional imaging studies provide valuable insights into the circuitry underlying specific brain functions but—fundamentally—are correlative in nature. Invasive measurements in humans during tasks provide markedly better spatial resolution (down to the single neuron) and temporal resolution (down to 5-10 milliseconds). More critically, the ability to stimulate using the same electrodes allows for unique “backwards neuroimaging.” Instead of performing a task and observing which brain networks are involved, one can stimulate different brain regions at different amplitudes, frequencies, and task epochs to observe effects on task performance all while simultaneously recording.
This project will study approach-avoidance conflict in two human models: deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) and surgical epilepsy monitoring.
The goal of Project 3 is to identify neural circuit mechanisms underlying MDD and anxiety disorders to advance therapeutic treatments.
Project 3 will capitalize on findings on the physiology and function of the anterior cingulate cortex, strongly linked to MDD and anxiety disorders, and its connections with specialized neurochemical compartments of the striatum called striosomes. Striosomes are richly interconnected with the neuromodulatory dopamine system, a key site influencing motivational states and, in dysfunction, neuropsychiatric illness.
The Graybiel lab developed a non-human primate (NHP) version of the approach-avoidance (Ap-Av) task used in humans to study anxiety and depression, as well as rodent models allowing manipulation of the ACC-striatal circuit. They found that manipulation of this circuit can profoundly bias Ap-Av decisions, by increasing avoidance behavior, and that such effects can be mimicked by chronic stress. These effects can be reversed dose-dependently by anxiolytics in NHPs and can be induced by ACC-striosomal circuit manipulations in rodents. Project 3 will work to determine the influence of nociceptin receptors (NOPR) on this circuit and decision-making.
The overall goal of Project 4 is to determine how the nociceptin/receptor system modulates the mesolimbic dopamine (DA) system and behavioral responses associated with stress, aversion, and motivated behaviors.
Bruchas’ lab recently identified a population of paranigral ventral tegmental area (pnVTA) nociceptin (PNOC+) neurons that constrain motivated behavior and regulate the motivation for natural reward seeking. These PNOC+ pnVTA neurons are engaged during motivation, as well as carry a negative valence when activated. The extensive body of preliminary findings strongly implicates these neurons in regulating motivated behaviors, stress responsivity, and avoidance behavior.
Project 4 will use newly developed mouse models for accessing endogenous nociception circuits and focus on the neurobiological mechanisms of how the prepronociceptin system engages the dopamine system to regulate motivation—a key component of depressive disorders.
The overarching goal of the Computational Modeling Core is to provide a common formal framework that can quantify dynamic decision processes in approach-avoidance conflict across species in Projects 1-4, including the impact of neural recordings and manipulations.
The core leverages hierarchical Bayesian parameter estimation of the drift-diffusion model (HDDM), which captures not only choice proportions for varying reward, aversion, and conflict but also the full response time distributions associated with these choices. HDDM facilitates reliable estimation of decision parameters and their modulation by trial-by-trial variance in neural signals and supports Bayesian hypothesis testing for how these parameters may differ as a function of clinical status, brain state, and manipulations (e.g., nociceptin antagonism, acute/chronic stress, stimulation). The team has shown how such “computational biomarkers” can provide enhanced sensitivity to discriminate between patient conditions and symptoms relative to traditional measures of behavior and brain activity.
The overarching goals of the Administrative Core are to oversee all scientific and administrative operations across projects and participating scientists; maximize integration and synergies across the four projects and the Computational Modeling Core; coordinate and implement training and educational activities within the center, with a specific focus on attracting new investigators to the field of affective translational neuroscience from diverse backgrounds; and interact with existing resources to enhance the research, education, and community outreach goals of the center.
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