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The Silvio O. Conte Center for Stress Peptide Advanced Research, Education, & Dissemination (SPARED) at McLean Hospital, funded by the National Institutes of Health, is dedicated to basic and translational neuroscience research that probes the role of stress peptides in neuropsychiatric disorders.
Scientists in the SPARED Conte Center are pioneers and leading experts in the diverse fields of behavioral neuroscience, genetics, electrophysiology, stress, and neuroimaging, collaborating with experts in bioinformatics and statistical genetics to establish a translational approach for understanding the roll of stress peptides in psychiatric disorders.
The mission of the SPARED Conte Center is to combine world-renowned pre-clinical and clinical research in the field of stress biology to comprehensively examine, compare, and contrast the neurobiological effects of CRF and PACAP. These scientific elements include complementary molecular, cellular, circuit, physiologic, and behavioral measures in mice and humans, as well as detailed hypothesis testing in postmortem brain samples obtained from individuals with post-traumatic stress disorder (PTSD) and healthy controls.
The mechanisms by which stress triggers mood and anxiety disorders remain unclear, which impedes the development of improved therapeutics.
CRF (corticotropin-releasing factor) and PACAP (pituitary adenylate cyclase-activating polypeptide) are peptides with well-validated roles in the biology of stress-related conditions. Genetic alterations in these systems render people more vulnerable to stress, administration of either peptide mimics key stress effects, and both systems are altered by stress. Their high degree of conservation across species suggests that each regulates equally important—yet subtly different—aspects of stress responsiveness.
A major difference revealed by animal models is that the stressful effects of PACAP system activation tend to be more persistent than those of CRF system activation. Such differences, together with reciprocal, complementary, and homeostatic interactions between the peptides, may explain difficulties in developing CRF antagonist monotherapy for clinical use.
Neurobiology-based treatments that reduce stress would have utility across a range of DSM-defined psychiatric disorders and a major impact on health. The SPARED Conte Center combines world-renowned pre-clinical and clinical research in the field of stress biology to comprehensively examine, compare, and contrast the neurobiological effects of CRF and PACAP.
Our premise is that CRF and PACAP systems are interwoven and must be studied in tandem to understand their individual and interactive roles in stress responsiveness. Our overarching hypothesis is that CRF and PACAP effects can be differentiated, revealing CRF-, PACAP- and CRF+PACAP-predominant signatures that reflect different pathological states.
We will leverage group discoveries to enable active refinement and increasingly rigorous tests of the overarching hypothesis. Our scientific goals are to promote a mechanistic (cell- and circuit-based) understanding of features that distinguish CRF and PACAP effects and facilitate diagnostic and treatment advances that derive from appreciating the contributions of each system.
To complement the science, SPARED will also support a broad range of training and educational activities, including expansion of outreach programs as well as social media approaches to engage scientists and laypersons.
Our overall aims provide the basis for synergy that will transform this work from a collection of individual projects into a cohesive center where each element enriches—and is enriched by—the activities of the others, serving as a resource that benefits the scientific community and beyond.
SPARED brings together leading researchers who are committed to understanding stress and reducing its health burdens by combining new insights on biology with cutting-edge technologies and establishing a framework that enables sustained collaboration in the service of advancing discovery and innovation.
We use a multidisciplinary, RDoC-compatible approach to conduct high-impact research that transforms our mechanistic understanding of CRF and PACAP systems to facilitate the development of improved diagnostics and therapeutics for a range of DSM-defined psychiatric disorders that are caused or exacerbated by stress.
Our scientists intend to implement unique and impactful approaches that enhance education, training, and career development for future generations of translationally oriented stress researchers.
We use information and internet technologies to transform collaboration, investigation, and outreach to achieve broad communication of center-related activities. This includes sharing educational materials and strategies, news and updates, and data sets.
William (Bill) Carlezon, PhD, Program Director, Silvio O. Conte Center: SPARED
Dr. Carlezon is chief of the Basic Neuroscience Division at McLean Hospital and a professor of psychiatry at Harvard Medical School. He also directs the Behavioral Genetics Laboratory at McLean.
Kerry J. Ressler, MD, PhD, Co-Director Silvio O. Conte Center: SPARED
Dr. Ressler is chief scientific officer and chief of the Division of Depression and Anxiety Disorders at McLean Hospital and a professor of psychiatry at Harvard Medical School. He also directs the Neurobiology of Fear Laboratory at McLean.
Elena Chartoff, PhD, Director, Education & Training, Basic Neuroscience Division and Silvio O. Conte Center: SPARED
Dr. Chartoff is the director of the Neurobiology of Motivated Behavior Laboratory at McLean Hospital and is an associate professor of psychiatry at Harvard Medical School.
Sabina Berretta, MD, PhD, Investigator, Silvio O. Conte Center: SPARED
Dr. Berretta is the scientific director of Harvard Brain Tissue Resource Center and director of the Translational Neuroscience Laboratory at McLean Hospital. She is an associate professor of psychiatry at Harvard Medical School.
Vadim Bolshakov, PhD, Investigator, Silvio O. Conte Center: SPARED
Dr. Bolshakov is the director of the Cellular Neurobiology Laboratory at McLean Hospital and a professor of Psychiatry at Harvard Medical School.
Scott L. Rauch, MD, PhD, Co-Investigator, Silvio O. Conte Center: SPARED
Dr. Rauch is the president, psychiatrist in chief, and Rose-Marie & Eijk van Otterloo Chair of Psychiatry at McLean Hospital, chair of Partners Psychiatry & Mental Health, and a professor of psychiatry at Harvard Medical School.
Isabelle M. Rosso, PhD, Investigator, Silvio O. Conte Center: SPARED
Dr. Rosso is the director of the Anxiety and Traumatic Stress Disorders Laboratory at McLean Hospital and an associate professor of psychology in the Department of Psychiatry at Harvard Medical School.
The goal of Project 1 is to dissect the molecular events within specific neuron populations that underlie the stress response.
Project 1 is designed to operate at a deep mechanistic level to understand the role of cell-type-specific CRF- and PACAP-expressing neuron populations within central amygdala (CeA), bed nucleus of the stria terminalis (BNST), prefrontal cortex (PFC), and parabrachial nucleus (PBn).
Our hypothesis is that differential regulation of miRNA, mRNA, and DNA methylation in CRF and PACAP neurons of the CeA, BNST, PFC, and PBn will identify new targets for stress-related disorders.
The goal of Project 2 is to understand how PACAP and CRF interact within the basolateral amygdala (BLA) and the BNST to regulate anxiety-related behaviors.
Two neuropeptides—corticotropin-releasing factor (CRF) and pituitary adenylate cyclase-activating polypeptide (PACAP)—have been previously implicated in the regulation of anxiety in both humans and laboratory animals. The neurocircuitry of their effects is poorly understood.
Both neuropeptides are expressed in brain structures involved in control of anxiety-related states—in the BLA and the BNST, specifically—and could contribute to the production of anxiety by directing information flow in BLA-BNST circuits that regulate anxiety-related behaviors.
We will address this possibility by combining the use of optogenetic techniques with ex vivo and in vivo electrophysiology, mouse genetics, tract tracing with viral vectors, and behavioral testing.
The goal of Project 3 is to develop a more comprehensive understanding of how PACAP and CRF systems affect sleep and circadian rhythm.
Sleep is affected in many psychiatric illnesses. Some people with stress-related disorders, like post-traumatic stress disorder (PTSD), sleep less than normal, whereas others sleep more, or have fragmented sleep patterns that reflect more frequent bouts of sleep and wakefulness. There is considerable evidence that stress disrupts sleep, and we have shown that chronic stress in mice causes profound alterations in sleep and diurnal rhythms.
In contrast, the effects of sleep dysregulation on brain systems that mediate stress effects are not thoroughly understood. Periods of poor or restricted sleep may produce molecular alterations that subsequently affect sleep. Work in rodents demonstrates important similarities and differences between CRF (corticotropin-releasing factor) and PACAP (pituitary adenylate cyclase-activating polypeptide) effects on behavior. Although both peptides increase acoustic startle, a measure of vigilance often used in preclinical and clinical studies of anxiety and fear, PACAP effects tend to be persistent (lasting more than 1 week), whereas CRF effects resolve quickly.
These types of findings, together with known genetic alterations in CRF and PACAP systems in people vulnerable to stress-related illness, provide a rationale for comparing and contrasting the neurobiology of these peptides. The effects of CRF and PACAP on sleep have not been directly compared, particularly over extended periods of time.
Our premise is that these peptide systems affect—and are affected by—sleep. Our hypothesis is that there is a reciprocal relationship between these peptides and sleep, such that activation of CRF and/or PACAP systems will affect sleep and, conversely, sleep restriction will affect CRF and/or PACAP systems, but that the persistence of these effects will differ.
Tests will be conducted in male and female mice implanted with wireless transmitters that enable continuous collection of EEG, EMG, body temperature, and activity data for several weeks. Molecular analyses will focus on brain areas implicated in the emotional aspects of stress, including the amygdala (AMG), bed nucleus of the stria terminalis (BNST), and prefrontal cortex (PFC), as well as areas more traditionally implicated in sleep and biological rhythms. We will also perform circuit-mapping studies to provide insights on neural connections between regions that regulate emotional behavior and those that regulate sleep.
The goal of Project 4 is to determine whether variation in CRF and PACAP system signaling tracks with hyperarousal intermediate phenotypes in women and men with PTSD.
Although PTSD was once conceptualized as a direct consequence of extreme stress, the influence of constitutional factors on illness liability is now recognized. Prominent among these factors are genetic risk and biological sex. PTSD is 30-40% heritable and twice as common in women.
Neurobiological mechanisms have been difficult to identify, leading to efforts to identify dimensional symptom measures and intermediate phenotypes that are sensitive to disease-promoting influences. Altered function of CRF (corticotropin-releasing factor) and PACAP (pituitary adenylate cyclase-activating polypeptide) systems are candidate mechanisms of sex-dependent moderation of risk for PTSD and other DSM-defined conditions, including major depressive disorder (MDD).
In women with PTSD, higher blood PACAP levels and allelic variation in the PAC1 receptor (PAC1R) predict greater anxious arousal symptoms and total symptoms, and greater physiological arousal during anxiety-related paradigms.
Variation in CRF and its type-I receptor (CRFR1) are associated with PTSD and MDD, and contribute to sex differences in physiological arousal following severe stress. CRF and PACAP systems overlap with brain areas implicated in alterations in RDoC domains (fear, anxiety, arousal) seen in PTSD, including extended amygdala (extAMG) and medial prefrontal cortex (mPFC).
Our premise is that studying dimensions of hyperarousal across multiple levels of analysis will identify intermediate phenotypes of PTSD. In 230 patients with DSM-defined PTSD (115 women and 115 men), we will examine relationships of CRF/PACAP biomarkers with neuroimaging measures of the amygdala (AMG) and bed nucleus of the stria terminalis (BNST), due to evidence of their roles in fear and anxiety, and of their relevance to PTSD. We also will examine the mPFC, which affects arousal responses to threat via reciprocal connections with the AMG and BNST.
We propose an innovative combination of CRF/PACAP, physiology, and brain measures:
Our overarching hypothesis is that we will identify CRF-, PACAP-, and CRF+PACAP-predominant intermediate phenotypes, and sex-dependent relationships.
The goal of Project 5 is to elucidate relationships among PACAP and CRF signaling, circadian rhythm regulation, and sex differences in the pathophysiology of PTSD from the postmortem human brain.
Compelling evidence indicates that CRF and PACAP, as well as their interactions together, make critical contributions to stress responses, anxiety, circadian rhythm regulation, and the pathophysiological mechanisms of PTSD.
The underlying neural circuitry involved is poorly understood, but important clues point to the bed nucleus of the stria terminalis (BNST), amygdala (AMG), dorsal anterior cingulate gyrus (dACG), and the hypothalamus (HPTh) as critical regulators of these functions. Current evidence indicates that CRF and PACAP mechanisms that contribute to PTSD may be sex-specific, raising the possibility that the underlying brain changes and potential therapeutic targets may differ in males and females.
Current and preliminary data suggest that PACAP signaling may directly affect CRF expressing cells and that circadian expression of PACAP and its cognate receptor PAC1R, and their subsequent regulation of CRF systems, may vary during the course of the day. Such variations may potentially contribute to disruptions of sleep/wake cycles associated with DSM-defined illnesses, including PTSD, major depression, and anxiety disorders. Surprisingly, virtually no information is available on cell-level expression of CRF and PACAP signaling pathways in the human AMG, BNST, dACG and HPTh, their relationships to circadian rhythms, and the involvement of CRF/PACAP interactions in the neuropathology of PTSD.
Our overarching hypothesis is that abnormalities affecting CRF/PACAP pathways in the BNST, AMG and dACG and HPTh contribute to the pathology of PTSD.
The Administrative Core maintains the organizational structure necessary for enabling successful communication, integration, and cooperation among SPARED Center projects. The core serves as a mechanism for frequent updating, and ensuring effective allocation and utilization of resources for maximizing synergy and scientific advancement.
The core also supports the education and training activities needed to develop future researchers at McLean, a national leader as the premier psychiatric teaching hospital of Harvard Medical School. The core is co-directed by William Carlezon, PhD, and Kerry J. Ressler, MD, PhD and has four specific aims.
The core coordinates, integrates, and advances center research, taking responsibility for the overall coordination of the 5 research groups in the SPARED Center. The core also directs the education, training, outreach, and statistics components of the center. Core leaders work directly with the directors of the education, training, and outreach initiative and statistics/data management components.
So that our work will have a global reach, the core maintains a SPARED Center web and social media presence. The core uses these resources to disseminate our work to target audiences of scientists and health care practitioners, students (K-12, college, medical school, and graduate students), educators, NIMH outreach partners, and the general public.
The core provides multiple career-building opportunities for early-career scientists conducting SPARED Center-related research. This includes seed grants and travel awards. In addition, we organize a SPARED symposium for faculty and international stress leaders to present their work. We also encourage SPARED faculty to submit symposia proposals to relevant scientific meetings, such as the Society for Neuroscience (SfN), the American College for Neuropsychopharmacology (ACNP), and the Society of Biological Psychiatry (SOBP). The core also provides an educational platform that supports developing and delivering new courses.
The core shares our collective enthusiasm and expertise with the larger community through outreach. Our outreach mission focuses on initiatives aimed at the public and students, K-12 and college. This includes ongoing collaboration with the Boston Museum of Science and developing a new outreach pipeline with regional liberal arts colleges by sending SPARED Center faculty to give research talks, meet with students, and recruit future investigators. Thus, the core will support the research mission while enhancing career development and maximizing the impact of the work for experts and laypersons.
The SPARED Conte Center is actively engaged in sharing our enthusiasm for neuroscience and our commitment for brain and behavior-based mental health research with the members of our community and general public. Not only do we endeavor to inspire future generations of neuroscientists, but also to foster candid communication with the public about the science of mental health to increase support for research. To meet these goals we conduct a series of events and activities appropriate for diverse non-expert audiences about the brain and its role in behavior.
Given our shared interest in uncovering the consequences of stress on the brain and behavior, and appreciation that stress is commonplace in our everyday lives, many of our events also include discussion regarding the current understanding of the consequences of stress on the brain and their relationship to mental illness.
Through collaborations with Brains Matter, McLean’s neuroscience education and outreach program, we engage in large public science outreach activities, including participation in the Cambridge Science Festival and the Museum of Science’s Annual Health Fair. We also welcome the opportunity to enter local schools to conduct fun, engaging, and interactive events focusing on the basic principles of brain function and health, discuss recent neuroscience discoveries that have changed the way we understand brain function, and share the experiences that inspired our entry into the realm of neuroscience.
Our presentations are often supported by postmortem human brain specimens provided by the Harvard Brain Tissue Research Center as well as a variety of animal brain specimens. This allows us to discuss the importance of access to brain tissue in neuroscience research and also how brains differ among species.
Presentations are led by members of the SPARED Center, including researchers, staff, and undergraduate students from local universities engaged in research with SPARED. Collectively we hope to share our knowledge with the public concerning the central role that neuroscience plays in uncovering the inner-workings of our brains and behavior.
Part of our mission as a Conte Center is a dual initiative of research and outreach. This mission means that our center members have the opportunity to share their work with scientist, medical, and lay audiences. Students, fellows, and staff in the center—as well as scientists from neighboring labs and departments—are invited to participate in our outreach programs whenever possible, and to suggest ideas for new programs.
Some ways to get involved include:
To get more information or propose a new outreach idea, contact us by email.
Please feel free to contact the Silvio O. Conte Center at McLean Hospital:
Contact: Shannon MacDonald, Center Coordinator
Follow us on Twitter @AtSpared