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This activity was supported by contracts between the National Academy of Sciences and Alzheimer’s Association; American Academy of Neurology; American Brain Coalition; American College of Clinical Pharmacy; American College of Neuropsychopharmacology; American Neurological Association; American Psychiatric Nurses Association; American Psychological Association; Boehringer Ingelheim; BrightFocus Foundation; California Institute for Regenerative Medicine; Cohen Veterans Bioscience; Council on Social Work Education; Dana Foundation; Department of Health and Human Services’ Centers for Disease Control and Prevention; Centers for Medicare & Medicaid Services (75FCMC24P0022); Food and Drug Administration (R13FD005362); National Institutes of Health (75N98024F00001 [Under Master Base HHSN263201800029I]) through the National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Environmental Health Sciences, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, and National Institutes of Health BRAIN Initiative; Office of the Assistant Secretary for Planning and Evaluation (75P00124P00080); and Substance Abuse and Mental Health Services Administration (75S20223P00002); Department of Veterans Affairs (36C24E20C0009); Eisai Inc.; Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Harmony Biosciences; Hogg Foundation for Mental Health; Huo Family Foundation; Janssen Research & Development, LLC; The Jed Foundation; Lundbeck Research USA; The Michael J. Fox Foundation for Parkinson’s Research; National Association of Addiction Treatment Providers; National Multiple Sclerosis Society; National Science Foundation (DBI-1839674); One Mind; Paul G. Allen Frontiers Group; and Simons Foundation Autism Research Initiative. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2025. Applying Neurobiological Insights on Stress to Foster Resilience Across Life Stages: Proceedings of a Workshop. Washington, DC: National Academies Press. https://doi.org/10.17226/29243.

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APPLYING NEUROBIOLOGICAL INSIGHTS ON STRESS TO FOSTER RESILIENCE ACROSS THE LIFESPAN PLANNING COMMITTEE¹

HUDA AKIL (Co-chair), University of Michigan

ERIC NESTLER (Co-chair), Icahn School of Medicine at Mount Sinai

DEANNA BARCH, Washington University in St. Louis

INDIDA BIRTO, Here’s to Life

NADINE BURKE HARRIS, ACE Resource Network

BRIAN DIAS, University of Southern California

EVA FELDMAN, University of Michigan

ANDREW FULIGNI, University of California, Los Angeles

FRANCES JENSEN, University of Pennsylvania

JOHN KRYSTAL, Yale University

HUSSEINI MANJI, Oxford University; Duke University; Yale University; UK Government Mental Health

MICHAEL MILHAM, Child Mind Institute

CATHERINE JENSEN PEÑA, Princeton University

ALEKSANDRA VICENTIC, National Institute of Mental Health

Health and Medicine Division Staff

SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders

ALEXANDRA ANDRADA SILVER, Director, Forum on Mental Health and Substance Use Disorders

EVA CHILDERS, Program Officer (until July 2025)

KIMBERLY OGUN, Senior Program Assistant (until July 2025)

CHRISTIE BELL, Senior Finance Business Partner

CLARE STROUD, Senior Director, Board on Health Sciences Policy

Fellow

SHAIKHAH (SHAY) ALSHUAIB, Christine Mirzayan Science and Technology Policy Fellow (until May 2025)

Consultant

JANELL PAYANO SOSA, Science Writer

FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS¹

DEANNA BARCH (Co-chair), Washington University in St. Louis

FRANCES JENSEN (Co-chair), University of Pennsylvania

SHELLI AVENEVOLI, National Institute of Mental Health (until April 2025)

BRUCE BEBO, National Multiple Sclerosis Society

DIANE BOVENKAMP, BrightFocus Foundation

KATJA BROSE, The Chan Zuckerberg Initiative (until September 2025)

TERESA BURACCHIO, Food and Drug Administration

SARAH CADDICK, The Gatsby Charitable Foundation

ROSA CANET-AVILÉS, California Institute for Regenerative Medicine

MICHAEL CHIANG, National Eye Institute

MERIT CUDKOWICZ, Harvard Medical School; Massachusetts General Hospital

BEVERLY DAVIDSON, University of Pennsylvania

M. DENISE DEARING, National Science Foundation

NITA FARAHANY, Duke University

EVA FELDMAN, University of Michigan

BRIAN FISKE, The Michael J. Fox Foundation for Parkinson’s Research

DANIELLE GRAHAM, American College of Neuropsychopharmacology

MORTEN GRUNNET, Lundbeck (until December 2024)

MAGALI HAAS, Cohen Veterans Bioscience

H. E. HINSON, American Academy of Neurology

RICHARD J. HODES, National Institute on Aging

STUART W. HOFFMAN, Department of Veterans Affairs

YASMIN HURD, Icahn School of Medicine at Mount Sinai

STEVEN E. HYMAN, The Broad Institute of MIT and Harvard

MICHAEL IRIZARRY, Eisai Inc.

GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism

WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke

JOHN KRYSTAL, Yale University

ROBERT MALENKA, Stanford University

HUSSEINI MANJI, Oxford University; Duke University; Yale University; UK Government Mental Health

HUGH MARSTON, Boehringer Ingelheim (until May 2025)

BILL MARTIN, The Janssen Pharmaceutical Companies of Johnson & Johnson

DAVID McMULLEN, Food and Drug Administration

CAROLINE MONTOJO, Dana Foundation

JOHN NGAI, BRAIN Initiative

SANJEEV PATHAK, Acadia Pharmaceuticals

GENTRY PATRICK, University of California San Diego

STEVE PAUL, Seaport Therapeutics

SRI RAMULU PULLAGURA, Foundation for the National Institutes of Health (starting June 2025)

KATHRYN RICHMOND, Allen Institute

MARSIE ROSS, Harmony Biosciences

M. ELIZABETH ROSS, American Neurological Association

KATIE SALE, American Brain Coalition

RAYMOND SANCHEZ, Bain Capital Life Sciences

TERRENCE SEJNOWSKI, Salk Institute for Biological Studies

JOAN SERENO, National Science Foundation

SARA SHNIDER, One Mind

DAVID SHURTLEFF, National Center for Complementary and Integrative Health

JOHN SPIRO, Simons Foundation

ALESSIO TRAVAGLIA, Foundation for the National Institutes of Health (until June 2025)

NORA VOLKOW, National Institute on Drug Abuse

CHRISTOPHER WEBER, Alzheimer’s Association

DOUG WILLIAMSON, Independent Consultant

GARY WILSON, Huo Family Foundation

RICHARD WOYCHIK, National Institute of Environmental Health Sciences

STEVIN ZORN, MindImmune Therapeutics, Inc.

Health and Medicine Division Staff

SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders

EVA CHILDERS, Program Officer (until July 2025)

KIMBERLY OGUN, Senior Program Assistant (until July 2025)

CHRISTIE BELL, Senior Finance Business Partner

CLARE STROUD, Senior Director, Board on Health Sciences Policy

FORUM ON MENTAL HEALTH AND SUBSTANCE USE DISORDERS¹

MARGARITA ALEGRÍA (Co-chair), Harvard Medical School

ROSALIE LICCARDO PACULA (Co-chair), University of Southern California

CARLOS BLANCO, National Institute on Drug Abuse

W. PERRY DICKINSON, University of Colorado (representing the American Board of Family Medicine)

JOEL DUBENITZ, Office of the Assistant Secretary for Planning and Evaluation

RICHARD G. FRANK, Brookings Institution

HOWARD H. GOLDMAN, University of Maryland at Baltimore School of Medicine

KRISTIN KROEGER, American Psychiatric Association

OCTAVIO N. MARTINEZ, Hogg Foundation for Mental Health

BENJAMIN MILLER, Stanford School of Medicine

ZAINAB OKOLO, The Jed Foundation

ANNIE PETERS, National Association of Addiction Treatment Providers

KATHY PHAM, American College of Clinical Pharmacy

JULIE SEIBERT, National Committee for Quality Assurance

RUTH SHIM, University of California, Davis

MATTHEW TIERNEY, University of California, San Francisco (representing the American Psychiatric Nurses Association)

HALAEVALU VAKALAHI, Council on Social Work Education

AARON WEINER, Bridge Forward Group; University of Illinois UrbanaChampaign (representing the American Psychological Association)

Health and Medicine Division Staff

ALEXANDRA ANDRADA SILVER, Director, Forum on Mental Health and Substance Use Disorders

ADAEZE OKORO-AJUZIE, Senior Program Assistant (until May 2025)

SHARYL NASS, Senior Director, Board on Health Care Services

Reviewers

This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.

We thank the following individuals for their review of this proceedings:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by TRACY L. BALE, University of Colorado. She was responsible for making certain that an independent examination of this proceedings was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.

Acknowledgments

The National Academies of Sciences, Engineering, and Medicine staff would like to express gratitude to the sponsors of the Forum on Neuroscience and Nervous System Disorders and the Forum on Mental Health and Substance Use Disorders for supporting this workshop and other work of the National Academies; to the speakers whose presentations and remarks informed workshop discussions on the mechanisms of stress and resilience across the lifespan and how that knowledge can inform the development of public health interventions to cultivate resilience; to the planning committee members for their time and effort in the development of the workshop scope and agenda; to Stephanie Eldridge (Spark Street Digital), Tunde Ogunfolaju (Spark Street Digital), and Caset Associates for their support in the broadcasting and transcription of the workshop; to Janell Payano Sosa and Billie Smith-Haffener for their writing and copyediting expertise and contributions, respectively, on this proceedings; and to the additional National Academies staff who provided critical support to the workshop and this proceedings: Christie Bell, Lori Brenig, Samantha Chao, Amber McLaughlin, Alexandra Molina, Marguerite Romatelli, Leslie Sim, and Taryn Young.

Contents

1 INTRODUCTION AND BACKGROUND

State of Science on Stress and Resilience

Workshop Objectives

Organization of Proceedings

2 LIVED-EXPERIENCE PERSPECTIVES ON BUILDING RESILIENCE

A Spark in the Darkness: Electricity as Medicine

Mending Life’s Fractures with Golden Strength

3 UNDERSTANDING THE NEUROSCIENCE OF STRESS AND RESILIENCE

The Role of the Lateral Septum in Social Trauma

The Dynamics of the Amygdala–Hippocampal Circuit in Stress Resilience

Stress Controllability and Sex Differences in Neural Responses

Early Life Stress and the Role of Social Support

Recovery, Plasticity, and Intergenerational Mechanisms of Resilience

Discussion

4 CRITICAL AND SENSITIVE PERIODS TO BUILD RESILIENCE

Animal Models of Early Life Stress and Epigenetic Priming

Environmental Enrichment as a Pathway to Resilience Activation

Prenatal and Early Childhood Environmental Influences on Brain Structure

Early Childhood Environmental Influences on Adolescent Brain

Transition to Parenthood: A Unique Window for Neuroplasticity

Discussion

5 THE BRAIN–BODY CONNECTION BETWEEN STRESS SUSCEPTIBILITY AND RESILIENCE

Epigenetic Regulation and Immune Dysregulation in Stress-Related Outcomes

Maternal Stress, the Gut Microbiome, and Infant Neurodevelopment

Cardiovascular Consequences of Stress and Brain–Heart Communication

Discussion

6 PUBLIC HEALTH AND CLINICAL STRATEGIES TO ENHANCE RESILIENCE

Evidence-Based Mechanisms for Early Intervention and Public Awareness

Clinical Interventions and Public Health Strategies Promoting Resilience

Optimism in Treatment Among Complexities in Childhood Abuse

Discussion

7 ADVANCING RESILIENCE RESEARCH: KEY INSIGHTS AND POTENTIAL NEXT STEPS

Leveraging Biological Mechanisms for Early Detection and Intervention

Challenges After Stress Recovery

Discussion

Concluding Remarks

APPENDIXES

A References

B Workshop Agenda

Boxes and Figures

BOXES

1-1 Statement of Task

7-1 Key Points Raised Throughout the Workshop by Individual Speakers

FIGURES

1-1 The interplay between the factors that contribute to an individual’s susceptibility to stress and various stressors

1-2 The biological effects of allostatic load

2-1 The Japanese art of Kintsugi

3-1 Earlier introduction of a foster mother monkey significantly enhances social recovery, helping the separated infant monkey reintegrate more effectively

4-1 Maternal–fetal stress transfer occurs through multiple interconnected mechanisms that work synergistically to influence fetal development

4-2 Paternal brain volume reduction during early fatherhood

5-1 Illustration of how stress-induced changes activate physiological pathways that can influence the maternal microbiome, which in turn affects the developing fetus

5-2 Negative effects of PTSD on cardiovascular health

6-1 Categories of adverse childhood experiences (ACEs)

6-2 The bio-exposome represents the dynamic links across molecular, physiological, clinical, and societal levels

6-3 Rubber suit metaphor illustrating the protective gear Black family members rely on to navigate the challenges of society

Acronyms and Abbreviations