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Neurobiology of Resilience: Interface Between Mind and Body
Open accessAbstract
Stress-related neuropsychiatric disorders, such as major depressive disorder and posttraumatic stress disorder, exact enormous socioeconomic and individual consequences. Resilience, the process of adaptation in the face of adversity, is an important concept that is enabling the field to understand individual differences in stress responses, with the hope of harnessing this information for the development of novel therapeutics that mimic the body's natural resilience mechanisms. This review provides an update on the current state of research of the neurobiological mechanisms of stress resilience. We focus on physiological and transcriptional adaptations of specific brain circuits, the role of cellular and humoral factors of the immune system, the gut microbiota, and changes at the interface between the brain and the periphery, the blood-brain barrier. We propose viewing resilience as a process that requires the integration of multiple central and peripheral systems and that elucidating the underlying neurobiological mechanisms will ultimately lead to novel therapeutic options.
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“These findings reveal alterations at the levels of intracellular signaling, gene expression, neurotrophic factors, neurogenesis, neuroinflammation, excitatory and inhibitory neurotransmission, and synaptic number and function, and have been described in several brain regions implicated in depression 13-22 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [21]
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“For example, studies demonstrate that social defeat stress increases BDNF in the VTA-NAc pathway, leading to enhanced function that is thought to contribute to disruption of reward and motivation behaviors in depression 20,21 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [21]
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BackgroundProphylactic action of ayahuasca in a non-human primate model of depressive-like behavior
Grilo, M. L. P. D. M., de Sousa, G. M., de Mendonça, L. A. C., Soares, B. L., de Sousa, M. B. C., Palhano-Fontes, F., de Araújo, D. B., Perkins, D., Hallak, J. E. C., & Coelho, N. L. G. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.901425 · Cited by 16
“The processes that modulate resilience may be either innate or achieved during life (Russo et al., 2012; Borsboom, 2017; Cathomas et al., 2019).”
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“50 different drugs, the treatment of MDD is far from ideal, nor is the understanding of the mechanism of action of antidepressant drugs that are administered repeatedly (which is necessary to achieve clinical efficacy).”
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Pathophysiology of cognitive impairment in chronic kidney disease
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“Rather than a dichotomy, resilience and vulnerability can be understood as opposite ends of a continuum, which likely reflects the dynamic product of a complex interplay of individual and environmental factors (Cathomas et al., 2019; Rutter, 2012; Tost et al., 2015), including genetic and demographic characteristics,…”
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“…(i.e., IL-6) and immune cells (i.e., monocytes and neutrophils), which have been associated with mental disorders, like anxiety and depression (Cathomas et al., 2019; Raison et al., 2006; Weber et al., 2017), and also contribute to the chronicity and exacerbation of different inflammatory…”
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“(2019) covering the aspects linking the immune system and stress vulnerability (Cathomas et al., 2019).”
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“14 The HPA axis in the human body is a crucial stress response system that reacts to both acute and chronic stressors.”
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“Although it has been shown that stress can underlie the development and relapse of MDD, it is important to note that not all stress-exposed individuals develop this psychiatric manifestation [6 – 8].”
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Bertollo, A. G., Capitanio, M. Z., Schuh, L. A., Pradella, N., & Ignácio, Z. M. (2025) · Behavioural Brain Research · doi:10.1016/j.bbr.2025.115630 · Cited by 10
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Trauma and Remembering: From Neuronal Circuits to Molecules
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“…Philadelphia, PA, USA 4 VISN4 Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA One key challenge of understanding of resilience is characterizing its biological basis (Cathomas et al. 2019; Russo et al. 2012 ).”
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“Resilience is established through complex neurobiological processes that involve limbic structures and systems, the blood–brain barrier (BBB), and other structures and mechanisms [163–167].”
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“Previous studies have shown that the neurobiology of susceptibility and resilience to depression could involve alterations in neuronal circuits, neuroin fl ammation, and exacerbation of the endocrine system (16).”
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“In depression, positive responses to anti-depressants have been associated with increased hippocampal volume [84, 97].”
InfluentialHe, H., Cathomas, F., Parise, L. F., David, E., Rizk, M., Hawkins, K. A., Karpman, E., Russo, S. J., Guttman, E., & Murrough, J. W. (2026) · Molecular Psychiatry · doi:10.1038/s41380-025-03383-5 · Cited by 9
Self-citationNorweg, A. M., Hofferber, B., Maguire, S., Oh, C., Raveis, V. H., & Simon, N. M. (2023) · Respiratory Medicine · doi:10.1016/j.rmed.2023.107505 · Cited by 7
Early life adversities, psychopathologies and novel pharmacological strategies
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Perceived Stress, Resilience and Emotional Intelligence in Romanian Healthcare Professionals
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Stress and Reward: A Multimodal Assessment of Resilience after Childhood Sexual Abuse
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“Critically, although resilience is often operationalized as the absence of a pathological response, it likely comprises an active underlying process that enables individuals to adapt to past and future stressors [10-12].”
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“Although the stress response is physiological in nature, being aimed at coping with environmental changes, in stress-susceptible subjects, adaptive processes can turn into maladaptive ones, thus increasing the psychopathological risk [5].”
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“…a framework to interpret human behaviors in occupational settings [16] based on its premise that learning can occur in a social context through a dynamic, reciprocal interaction of the biological, personal, and environmental factors that contribute to the manifestation of resilience [17 – 20].”
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“It has been proven that the development of stress-induced mental disorders, e.g., psychotic depression, is based on the close interaction between the central and peripheral mechanisms [22].”
Di-aryl guanidinium derivatives: Towards improved α2-Adrenergic affinity and antagonist activity
McMullan, M., Kelly, B., Mihigo, H. B., Keogh, A. P., Rodrı́guez, F., Brocos‐Mosquera, I., García‐Bea, A., Miranda-Azpiazu, P., Callado, L. F., & Rozas, I. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112947 · Cited by 6
Promoting salutogenic pathways to health through complementary and integrative health approaches
Quinlan, E. B., Baumgartner, J. N., Chen, W., Weber, W. J., Horgusluoglu, E., & Edwards, E. (2024) · Frontiers in Psychology · doi:10.3389/fpsyg.2024.1473735 · Cited by 9
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“The level of resilience is modulated by various factors, of which meaning-making is a crucial coping mechanism [13,18,21-24].”
Enhancing cognition: The power of neuroplasticity
Mukhtar, I., & Iftikhar, K. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102882 · Cited by 7
The Immune Mind: Linking Dietary Patterns, Microbiota, and Psychological Health
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“Together, these findings converge on the concept of an “immune mind”, a model in which nutritional patterns shape neurobiological resilience through modulation of the gut microbiota and immune–inflammatory signaling [18–20].”
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Gastrodin enhances stress resilience through promoting Wnt/β-Catenin-dependent neurogenesis
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“Studies have found the inverse correlation between stress resilience and the risk of developing depression [12,13].”
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“In both humans and animal models, the phenomenon of resilience has been observed, involving complex neurobiological mechanisms (Cathomas et al., 2019; Feder et al., 2019; Murrough and Russo, 2019; Russo et al., 2012; Wood and Bhatnagar, 2015).”
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Stress History Modulates Corticotropin-Releasing Factor Neurons to Establish Resilience
Haynes, S. E., Lacagnina, A. F., Seo, H. S., Fang, L., Yang, X., Afzal, M. F., Morel, C., Menigoz, A., Rajan, K., Clem, R. L., et al. (2025) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2025.100656 · Cited by 5
“Stress resilience has long been considered a response separate from or in the absence of stimuli that gives rise to stress susceptibility, mediated by parallel circuits or cell types in a particular brain region (12,13,84).”
Self-citationIncreased random exploration in schizophrenia is associated with inflammationPreprint
Cathomas, F., Klaus, F., Guetter, K., Chung, H.-K., Beharelle, A. R., Spiller, T. R., Schlegel, R., Seifritz, E., Hartmann-Riemer, M. N., Tobler, P. N., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.15.989483 · Cited by 5
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Prefrontal corticotropin-releasing factor promotes resilience to social stress
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Brivio, P., Gallo, M. T., Volpari, E., Gruca, P., Łasoń, M., Litwa, E., Fumagalli, F., Papp, M., & Calabrese, F. (2025) · Neurobiology of Stress · doi:10.1016/j.ynstr.2025.100769 · Cited by 4
“Resilient individuals activate a range of adaptive stress-response mechanisms that enable them to cope effectively with stressful life events without developing persistent psycho-pathology (Cathomas et al., 2019; Nestler and Russo, 2024; Russo et al., 2012).”
Lupu, V. V., Nedelcu, A. H., Miron, I. C., Anton, S. C., Săsăran, M. O., Frăsinariu, O. E., Jechel, E., Bozomitu, L. I., Chisnoiu, T., Anton, C., et al. (2026) · Nutrients · doi:10.3390/nu18101541 · Cited by 4
“These interactions are best interpreted as multi-level and context-dependent processes that may influence neuronal responsiveness to metabolic and immune cues, particularly during early development [83,87–89].”
Eser, H. Y., Ertuna, D., Yalçınay-İnan, M., Sabitay, I. K., Balli, M., Kilçiksiz, C. M., Küçüker, M. U., Kılıç, Ö., Ercan, A. C., Güçlü, O., et al. (2024) · Frontiers in Psychology · doi:10.3389/fpsyg.2024.1479845 · Cited by 4
Huang, G.-D., Iqbal, J., Shen, D., Xue, Y.-X., Yang, M., & Jia, X. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1247714 · Cited by 4
Pathogenesis of Post-Traumatic Stress Disorder, Therapeutic Targets
Lapshin, M. S., Kondashevskaya, М. V., Epishev, V., & Patochkina, N. A. (2023) · Успехи физиологических наук · doi:10.31857/s0301179823010058 · Cited by 4
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Montes-Rodríguez, C. J., Hernández‐Reyes, E. D., Piña‐Díaz, V., Muñoz‐Torres, Z., Pérez‐Zarazúa, I., Urías, E. U., & Prospero-Garcia, O. E. (2024) · Journal of Neuroscience Research · doi:10.1002/jnr.25377 · Cited by 4
“…factors, including the nature of the experience (intensity, duration), the developmental stage at which the experience occurs, the presence of social support and genetic factors (Cathomas et al. 2019; Daskalakis et al. 2013; Montes-Rodríguez and Urteaga-Urías 2018; Nederhof and Schmidt 2012).”
Main Biological Models of Resilience.
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Hormesis, Resilience and Mental Health: Enhancing Public Health and Therapeutic Options
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Traumatic Effect of Beirut Port Explosion on Lebanese People's ExperiencesPreprint
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Homeostasis to Allostasis: Prefrontal Astrocyte Roles in Cognitive Flexibility and Stress Biology
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Metadata
- Authors
- Cathomas, F., Murrough, J. W., Nestler, E. J., Han, M.-H., & Russo, S. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Russo, Scott J.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 86
- Issue
- 6
- Pages
- 410-420
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC6717018
- OpenAlex
- W2936176560
- Cited by
- 296
- References
- 151
- Citations by year
- 2026: 22 · 2025: 55 · 2024: 55 · 2023: 36 · 2022: 45 · 2021: 40 · 2020: 38 · 2019: 5
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Center for Complementary and Integrative Health (P50 AT008661-01)
- Janssen Pharmaceuticals
- National Institute of Mental Health (P50 MH096890, R01 MH090264, R01 MH104559, R56 MH115409)
- Sunovion
- Novartis
- Sage Therapeutics
- Avanir Pharmaceuticals
- Allergan Foundation
- Janssen Research and Development
- Topics
- Social Sciences › Psychology › Clinical Psychology › Resilience and Mental Health
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- resilience, stress resilience, stress-related neuropsychiatric disorders, major depressive disorder, post-traumatic stress disorder, individual differences in stress response, brain circuits, immune system, gut microbiota, blood-brain barrier, neuroimmune interactions
- MeSH terms
- Gastrointestinal Microbiome, Adaptation, Psychological, Blood-Brain Barrier, Brain, Major Depressive Disorder, Humans, Immune System, Synaptic Transmission, Neurobiology, Psychophysiology, Stress Disorders, Post-Traumatic, Resilience, Psychological
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