Hidden biology of chronic stress

This article is authored by Simantini Ghosh, assistant professor, psychology, Ashoka University, Delhi NCR.

Stress has become one of the defining experiences of modern life. We often describe it as an emotional burden—a demanding workplace, financial uncertainty, caregiving responsibilities, or difficult relationships. Yet what if chronic stress is not simply something we feel, but something that gradually rewires our biology?

Stress (Pexel)

Over the past decade, neuroscience has undergone a quiet but profound shift. Rather than viewing several neurological and psychological disorders solely through the lens of psychology or brain chemistry, researchers are increasingly recognising the central role of the body and the immune system in their pathophysiology. In my lab, we seek the answer to one of the most fundamental questions in this emerging field: How does chronic psychosocial stress become biologically embedded in the brain? The connection between the brain and the body has stoked some of the most fundamental questions since the age of Descartes. It is only recently through advent of advanced technology have scientists been able to understand how truly interlinked the brain and the body actually are.

However, in chronic disorders, immune activation may show a persistent activated pattern—this enhances the general wear and tear on the body, a term the scientific community now calls “Allostatic load.” When this activation becomes persistent, inflammation can spread beyond the body and begin to influence the brain itself. This idea came into being in the early 1980s when groups of neurologists studying disorders such as Alzheimer’s disease, Multiple sclerosis or stroke started garnering evidence that the brain, contrary to classical thoughts was not as immunologically inert or sequestered as believed since the 1900s. Gradually their work paved the way for a new discipline- neuro-immunity.

The field of neuro-immunity exploded through the 1990s and early 2000s when research groups across the world started understanding the bodies’ chemical messaging system, like the hormones also includes immune mediators, all of which are bidirectionally regulated from the brain. The advent of psychoneuro-immunity logically arose, as scientists started faithfully documenting neuro-immune changes of all kinds, not only in neurological but all psychological disorders.

Now we can safely conclude that the immune system does not distinguish only between bacteria and viruses. It also responds to prolonged psychological adversity. Repeated experiences of fear, uncertainty, social isolation or chronic conflict can activate the same ancient danger-sensing pathways that evolved to protect us from physical threats. Over time they can enhance the allostatic load and further cause problems in the way brain functions.

This changes the way we think about chronic stress. It is not "all in the mind." It is a whole-body process in which psychological experiences leave measurable biological signatures.

Our research focused on identifying the precise molecular machinery responsible for this transformation. While scientists have long known that stress and inflammation are associated, correlation alone does not explain mechanism. The critical question has been: Which biological pathways convert prolonged social stress into changes in brain function and behaviour?

Across a series of studies, our team mapped several interconnected immune pathways that are activated by chronic psychosocial stress. We identified molecules that function as upstream regulators of inflammatory signalling. Together, these pathways drive the production of inflammatory molecules such as interleukin-1β (IL-1β), disrupt the blood-brain barrier, damage synaptic connections, and ultimately alter behaviour.

These findings help answer an important biological puzzle. Chronic stress does not simply change our thoughts; it activates immune signalling that can reshape the brain's structure and function over time.

This emerging understanding has significant implications for psychiatry. For decades, most treatments for anxiety and depression have focused on neurotransmitters such as serotonin or dopamine. These treatments have transformed countless lives, yet many patients continue to experience only partial relief. One possible reason is that for some individuals, the underlying driver may not lie exclusively within neuronal signalling, but also within persistent immune activation.

This does not mean depression is "an inflammatory disease" or that psychological therapies have become less important. Rather, it suggests that mental health disorders arise through multiple interacting biological systems. The immune system appears to be one of them, and perhaps a more important one than previously recognised.

One particularly exciting aspect of this research is its translational potential. Several of the molecules we identified can already be targeted using drugs approved for entirely different medical conditions. In our proof-of-concept experiments, compounds such as Ibrutinib—currently used to treat certain blood cancers—and Disulfiram, a long-established medication for alcohol dependence, reduced inflammatory signalling and improved behavioural outcomes in preclinical models.

It is important to emphasise that these findings do not mean people experiencing stress or depression should begin taking immune-targeting drugs. Much more research, including carefully designed clinical trials, is needed before these approaches can be considered for psychiatric care. Nevertheless, the possibility of repurposing existing medicines offers an intriguing pathway towards developing more precise and personalised treatments.

Perhaps the broader message extends beyond pharmacology. If chronic stress leaves biological footprints in the brain, then preventing stress becomes far more than a matter of improving emotional well-being. It becomes a public health priority.

Persistent workplace pressure, domestic violence, social exclusion, financial insecurity and prolonged caregiving are not simply difficult life circumstances. They are experiences capable of activating biological processes that may increase vulnerability to mental illness. Recognising this does not diminish the importance of resilience or coping strategies. Instead, it reminds us that resilience also has biological limits, and that social environments profoundly influence physical health.

The future of mental health research lies in bringing these perspectives together. Psychology, neuroscience and immunology can no longer operate in isolation. Understanding how social experiences become molecular events—and how those molecular events reshape the brain—opens entirely new possibilities for prevention, diagnosis and treatment.

For too long, we have viewed chronic stress primarily as an emotional experience that affects the mind. Science is revealing a more complex reality. Stress is also a biological process that can alter immune function, brain health and behaviour. By uncovering the molecular pathways through which this happens, we move closer to understanding not only how mental illness develops, but also how it might one day be prevented at its source, rather than merely managed after symptoms appear.

(The views expressed are personal)

This article is authored by Simantini Ghosh, assistant professor, psychology, Ashoka University, Delhi NCR.