Why chronic stress changes the brain – the neurobiology of a persistent alarm
Chronic stress is not just a “difficult period" or a “tense week". It is a state in which the nervous system and the brain operate in threat mode for weeks, months, or sometimes years. During this time real, measurable structural and functional changes occur in the brain – not metaphors, but changes that can be seen in imaging studies and measured with cognitive tests.
The question “how does stress affect the brain" has ceased to be theoretical – today we know which areas shrink, which expand, how brain chemistry changes and why chronic stress and the brain is a relationship that can determine the risk of depression, anxiety, cognitive disorders, and in the longer term – even dementia.
How the stress response works – short-term and long-term
In response to threat the body activates the hypothalamic-pituitary-adrenal (HPA) axis, which produces cortisol – the main stress hormone. In short-term stress cortisol mobilizes the body: it raises blood glucose, improves alertness, supports rapid reaction and short-term memory consolidation.
The problem arises when stress is long-lasting (chronic) and does not subside – then cortisol shifts from helper to threat:
Instead of protecting neurons, it begins to damage them.
Instead of supporting memory, it weakens neurogenesis (the creation of new neurons) in the hippocampus.
Instead of mobilizing, it leads to chronic inflammation, oxidative stress and disruptions in the production of neurotrophic factors (e.g., BDNF – brain-derived neurotrophic factor).
As a result chronic stress acts like a permanent “renovation" in the brain – but in a harmful way.
Three key brain areas changed by chronic stress
1. Hippocampus – it shrinks and weakens
The hippocampus is the center of memory and learning, and also an important structure in regulation of the HPA axis (it has cortisol receptors and “inhibits" further production of the stress hormone).
Effects of chronic stress:
Reduction in hippocampal volume visible in MRI studies of people with chronic stress, depression, PTSD.
Decrease in the number of dendritic spines (the contact points between neurons) – neurons “shrink."
Weakened neurogenesis – the generation of new neurons in the hippocampus is suppressed by high cortisol.
Lowered BDNF levels – the key protein supporting neuron survival, formation of new synaptic connections and neuroplasticity.
Clinical consequences:
Memory problems (particularly declarative memory – facts, dates, events).
Difficulty learning new information.
Reduced ability to inhibit the stress response (because the hippocampus no longer effectively “turns off" the HPA axis).
2. Prefrontal cortex (PFC) – loses connections and flexibility
The prefrontal cortex is responsible for executive functions: planning, decision-making, impulse inhibition, cognitive flexibility, and emotion regulation.
Effects of chronic stress:
Reduction of dendrites – neurons in the prefrontal cortex “shrink," losing branches.
Loss of dendritic spines and weakening of synaptic connections.
Reduced functional connectivity (functional connectivity) in cortico-cortical circuits.
Clinical consequences:
Problems with concentration and attention.
Reduced cognitive flexibility (rigidity in thinking, difficulty switching between tasks).
Poorer impulse control and emotion regulation.
3. Amygdala – it grows and strengthens
The amygdala is the center for processing emotions, particularly anxiety and fear. It is responsible for fast, automatic reactions to threat.
Effects of chronic stress:
Dendritic growth – unlike the hippocampus and prefrontal cortex, neurons in the amygdala grow under stress.
Increase in number of dendritic spines – more synaptic connections.
Increase in amygdala volume – studies show up to a 20% increase in chronically stressed individuals.
Clinical consequences:
Heightened emotional reactivity – “explosions" of anger, anxiety, panic.
Oversensitivity to stressful stimuli – even minor situations can trigger strong reactions.
Difficulty “calming down" fear responses.
The role of cortisol and BDNF – the neurochemical mechanism of damage
Cortisol – from protection to toxicity
In acute stress cortisol acts protectively, but in chronic stress:
It blocks neurogenesis in the hippocampus.
It damages NMDA receptors (key for learning and memory).
It increases glutamate activity, which leads to “excitotoxicity" – excessive excitation and neuronal damage.
BDNF – the brain growth factor “silenced" by stress
BDNF (brain-derived neurotrophic factor) is the key protein responsible for neuron survival, dendritic growth, hippocampal neurogenesis and neuroplasticity.
Chronic stress lowers BDNF levels, especially in the hippocampus and prefrontal cortex, which directly contributes to:
neuronal atrophy,
impairment of memory and cognitive functions,
greater risk of depression (low BDNF strongly correlates with depression).
Good news: physical activity, mindfulness, antidepressant medications can raise BDNF and reverse some of the stress-induced changes.
Are stress-induced changes reversible?
Yes – but with caveats.
In young adults structural changes in the hippocampus and prefrontal cortex are partially or fully reversible after stress subsides – especially when the stress period was not extremely long.
In middle-aged and older adults the ability to reverse structural changes is significantly reduced.
What helps reverse the changes:
Ending exposure to chronic stress.
Physical activity (especially vigorous aerobic exercise).
Mindfulness and enriched cognitive environment (new challenges, learning).
Pharmacotherapy (antidepressants acting on the serotonin system may support BDNF production).
Psychotherapy (CBT, mindfulness-based therapies) – reduce HPA axis activation.
Clinical implications – how to recognize and intervene
When to suspect that chronic stress is affecting the brain?
Symptoms suggesting structural/functional changes:
Memory: difficulty remembering new information, “brain fog".
Executive functions: difficulty planning, making decisions, organizing.
Cognitive flexibility: rigid thinking, difficulty switching between tasks.
Emotion regulation: emotional oversensitivity, outbursts of anger/crying.
What can be done in clinical practice?
Interventions:
Pharmacotherapy: SSRI/SNRI (supporting neuroplasticity through modulation of serotonin and BDNF).
Psychotherapy: CBT, mindfulness-based therapies.
Physical activity: regular aerobic exercise (the strongest stimulus to increase BDNF).
Nervous system regulation techniques: controlled breathing, mindfulness, yoga, HRV biofeedback.
Enrichment of the cognitive environment: new intellectual challenges, learning, exposure to nature.
Selected sources
McEwen BS, Bowles NP, Gray JD, et al. Mechanisms of stress in the brain. Nat Neurosci. 2015;18(10):1353-1363.
The impact of chronic stress on brain function and structure. Int J Adv Innov. 2024.
The impact of cortisol on brain function in stress and the nervous system. Int J Adv Innov. 2025.
Arnsten AFT, Datta D, Del Tredici K, Braak H. Chronic stress weakens connectivity in the prefrontal cortex. Alzheimers Dement. 2021.
Serotonin, BDNF & neuroplasticity in brain health. 2026. https://www.youtube.com/watch?v=VIg61YHKJhc
BDNF and glucocorticoids (Gray, Milner, & McEwen, 2013). 2026.
Neuroplasticity & depression relief: BDNF. 2023.
Peavy GM, et al. Effects of chronic stress on memory decline. Am J Psychiatry. 2009;166(12):1384–1391.
Shields GS, Moons WG, Slavich GM. Neurocognitive effects of stress. Mol Psychiatry. 2023.
Alzheimer's Society UK. Can stress cause dementia? 2025.
Rewired Brain. The impact of chronic stress on brain function. 2025.
Deppermann S, et al. Stress-induced neuroplasticity. Neuroscience. 2014;283:166–177.
Novais A, et al. Chronic stress-induced neuroplasticity in the prefrontal cortex. Int J Mol Sci. 2023.
Depression and BDNF. 2020. https://www.youtube.com/watch?v=zS9NmAS7Hq4
BDNF unveiled: Role in major depression disorder. 2024.
