Every single day of our life, we have to deal with an enormous amount and variety of stimuli that, since the day of our birth, we must learn to process in a way that allows us to live in harmony with our environment.

Generally speaking, our brain has evolved to allow us to both take advantage of the resources present in the environment and also survive to the most diverse challenges.

In this context, there is agreement among evolutionary biologists, neuroscientists and neurobiologists that learning how to deal with stressful stimuli and situations has been key to developing our survival skills as humans and even prosper in the most challenging situations.

This ability of our brain to change and adapt in accordance to the most diverse environmental stimuli is called neuroplasticity and recent research has demonstrated that it is heavily based on both our most primal physiological reactions to stress as well as learning and memory processes.

Neuroplasticity: The ability of the brain to remodel

in response to environmental stimuli.

In a nutshell, every time we are presented with a potentially stressful stimulus, our brain develops a response that is meant to tell us if the stimulus is potentially dangerous and to change our behaviour in order to stay safe.

This apparently simple process consists in reality of very complex interactions of biochemical and physiological responses that start in the brain and the affect the whole body in the effort of preparing it for a potentially life-threatening situation.

Learning is important in this whole stress coping story because our brain assumes that if a specific stressor has challenged us once in a given environment, it is very likely that it will do it again in the future. So the brain works non-stop to accumulate all relevant information adapting as quickly as possible to the environment, getting ready to promptly respond to all kinds of stressful situations.

However, in some cases our stress coping abilities are challenged to a point where our brain is unable to find the right adaptive strategy and instead starts showing increased vulnerability to all kinds of stressful stimuli, eventually changing its structure and activity in way that, altogether, undermines our survival.

Fig.1 The stress response system — **Fig.1** The stress response system

As mentioned, the normal stress response (Fig.1) is associated with emotional arousal and with the release of chemicals that are meant to prepare our physiology to a challenge. In conditions where stress levels are too high or if we are exposed to hard-to-solve challenges for too long, these physiological changes can become too expensive to maintain and even dangerous in the long run [1].

For instance, increased blood pressure increases the risk or myocardial infarction and atherosclerosis, a moderately elevated concentration in serum cortisol inhibits bone formation, while persistent activation of the stress response has been shown to foster weight loss, amenorrhea, and trigger emotional disorders such as generalised anxiety disorder (GAD), post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) [2, 3]. Therefore, it is key to our survival that, once activated, physiological and psychological stress responses be terminated as soon as possible [2-4].

How we usually stop potentially life-threatening stress

In humans, stress coping strategies are numerous, but they can be essentially be grouped into two categories: 1) problem-focused and 2) emotion-focused [5, 6].

Problem-focused stress coping strategies are based on the development of behaviours aimed at removing, avoiding or escaping from the stressor., whereas emotion-focused stress coping strategies are based on changing the emotional reaction to a stressor [7, 8]. In other words, we can change how we feel about a stressful situation and possibly find out that it’s not too stressful after all.

When stress coping fails

Both problem-focused and emotion-focused stress coping strategies have an adaptive value and can lead us to making healthy decisions in the short and in the long term. In other cases however, stress coping can take the wrong avenue and lead to a situation where not only the source of stress is not removed or controlled but perception of the environment is altered in a way that normal stress coping is sabotaged and made ineffective.

This is the case when overgeneralization, inflexibility, perseveration with an ineffective behaviour start taking over, leading to what is called maladaptive coping.

overgeneralization, inflexibility and perseveration with an ineffective behaviour

can lead to maladaptive stress coping.

The classic experimental model of maladaptive coping is learned helplessness. Learned helplessness is a generalization we can make when we seem to be unable to cope with a stressful situation and which is usually fostered by prolonged exposure to experiences with inescapable/uncontrollable stressors.

Research with laboratory animals shows that in a situation where a stressor cannot be avoided, the animal starts displaying signs of learned helplessness (e.g., freezing) and that abnormal (maladaptive) structural changes can be observed in areas of the brain that are key to both emotional regulation (e.g., the amygdala) and learning processes (e.g., the hippocampus) [9, 10].

In human subjects with emotional disturbances like anxiety and major depressive disorder, magnetic resonance imaging (MRI) research has shown similar results, and accumulating evidence also suggests that stress-induced chemical changes due to the chronic activation of the stress response system (e.g., increased blood concentration of glucocorticoids) are involved in maladaptive remodelling of emotion and learning centres [11].

Fig.2 Overall brain gray matter density decline during 3 years in patients with major depression [10] — **Fig.2** Overall brain gray matter density decline during 3 years in patients with major depression [10]

For example, a study on 30 patients with MDD and 30 healthy subjects found a link between poor response to antidepressive therapy and smaller volume in the hippocampus, amygdala, anterior cingulate cortex, and dorsomedial prefrontal cortex [12], all areas involved in emotion regulation and learning (Fig.2).

Take-home message

How we cope with stress has a major effect on the quality of our life and our health.

While our physiology is altered in response to acute stressful situations, under excessive, continued and/or inescapable stress, return to normal health conditions can be problematic.

Especially in vulnerable individuals, chronic stress can induce pathophysiological alterations in the normal stress-sensitive neuroendocrine, cardiovascular, immune and neural systems.

References

1. McEwen, B.S. and P.J. Gianaros, Stress- and allostasis-induced brain plasticity. Annu Rev Med, 2011. 62: p. 431-45.

2. McEwen, B.S., Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol, 2008. 583(2-3): p. 174-85.

3. Cabib, S., P. Campus, and V. Colelli, Learning to cope with stress: psychobiological mechanisms of stress resilience. Rev Neurosci, 2012. 23(5-6): p. 659-72.

4. Cabib, S. and S. Puglisi-Allegra, The mesoaccumbens dopamine in coping with stress. Neurosci Biobehav Rev, 2012. 36(1): p. 79-89.

5. Folkman, S., et al., Appraisal, coping, health status, and psychological symptoms. J Pers Soc Psychol, 1986. 50(3): p. 571-9

6. Lazarus, R.S., Toward better research on stress and coping. Am Psychol, 2000. 55(6): p. 665-73

7. Drugan, R.C., et al., Impact of water temperature and stressor controllability on swim stress-induced changes in body temperature, serum corticosterone, and immobility in rats. Pharmacol Biochem Behav, 2005. 82(2): p. 397-403.

8. Maier, S.F. and L.R. Watkins, Role of the medial prefrontal cortex in coping and resilience. Brain Res, 2010. 1355: p. 52-60.

9. Su, C.L., et al., Epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression. J Psychiatr Res, 2016. 76: p. 101-10.

10. Nakagawa, Y., et al., Effect of social isolation stress on saliva BDNF in rat. J Oral Sci, 2019. 61(4): p. 516-520.

11. Frodl, T. and F. Amico, Is there an association between peripheral immune markers and structural/functional neuroimaging findings? Prog Neuropsychopharmacol Biol Psychiatry, 2014. 48: p. 295-303.

12. Frodl, T.S., et al., Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry, 2008. 65(10): p. 1156-65.

When and How Stress Can Harm Your Brain