Exposure to chronic stress induces structural and functional changes in multiple regions of the brain that are important for motivation, memory/learning, decision-making, goal-directed behaviour and emotions.
These brain regions include limbic structures, involved in regulating our emotions and memory, such as amygdala, hippocampus, stria terminalis, solitary tract, arcuate nucleus and paraventricular nucleus, as well as higher level brain regions that are involved in complex behaviours such as medial prefrontal cortex (Sousa, 2016). Response to acute stress is controlled by connectivity between these regions, and chronic stress induces structural changes on these structures on the cell level, such as dendritic loss, receptor downregulation and tissue atrophy. These structural changes permanently change the pattern of connectivity between these regions, and damage brain plasticity. The network under chronic stress becomes markedly different from the healthy network under acute stress (Sousa, 2016).
The key differences between healthy acute stress and long-term chronic stress is a dysfunction of the maintenance and recovery from a state of stress. (Figure from Sousa, 2016)
Let’s dive deep into some brain regions that are first targets of chronic stress, and how exposure to chronic stress here manifests itself as lessened skills in memory and learning, unhelpful behaviours and repetitive thoughts.
MEMORY AND LEARNING
Hippocampus is a highly vulnerable brain region that is important for memory and learning (Anand and Dhikav 2012). It has a rich population of adrenal receptors where stress hormones such as glucocorticoids bind to. Chronic exposure to stress results in structural changes in the dorsal regions of this brain structure such as dendritic shrinkage, atrophy and spinal loss (Haber 2016). These changes contribute to the loss of feedback inhibitory activity in the Hypothalamic-Pituitary axis, which controls glucocorticoid release and secretion, and as a result neurons here become more vulnerable to stress. Glucocorticoid cascade hypothesis claims that this change in activity feeds back to induce even more problems in the hypothalamic-pituitary axis (Sapolsky et al., 1986).
Chronic stress-mediated changes alter the hippocampal release of the neurotransmitter glutamate to fronto-cortical circuits. The fronto-cortical circuits is a collection of brain regions that are important for working memory and flexible goal directed behaviour. Structural changes that happen in the fronto-cortical circuit as a result are widespread; including dendritic retraction and decreased spine density in prefrontal cortex (Cerqueira et al., 2007; Radley et al., 2004; Shansky et al., 2009; Wellman, 2001), atrophy and decrease in spine density in orbitofrontal cortex (Dias-Ferreira et al., 2009; Shansky et al., 2009), hypertrophy in dorsal and ventral striatum (Bessa et al., 2013; Dias-Ferreira et al., 2009; Rodrigues et al., 2012), dendritic remodelling in amygdala (Pêgo et al., 2008; Vyas et al., 2012) and dendritic remodelling and altered gene expression in bed nucleus of stria terminalis (Ventura‐Silva et al., 2012).
Continuous stress in the hippocampus leads to abnormal amyloid precursor protein synthesis and Tau hyperphosphorylation, which are shown to be markers for Alzheimers. It is reported that these effects start in the hippocampus, and then spread to fronto-cortical areas (Sapolsky et al., 1986).
MRI studies show that hippocampal spinal loss, namely atrophy, is correlated with memory deficits (Sousa, 2016), which agrees well with evidence showing that chronic stress impairs spatial and working memory(McEwen and Gianaros, 2011; Pinto et al., 2015), and that chronic stress disrupts spatial and sequence learning (Maran et al., 2017).
Prefrontal cortex is responsible for selective attention as well as internal construction of goals (McEwen and Morrison, 2013), and it is a part of corti-costrial network which executes planned behaviours (Haber 2016). Prefrontal cortex is altered in attention deficit disorder, schizophrenia, depression and PTSD (Arnsten, 2009 Drevets et al., 1997; Gamo and Arnsten, 2011; Tan et al., 2007). Chronic stress induces structural changes in prefrontal cortex, alongside changes in the corti-costrial network, which creates resistance to behavioral flexibility and yields to habit formation. These effects come out as an inability to initiate or switch between tasks.
The multitude of support for these findings include studies by Dias-Ferreria and colleagues who report that rats that were subjected to chronic stress exhibited less flexibility between behavioural strategies. This behaviour was accompanied by spinal loss in medial prefrontal cortex and associative striatum which are regions in corticostriatal network important in acquisition and execution of goal directed action, and spinal increase in sensorimotor striatum which plays an important role in habit formation (Dias-Ferreira et al., 2009). The switch from flexible and contextualised goal directed system to a rigid habit based system, characterised by these structural changes, is also shown to impact decision making (Simonovic et al., 2018), and produces potentially less favourable decisions (Mason et al., 2007).
Researchers recognise that optimisation of decision making strategies between habit-based and goal-directed systems is an important evolutionary advantage. Under uncertainty, where information is not available to guide goal selection and planning, general rules and habits can be advantageous(Dias-Ferreira et al., 2009). Stress shifts the strategical balances towards habitual behaviours to obtain the most benefits under uncertainty. However, when information is available and can be updated, switching to goal oriented behaviour is more beneficial so the organism can engage in contextualised action. Chronic stress, through its structural effect in the corticostriatal network, diminishes the ability to do this switch, which is how researchers believe continuous stress can give rise to addiction and compulsivity (Koob, 2008; Starcke et al., 2017).
Chronic stress also changes how our emotional state interacts with our cognition, through its effect in default mode network, a connection of regions that are activated at rest and guide stimulus-independent thought.(Greicius et al., 2003; Mason et al., 2007).Chronic stress increases the activation of this network when no task is present, and decreases its ability to deactivate between tasks (Soares et al., 2013). The altered activity of this network changes interactions between emotional processing and cognitive functions (Greicius et al., 2003; Mason et al., 2007). Researchers show that chronic stress depletes attentional resources and results in unconstructive repetitive thoughts (Scott et al., 2015;Sousa, 2016). Scott and colleagues support that rumination, this type of unconstructive repetitive thought, can explain the link between stress and cognitive decline.
Sousa indicates that the far reaching effects of stress in these brain regions is reversible to some extent, with reversibility being more likely in young age (Sousa, 2016). There are attempts in the field to understand the reversibility of these changes but the point of no return is mostly unexplored (Sousa, 2016). This only shows that we better need to decelerate the damaging effects of chronic stress on us and initiate this reversal, soon as we can.