Brain-derived neurotropic factor and cortisol levels negatively predict working memory performance in healthy males

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Abstract

There is now significant literature suggesting that increasing brain-derived neurotropic factor (BDNF) signalling may improve memory-related disorders such as Alzheimer’s disease. However, the effects of BDNF on short-term and working memory are not clear and existing evidence is inconsistent. Here we measured plasma BDNF and salivary cortisol levels, as well as working memory, on an N-Back task before and after mixed psychosocial/physiological stress induction in healthy males (N = 29). Stress induction was associated with higher circulating cortisol, but not BDNF levels. Higher cortisol and BDNF levels were significantly associated with poorer accuracy before and after stress induction. There was also a significant interaction, such that higher BDNF was associated with a buffering effect on the negative association between high cortisol and working memory. Future studies should replicate this data in larger samples, with emphasis on cortisol/BDNF interactions in determining working memory performance.

Introduction

Acute stress is associated with physiological and cognitive changes that are believed to facilitate adaptive responding to potentially threatening situations (Sapolsky, Romero, & Munck, 2000). These rapid and usually transitory changes result in enhanced memory and attention towards stress-related over non-stress related stimuli. Consequently, impairment of most ‘top-down’ working memory processes have been reported following psychosocial and physiological stress (Oei et al., 2006, Shields et al., 2016), with some studies showing transition from cognitive to habitual, non-cognitively demanding strategies (Gagnon and Wagner, 2016, Schwabe et al., 2012, Vogel et al., 2016). Impairment of cognitive functioning following stress occurs largely under high cognitive load and moderate-high stress severity, with little to no effect observed under low cognitive load or low stress conditions (Oei et al., 2006, Shields et al., 2016). Meta-analysis suggests that impairment of performance on working memory tasks is apparent in terms of accuracy but not reaction time (Shields et al., 2016).

Many of the changes following acute stress can be explained by activity-dependent fluctuation of hormones and other molecules. Cortisol is the most researched hormone in the stress field, with increases in cortisol levels in saliva and blood observed between 20 and 45 min following acute stress (Kirschbaum & Hellhammer, 1994). Whereas chronic dysregulation of cortisol is associated with multiple illnesses, including psychiatric disorders, Cushing’s syndrome, dementia, chronic pain, and others (Hannibal and Bishop, 2014, Nieman, 2015, Ouanes and Popp, 2019, Yehuda, 2009), acute fluctuation of cortisol serves a useful function and is associated with adaptive changes to mental and physiological functioning due to its role in reallocating energy and resource processing in response to stress (Sapolsky et al., 2000). Phasic cortisol signalling is believed to impair working memory by reducing prefrontal cortex activity (Porcelli et al., 2008), which is associated with executive functions such as working memory. Prefrontal cortex inhibition is thought by some groups to be mediated by the cortisol-responsive minerocorticoid receptor, which are localised in both the prefrontal cortex as well as amygdala and striatum (Vogel et al., 2016). Interestingly, impaired cognitive performance only occurs shortly (i.e. up to 1 h) following cortisol administration (Shields, Bonner, & Moons, 2015), but continues after the initial hour following induced stress (Shields et al., 2016).

There is recent evidence that serum levels of brain-derived neurotropic factor (BDNF) increase transiently following acute stress, with a large study (N = 124) finding an increase after 15 min post-stress and restoration to basal levels 60 min following the Trier Social Stress Task (Linz et al., 2019). This study follows a series of smaller samples where serum BDNF levels either increased 20 min following the Trier Social Stress Task (N = 24; Meng et al., 2011), or decreased following a 25 min stress induction session using the Paced Auditory Serial Additional Test followed by the cold-pressor task (CPT; N = 68; Sharma, Graham, Rohde, & Ceballos, 2017). Notably, Sharma et al., 2017 used a mixed psychosocial and physical stress task, whereas Meng et al., 2011, Linz et al., 2019 used purely psychosocial tasks. Further, whereas Meng et al. recruited only men in their twenties with half being alcohol dependent, Sharma et al. recruited men and women in their twenties, and Linz et al. recruited men and women with an average age of 40 (range 20–55). Sharma et al. also measured BDNF almost immediately following stress cessation, despite it being a longer stressor. It is also worth noting that circulating levels of BDNF consistently increase to physical exercise approximately 20 min following induction (Dinoff et al., 2017, Ferris et al., 2007, Rojas Vega et al., 2006, Szuhany et al., 2015).

BDNF is also a critical facilitator of synaptic plasticity underlying learning and memory in the hippocampus and prefrontal cortex (Bekinschtein et al., 2014, Jeanneteau et al., 2019, Lu et al., 2014). Short-term, BDNF is activity-dependent, acts as a synaptic messenger and is released within seconds to minutes from initiation of activity (Brigadski et al., 2005, Hartmann et al., 2001, Sasi et al., 2017). Following this, BDNF initiates multiple signalling cascades resulting in increased NMDA receptor conductance, increased dendritic growth, and other aspects of synaptic plasticity (Kuczewski et al., 2010, Park and Poo, 2013). The implications of this short-term activity is generally considered to be long-term development of memories through enhanced neural conductance, structural morphology and long-term potentiation (Kuczewski et al., 2010). Consequently, most contemporary studies have looked at the relationship between BDNF and long-term memory, particularly with relevance to disorders such as dementia (Egan et al., 2003, Fukumoto et al., 2010).

However, the relatively few studies that have tested short-term memory have also shown that activity-dependent BDNF is required for short-term and working memory in rodents (Alonso et al., 2002, Bimonte-Nelson et al., 2003, Galloway et al., 2008, Ma et al., 2011). Further, carriers of BDNF polymorphisms associated with lower BDNF efficiency perform worse on working memory tasks (Brooks et al., 2014). Conversely, other studies have found that overexpression of BDNF is associated with impaired working memory, short-term memory and passive avoidance in transgenic mice (Croll et al., 1999, Cunha et al., 2009, Papaleo et al., 2011). One possibility for this discrepancy is that there are differential effects of BDNF, with overexpression and under expression of BDNF resulting in worse outcomes than moderate expression (Andero et al., 2014, Tsai, 2018).

Another possibility, and one that is clinically relevant to stress-related disorders, is that BDNF and cortisol interact to influence cognitive outcomes (Carbone and Handa, 2013, Gray et al., 2013, Jeanneteau et al., 2019). BDNF mRNA is produced immediately following stress in the prefrontal cortex (Bland et al., 2005), higher BDNF increases glucocorticoid transcription (Lambert et al., 2013), and magnitude of the cortisol response to stress is reduced by blockade of BDNF (Jeanneteau et al., 2012). Moreover, BDNF receptors (TrkB) can be activated directly by glucocorticoids (Jeanneteau, Garabedian, & Chao, 2008) and excessively high glucocorticoid levels can impair the effect of BDNF on hippocampal synaptic plasticity (Kumamaru et al., 2008).

No studies to date have examined the relationship between acute psychosocial stress, cortisol, BDNF and cognitive functioning in humans. In this study, we aimed to test the effect of acute stress on plasma BDNF and salivary cortisol levels, as well as their combined effect on working memory performance. We included only males in this study since increases in peripheral BDNF levels following a stressor seem to be more robust in males compared to females, as evidenced by meta-analysis (Dinoff et al., 2017, Szuhany et al., 2015). We used salivary cortisol, since it is a more accurate reflection of biologically active cortisol compared to plasma levels (Kirschbaum & Hellhammer, 1994). We hypothesized that cortisol and BDNF would increase following stress. On balance evidence suggests that working memory performance should be enhanced by higher BDNF levels and impaired by higher cortisol levels. Finally, meta-analysis has reported that these effects would be most apparent in accuracy relative to reaction time (Shields et al., 2016).

Section snippets

Participants

Thirty-two male participants aged 18–35 were recruited from the University of Tasmania undergraduate Psychology cohort, as well as the broader university population. Exclusion criteria included serious neurological or physical illnesses, current use of tobacco, heavy alcohol use (as measured by a score over 16 on the AUDIT), a current psychiatric diagnosis, use of psychiatric medications, use of illicit drugs in the previous six months, high psychological distress (as measured by a score

Descriptive statistics

Table 1 contains descriptive information for study participants. There were no significant differences between MAST and Control conditions in age (p = .909, d = 0.04), AUDIT score (p = .856, d = 0.07) or K10 score (p = .318, d = 0.36).

Stress data

Data was incomplete from three participants who were unable to give final blood samples, which left 14 participants in the MAST group and 15 participants in the Control group for BDNF levels and 16 participants in each group for cortisol levels. Results are

Discussion

BDNF and cortisol are both considered to be important to cognitive functioning and working memory following stress. In this study, we hypothesised that working memory performance, particularly accuracy, would be impaired following stress. These impairments were hypothesised to be associated with higher cortisol levels and lower BDNF levels. We found evidence that cortisol, but not BDNF, was significantly responsive to stress, with salivary cortisol elevated 30 and 45 min post-stress in the

CRediT authorship contribution statement

Luke Ney: Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Visualization, Validation, Writing - original draft. Kim Felmingham: Conceptualization, Supervision, Funding acquisition, Writing - review & editing. David S. Nichols: Formal analysis, Resources, Supervision, Writing - review & editing. Allison Matthews: Conceptualization, Supervision, Formal analysis, Project administration, Writing - review & editing.

Acknowledgements

This work was supported by an NHMRC Program grant to KLF (APP1073041).

The authors have no conflicts of interest to report.

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