A temporal perspective on stress hormones and memory

Life is seldom devoid of stress. Stress is caused by external or internal environmental stimuli that challenge the homeostasis of the organism. In coping with these challenges, the body is mobilised to restate the inner balance. Among others, the central nervous system (CNS) is a key effector in this adaptive process (in dealing with the challenges by employing cognitive capabilities) as well as a major target of the stress-initiated physiological alterations. Correspondingly, the functionality of learning and memory is undergoing constant and dynamic modification in a stressful context. This
leads to commonly observed phenomena in which human memory formation and retention are susceptible to the influence of perceived stress. This has constituted the central interest of this research that aims to identify certain of the underlying mechanisms and definable rules of the stress’s impacts on learning and memory, and more specifically, to decipher the intriguing phenomenon that memory is not uniformly affected by stress, but often with opposing ends (i.e. enhanced versus impaired memory).
Perceived stress stimulates the sympatho-adrenomedullar system and the hypothalamic-pituitaryadrenal (HPA) axis, both of which eventually activate the adrenal gland which can, in response, release two categories of hormones: (nor)adrenaline and glucocorticoids. These are, among others, the neuromodulators that can, through their active forms in the CNS, manipulate the brain functions by molecular actions. Thus, they are the two major types of stress hormones on which we have focused our research interest. We have also narrowed down our observation of memory-related functionality to two main structures: the hippocampus and the amygdala; the former was selected due to its well-recognised role in declarative memory, and the latter for its renowned involvement in
emotional memory - as negative emotion is often linked to stress.

The entire research was conducted with a view to identifying functional relevances; and multiple levels of study were achieved - as in rodents and humans. In the animal, we adopted an electrophysiologically functional model at the network level - long-term potentiation (LTP), which represents a long-lasting increase in synaptic strength for neuronal contacts that have undergoneactivation and transmission events (activity-dependent synaptic plasticity). It shares various key characteristics with memory and is widely acknowledged as the best model to date to account for memory. In the human, we observed overall memory behaviour and employed fMRI technology to
monitor real-time brain functional activities during memory encoding.
Bearing our questions, focuses and approaches in mind, we first distilled insights from several previous studies and established a theoretical model in which the relationship between the stress hormones and memory is viewed from a new perspective that is centred on the time-dependency consideration of hormonal actions. We considered this as the starting-point to subsequent experimental attempts.

In Chapter 2, we elaborated on the proposed theory by elucidating several variables that can drive stress actions towards defined modulation of memory. Here, we highlighted the significance of convergence in time and space of the "stress factors" and the learning and memory activity to which they are intrinsically linked. Stress is part of the context or history of this learning activity, it modifies the way how new information is acquired and retained. Functional regulation
relies upon the molecular actions of modulatory factors. In our theory, the best example is
given by glucocorticoids. This major type of stress hormones, by employing different, timedependent mechanisms - genomic and nongenomic, can result in opposite regulations of neuronal physiology. The fast, nongenomic action, in combination with the effects from other fast-acting factors (e.g. noradrenaline, CRH), can facilitate synaptic transmission while the slow-onset, genemediate mechanism simply impairs it. In the following, we aimed to acquire more substantial evidence in support of this view.
We extended our observations concerning (inter)actions of corticosteroids and β-adrenoceptor agonists from the hippocampal CA1 area to the dentate gyrus. As shown in

Chapter 3, experiments were performed in in vitro rats brain slices. In the dentate gyrus, we were unable to demonstrate a corticosterone-mediated effect on LTP per se; however, a certain effect was revealed during inhibition of GABAergic transmission. A β-adrenergic agonist, isoproterenol, was capable of facilitating the induction of LTP after brief administration. The major finding was that, if corticosterone was supplied in unison with isoproterenol and LTP induction, synaptic potentiation was accelerated (or
enhanced during the early stage of potentiation), while a pretreatment of corticosterone hours in advance of isoproterenol and synaptic stimulation unequivocally hampered the LTP induced later on. This finding indicates that the time-dependent mechanisms of corticosteroids can enable bidirectional modifications of the interaction between the glucocorticoid and β-adrenergic systems, with direct impacts on activity-dependent synaptic plasticity within the hippocampus.

Reported in Chapter 4, we were able to replicate this study in the rat basolateral amygdala. Similarly, the β-adrenergic agonist, isoproterenol was shown to facilitate the induction of LTP within the amygdala, representing the efficacy of a fast-acting factor. However, corticosterone application predominantly displayed a suppressive effect on LTP, which was demonstrated by a gradual reversal of β-adrenergic-facilitated LTP in the case of co-application of corticosterone and isoproterenol around LTP induction, and by a full suppression of the isoproterenol-mediated LTP in the case of corticosterone pretreatment hours in advance. All these represent a slow-onset suppressive effect of corticosteroids on synaptic plasticity in the amygdala - a structure highly associated with emotional
memory.

We eventually elevated our research level to human study (Chapter 5), in which we asked our subjects to view and memorise both neutral and (negatively) emotional pictures and had their real-time brain activity monitored through fMRI. We concentrated on the time-dependent effects of glucocorticoids by administering an identical stress dose of cortisol to subjects at different time-points. In this study, we have identified a general enhanced memory of negative stimuli. Moreover, a prior adminiA temporal perspective on stress hormones and memory stration of cortisol (several hours in advance) was found to diminish the proportion of the negative pictures among all pictures remembered, without altering the absolute numbers of the remembered pictures, indicating a weight shift in memory encoding for emotional information. Neuroimaging has located this effect to the left hippocampus. This demonstrates a delayed, presumably genomic, glucocorticoid effect on human emotional memory.

In conclusion, we have investigated two types of stress hormones, focusing on measurement of functional outcomes and exploitation of multiple levels of research (i.e. in the rodent and human brains). Our results support the notion that a focus on the molecular mechanisms of stress hormones is valid in the exploration of stress-mediated regulation of cognitive functions. These molecular actions can drive diverse regulatory patterns, best exemplified by the effects of glucocorticoids; indeed, we have demonstrated their facilitative effects and suppressive actions in specific contexts. Above all, we have proposed a new perspective to take in examination of stress influences,
which is fundamentally based upon the understanding of the time-dependency of the
hormonal functions; by doing so, we can add significant value to established theories. Especially from human-level research, our results indicate a significant relevance to the control of the emotional bias reflected in memory - likely achievable through glucocorticoids manipulation; this may lend support to newly developed therapeutic approaches in the field.