Stress and cognition : mechanisms regulating memory and empathy

Stress kan cognitie op vele manieren beïnvloeden. Het is algemeen bekend dat niet al onze herinneringen even sterk zijn. Emotionele en traumatische levenservaringen worden beter opgeslagen in ons geheugen dan alledaagse gebeurtenissen. Daartegenover is het bekend dat stress juist het oproepen van eerder aangeleerde informatie uit ons geheugen kan verminderen. Voorbeelden van dit verschijnsel zijn de moeilijkheden die we kunnen hebben met het herinneren van simpele informatie tijdens een stressvol examen of sollicitatiegesprek. Eerder onderzoek heeft aangetoond dat stresshormonen (glucocorticoïden en adrenaline) die vrijkomen uit de bijnieren tijdens stressvolle gebeurtenissen een belangrijke rol spelen bij beide processen. Van oudsher is bekend dat glucocorticoïdhormonen werken via een langzaam mechanisme door middel van het beïnvloeden van genexpressie. Recent onderzoek heeft echter bewezen dat er ook hele snelle, niet-genomische glucocorticoïd effecten zijn. Maar het mechanisme dat hier achter zit is nauwelijks bekend. De resultaten van dit proefschift tonen aan dat het endocannabinoïde systeem, een snelwerkend lipide systeem in de hersenen, vooral bekend vanwege de psychoactieve effecten van cannabis, onmisbaar is bij deze snelle geheugeneffecten van glucocorticoïden. Deze bevindingen kunnen niet alleen leiden tot nieuwe inzichten bij het bestrijden van emotionele of traumatische geheugenprocessen in mensen met een post-traumatische stressstoornis maar kunnen mogelijk ook verklaren waarom het gebruik van cannabis zo hoog is in mensen met traumatische levenservaringen. Stress has multifaceted effects on cognition. It is well known that memories are not created equally, for instance emotionally arousing and traumatic life events are consolidated and thereby remembered better. This is an evolutionarily important mechanism since it promotes the remembrance of events that are significant for the survival of the organism. On the other hand, stress acutely impairs the retrieval of previously learned information. Daily life examples of this phenomenon could be the difficulty in retrieving information during an important exam or job interview. Prior studies indicated that both effects result from the influences of hormones (glucocorticoids and epinephrine) released from adrenal glands during stressful episodes. Classically, glucocorticoids act through slow genomic pathways that involve transcriptional regulation that take hours to emerge but they can also exert nongenomic actions (actions not involving transcriptional events) in a rapid fashion. The neurobiological mechanisms that are responsible for mediating these rapid glucocorticoid actions are however poorly understood. The findings of this thesis indicate that the endocannabinoid system, a fast-acting lipid system in the brain, mainly known for mediating the psychoactive effects of cannabis, is crucially involved in regulating the rapid effects of glucocorticoids on both the consolidation and retrieval of emotionally arousing experiences. These findings might not only result in the development of new treatment strategies for people with traumatic memories and posttraumatic stress disorder, but they might also explain why the prevalence of cannabis use is so high in people suffering from traumatic experiences.

The endocannabinoid system: a key modulator of stress effects on memory

As mentioned above, a large amount of evidence indicates that the endocannabinoid system is crucially involved in the modulation of memory consolidation for stressful experiences (Akirav, 2011; Campolongo et al, 2009; Kano et al, 2009; Marsicano et al, 2009; Wotjak, 2005). Indeed previous findings from our laboratory have demonstrated that CB1 receptor activation within the BLA enhances memory consolidation. In particular, the cannabinoid agonist WIN55,212-2, bilaterally infused into the BLA immediately after inhibitory avoidance training, enhanced memory consolidation. Conversely, the CB1 receptor antagonist AM251 administered after training into the BLA dosedependently impaired 48-h inhibitory avoidance retention (Campolongo et al, 2009). Based on these previous findings we hypothesized that after an aversive experience endocannabinoids might be released within the BLA in order to modulate the better storage of emotionally salient events

The endocannabinoid system: a key modulator of stress effects on memory

As mentioned above, a large amount of evidence indicates that the endocannabinoid system is crucially involved in the modulation of memory consolidation for stressful experiences (Akirav, 2011; Campolongo et al, 2009; Kano et al, 2009; Marsicano et al, 2009; Wotjak, 2005). Indeed previous findings from our laboratory have demonstrated that CB1 receptor activation within the BLA enhances memory consolidation. In particular, the cannabinoid agonist WIN55,212-2, bilaterally infused into the BLA immediately after inhibitory avoidance training, enhanced memory consolidation. Conversely, the CB1 receptor antagonist AM251 administered after training into the BLA dosedependently impaired 48-h inhibitory avoidance retention (Campolongo et al, 2009). Based on these previous findings we hypothesized that after an aversive experience endocannabinoids might be released within the BLA in order to modulate the better storage of emotionally salient events

Circadian rhythms and sex differences set endocannabinoids to influence memory under stress

A large amount of evidence indicates that stress exposure triggers the brain processing through different specific pathways that converge in both norepinephrine- and glucocorticoids-dependent regulation of memory processes by influencing central noradrenergic mechanisms (de Quervain et al., 1998; McGaugh and Roozendaal, 2002). The amygdala has long been known to be the hub of fear memory, which is usually remembered over time (Fanselow and LeDoux, 1999; Roozendaal et al., 2009). However, when an aversive stimulus occurs, it might happen that the accuracy of such emotional memory could be distorted progressively, leading to memory generalization (Asok et al., 2019). Drugs of abuse were identified to alter the experience of reality, thus affecting memory processes (Goodman and Packard, 2016). Chapter 1 explores more in deep the role of the psychostimulants amphetamine and MDPV in the modulation of memory strength and accuracy in a previously validated model exploiting the inhibitory avoidance discrimination task, in order to assess fear memory generalization for a novel/safe, yet not identical, context that was not used to induce shocks (Atucha and Roozendaal, 2015). Previous studies indicated that both amphetamine and MDPV, through different mechanisms of action, increase brain monoamines release, particularly norepinephrine and dopamine, two neurotransmitters extensively involved in the modulation of memory (LaLumiere et al., 2005; McGaugh and Roozendaal, 2009). Therefore, Chapter 1 investigates the involvement of the noradrenergic and dopaminergic systems in mediating the amphetamine effects on memory strength and both amphetamine and MDPV effects on fear memory generalization. Extensive evidence demonstrates that norepinephrine is crucially involved in the regulation of long-term memory consolidation for emotionally arousing experiences (Ferry et al., 1999; McGaugh and Roozendaal, 2002; Roozendaal et al., 2008; Lalumiere et al., 2017; Chen et al., 2018). It is widely recognized that amphetamine enhances the consolidation of memory processing in both humans and rodents (Soetens et al., 1993; Sanday et al., 2013). Chapter 2 evaluates the influence of different intensities of stress on the amphetamine modulation of long-term memory consolidation, further characterizing the involvement of any stress-induced activation of the peripheral adrenergic response in such process. The endocannabinoid system plays a key role in the control of emotional responses to environmental challenges (Morena and Campolongo, 2014). CB1 receptors are abundantly expressed within corticolimbic regions, including the basolateral complex of the amygdala (BLA), hippocampus and mPFC (Hill et al., 2011). Glucocorticoids are stress response mediators which interact with the endocannabinoid system in the regulation of memory function (Campolongo et al., 2009; Hill et al., 2010a; Atsak et al., 2012a; Morena et al., 2016; Balsevich et al., 2017), with an emotional buffer outcome in such interaction (Morena and Campolongo, 2014). Their synthesis is characterized by a circadian release pattern, with peak levels linked to the start of the activity phase and diurnal regulation under control of the circadian clock (Dickmeis, 2009). Literature evidence indicated that the endocannabinoid signaling exhibits a circadian rhythm with variations reported in CB1 receptor expression (Rueda- Orozco et al., 2008), endocannabinoids tissue contents and in the enzymes controlling their synthesis and degradation (Valenti et al., 2004). Chapter 3 investigates how different stress intensities, soon after encoding, influence rat short-term memory in an object recognition task, whether the effects depend on circadian rhythm and if exogenous augmentation of AEA levels restores any memory impairment provoked by stress exposure. Exposure to stress alters both hippocampal anatomy and functionality (McEwen, 1999), with negative consequences on memory processes (de Kloet et al., 2018). Indeed, the hippocampus represents a key forebrain structure highly associated with emotional and recognition memory processes (Broadbent et al., 2010). According to the timing of stress exposure, stress-mediated secretion of glucocorticoids alters hippocampal functions and plasticity (Kim et al., 2015), thus affecting hippocampal-dependent memories in rodents and humans (Donley et al., 2005). Furthermore, previous findings from our laboratory have demonstrated the involvement of the 2-AG signaling in counteracting the stress-mediated impairments on memory function (Morena et al., 2014, 2015; Ratano et al., 2018). By adding on Chapter 3 findings, Chapter 4 highlights that stress impairing effects on short-term recognition memory depend on time-of-day in a stress intensity-dependent fashion and examines if different stress intensities affect the hippocampal endocannabinoid system components, whether the effects are time-of- day-dependent, and if boosting 2-AG signaling ameliorates memory performance. Excessive fear and anxiety are hallmarks of a variety of disabling psychiatric disorders (Myers and Davis, 2007). The neurocircuitry of fear memory involves the BLA as the key region modulating the acquisition, retrieval and extinction of fear response (Johansen et al., 2011; Adolphs, 2013; Herry and Johansen, 2014; Zelikowsky et al., 2014), by receiving inputs from somatosensory cortex, thalamus, and hippocampus that encodes contextual information and compares current contextual cues to previously encoded memories (Maren and Quirk, 2004). Chapter 5 evaluates whether the endocannabinoids AEA and 2-AG, in the BLA or the CA1 region of the dorsal hippocampus, differentially regulate fear memory retrieval depending on the environment-associated emotional arousal, if these outcomes are mediated by indirect activation of CB1 and/or CB2 receptors, and whether the BLA-dorsal CA1 interplay plays any role in such effects. Women are twice as likely as men to develop PTSD making the search for biological mechanisms underlying these gender disparities especially crucial (Breslau, 2009). One striking feature of PTSD is the alteration in the ability to extinguish fear responses to trauma-associated cues (Yehuda et al., 2015). In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD (Morena et al., 2018; Segev et al., 2018). Chapter 6 investigates whether exogenous augmentation of the endocannabinoids AEA and 2-AG in male and female rats affect fear expression and extinction, which is the role of CB1 and transient potential receptor of vanilloid type-1 channel (TRPV1) receptors in such mediation, and how the endocannabinoid machinery within the amygdala, PFC and periaqueductal grey (PAG) is influenced post-extinction. Chapter 7 provides a review of the existing literature regarding the effects of time-of- day on memory function, shedding light on the underlying mechanisms of contrasting results by portraying how stress-dependent modulation of memory is influenced by circadian rhythms. Chapter 7 also focuses on the interaction between the endocannabinoid system and the level of stress associated to the experimental context / previous aversive experiences and capitalizes on our recent findings that a manipulation of the endocannabinoid system might be capable to effectively modulate the circadian- dependent effects of stress on memory and to prevent its detrimental effects on memory function

Amygdala and Emotional Modulation of Multiple Memory Systems

Stress and anxiety can either enhance or impair memory, and the direction of the effect partially depends on the type of memory being affected. Behavioral or pharmacological stressors typically impair cognitive memory mediated by the hippocampus, but enhance stimulus-response habit memory mediated by the dorsolateral striatum. Evidence also indicates that the effect of emotion on different kinds of memory critically depends on a modulatory role of the basolateral amygdala (BLA). BLA modulation of multiple memory systems may be achieved through its glutamatergic projections to other brain regions, which may enhance stress hormone activity, modulate competition between memory systems, and alter synaptic plasticity. The neurobiology underlying the emotional modulation of multiple memory systems may be relevant to understand the impact of emotional arousal on the development and expression of human psychopathologies characterized by maladaptive habitual behaviors (e.g., drug addiction and relapse)

Acute psychosocial stress effects on memory performance : relevance of age and sex

In recent decades, there has been a growing interest in investigating the effects of chronic and acute stress on cognitive processes, especially memory performance. However, research focusing on acute stress effects has reported contradictory findings, probably due to the many factors that can moderate this relationship. In addition to factors related to the individual, such as sex and age, other factors, such as the type of memory assessed, can play a critical role in the direction of these effects. This review summarizes the main findings of our research group and others about the effects of acute psychosocial stress on memory performance in young and older people of both sexes, taking into account the type and phase of memory assessed. In our opinion, an approach that addresses individual factors and other factors related to the type of stressor and temporal relationship between exposure to the stressor and performance will contribute to better understanding the mechanisms underlying the complex relationship between acute stress and memory. Finally, some new directions for future studies on this research topic are suggested

Stress Hormones Receptors in the Amygdala Mediate the Effects of Stress on the Consolidation, but Not the Retrieval, of a Non Aversive Spatial Task

This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on acquisition, consolidation and retrieval of a non-aversive hippocampal-dependent learning paradigm, the object location task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level) or extensive prior habituation (reduced novelty stress/arousal level). Results indicated that in the habituated rats, exposure to an out-of-context stressor (i.e, elevated platform stress) impaired consolidation and retrieval, but not acquisition, of the task. Non-habituated animals under both stressed and control conditions did not show retention of the task. In habituated rats, RU-486 (10 ng/side), a glucocorticoid receptor (GR) antagonist, or propranolol (0.75 µg/side), a beta-adrenergic antagonist, injected into the basolateral amygdala (BLA), prevented the impairing effects of the stressor on consolidation, but not on retrieval. The CB1/CB2 receptor agonist WIN55,212-2 (WIN, 5 µg/side) microinjected into the BLA did not prevent the effects of stress on either consolidation or retrieval. Taken together the results suggest that: (i) GR and β-adrenergic receptors in the BLA mediate the impairing effects of stress on the consolidation, but not the retrieval, of a neutral, non-aversive hippocampal-dependent task, (ii) the impairing effects of stress on hippocampal consolidation and retrieval are mediated by different neural mechanisms (i.e., different neurotransmitters or different brain areas), and (iii) the effects of stress on memory depend on the interaction between several main factors such as the stage of memory processing under investigation, the animal's level of arousal and the nature of the task (neutral or aversive)