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.

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