Brain histamine as a gateway for the improvement of stress-induced maladaptive behaviours and social memory

Stress-related disorders are common and debilitating conditions characterised in part by affective manifestations associated with cognitive and behavioural alterations. These disorders could be chronic and severe at some point in life (Tolentino and Schmidt 2018). Stress is a triggering factor for both anxiety and depression, therefore stress modulation may represent an winning strategy in the treatment of stress-associated disorders (Moritz et al. 2020). In addition, understanding the neurophysiological aspects implicated in the etiology of stress-associated disorders may ultimately contribute to their treatment. Lately, nutritional interventions to ameliorate stress-induced cognitive deficits is gaining worldwide interest. Since the discovery of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in 1929 by George and Mildred Burr (Burr 1929), research on ω-3 PUFAs became an appealing topic ranging from their role in cardiovascular risk and more recently neuropsychiatric pathologies such as depression and anxiety, cognitive decline or neurodegenerative diseases (Bazinet and Layé 2014, Joffre et al. 2014, Coulombe et al. 2018). The relevance of lipids in brain function is illustrated by the fact that the central nervous system (CNS) has the highest concentration of lipids in the organism after adipose tissue. Among these lipids, the brain is particularly enriched with PUFAs represented by the ω-6 and ω-3 series. In animal models, it has been shown that transient or maternal ω-3 PUFA-deficient diet induces depressive and anxiety-like symptoms (Carrié et al. 2000, DeMar et al. 2006, Bondi et al. 2014) as well as abnormal social behaviour (Lafourcade et al. 2011) in adolescent and adult offspring. However, the mechanisms underlying the effects of ω-3 PUFA-deficient diet on emotional behaviour remain largely unknown. In this thesis, I evaluated the role of a diet enriched with ω-3 PUFA (EPA and DHA) and vitamin A, another nutrient that plays a key role in the regulation of synaptic plasticity and in learning and memory in adult rats (Lane and Bailey 2005), by using a preclinical model of adolescent stress, the social instability paradigm. We studied the effects of the enriched diet in the cognitive and neurochemical deficits induced by this kind of stress. The results showed that the supplemented diet had beneficial effects preventing cognitive and neurochemical alterations of juvenile rats tested immediately after the stressful procedure. but also when rats were tested as adults. Furthermore, the detrimental behavioural and neurochemical effects of adolescent stress, as well as the protective effect of the enriched diet, were maintained throughout adulthood, long after the exposure to the stressful environment was terminated. Histamine is implicated in arousal, awakening and maintenance of wakefulness and has a pivotal role in the maintenance of high vigilance that is required for cognitive processes (Thakkar 2011, Thakkar et al. 1999). Not surprisingly, current research is providing evidence that malfunctioning of the histaminergic system is associated with neuropathological disorders (Shan, Bao and Swaab 2017). For this reason, in the second part of the thesis I evaluated the role of the brain histaminergic in the protective effects of the ω-3 PUFA and Vitamin A enriched diet. To this end I used genetically modified mice that do not synthesise histidine decarboxylase (HDC-/-, the only enzyme responsible for histamine synthesis) and HDC+/+ mice. These were exposed to chronic social defeat stress, a well-characterised preclinical model of anxiety and depression (Krishnan and Nestler 2011). The results demonstrated that the enriched diet prevented the memory impairment and social avoidance behaviour induced by stress only in animals whose histaminergic system is intact, thus supporting our hypothesis on the key role of the histaminergic system in the beneficial effects of this diet. Oleoylethanolamide (OEA) is derived from a monounsaturated fatty acid oleic acid (OA), which has beneficial effects on intestinal metabolism (Lama et al., 2020) regional fat distribution (Sarro-Ramírez et al. 2013), inflammation (Piomelli 2013). Furthermore, OEA has precognitive effects (Campolongo et al., 2009; Provensi et al., 2017) Previous preclinical studies in our laboratory showed that the central histaminergic system is essential for the central effects of OEA such as the hypophagia (Provensi et al. 2014), improved memory for aversive events (Provensi et al. 2017) and antidepressant-like action (Costa et al. 2018). For this reason, I also evaluated the effect of a chronic administration of OEA in mice subjected to the chronic social defeat stress. The results obtained showed that treatment with OEA prevents behavioural impairments induced by chronic stress in HDC+/+, but not in HDC-/- mice, further supporting the role of the histaminergic system in the beneficial effects of OEA. In the last part of my thesis I investigated the role of central histaminergic system on social recognition memory. Social memory is one of the crucial components of episodic memories. Among the four identified histamine receptors, H3 receptors are predominantly expressed in the central nervous system, act as autoreceptors as well as heteroreceptors, and control presynaptic release of histamine and other neurotransmitters (Haas, Sergeeva and Selbach 2008). The results demonstrated that acute and pharmacologically or genetically histamine depleted mice had long term, but not short-term memory impairment. However, histamine deprived mice treated with a selective H3 receptor agonist VUF16839, that supposedly decreases histamine and other neurotransmitters’ release showed short-term memory impairment as well. We interpret this finding as indicative of the involvement of H3 heteroceptors on non-histaminergic cells being involved in the amnesic effect. Indeed, treatment with the acetylcholinesterase inhibitor, donepezil, prevented the amnesic effect of VUF16839. The results presented in this thesis strongly suggest that central histaminergic system plays a crucial and fundamental role in mediating the beneficial effects of nutritional compounds such as the ω-3 PUFA and vitamin A enriched diet or OEA on behavioural impairments induced by stress. I also contributed to the understanding of the role of the central histaminergic and the interplay with other neurotransmitter systems on social recognition memory.