Histaminergic neuronal pathways underlie susceptibility and resilience to psychosocial stress

Psychosocial stress is considered a severe pathogenic factor of psychiatric disorders, characterized by dysfunctions of cognitive, emotional, and social domains. Not everyone though, who experiences an adverse or stressful event succumbs to negative outcomes and enters a pathological state, as some individuals are highly vulnerable to the pathological consequences of enduring stress, whereas others are resilient. We and others previously showed that manipulation of histaminergic neurons of the hypothalamic tuberomamillary nucleus (TMNHA) impacts on the instatement of a specific stress-induced phenotype [1,2]. Aims This study aims at understanding the implications of hypothalamic histaminergic nuclei in the unfolding of maladaptive behavioural responses to stress. In particular, we asked whether TMNHA neurons are engaged in the initial or more durable resilience/susceptibility responses to enduring stress in a preclinical setting. Methods To disentangle the involvement of the TMNHA neurons in stress susceptibility and resilience, chemogenetic, genetic and pharmacological manipulations techniques were used in the murine model of social defeat stress (SDS), consisting of daily exposure of the experimental animal to an aggressive conspecific for variable periods of time. Animals a) Histidine decarboxylase (HDC)cre male mice subjected to CNO-mediated activation or inhibition of TMNHA neurons via bilateral intra-TMN viral injection of either AAV8-hSyn-DIOhM3D(Gq)-mCherry or AAV8-hSyn-DIO-hM4D(Gi)-mCherry constructs, respectively; b) HDC-/- mice; c) HDC+/+ mice pharmacologically depleted of brain histamine with injections of the HDC inhibitor alpha-fluoromethylhistidine (aFMH; 1μg/ml, 5μl i.c.v. [3]); d) HDC+/+ mice treated with pitolisant (10mg/Kg i.p. [3,4] or VUF16839 (5mg/Kg i.p. [5]), histamine H3 receptor antagonist and agonist, respectively; mice receiving AAV8-hSyn-DIO-mCherry and non-stressed mice served as controls. Mice performance was then evaluated in paradigms relevant to social (social interaction test) and cognitive (novel object recognition test) domains. Statistical analysis: 2WayANOVA & Bonferroni MCT; significance p<0.05. N of animals ¼ 6-9/experimental group. Results Exposure to 10 day-SDS induced social avoidance and poor recognition memory in control mice. Chemogenetic, and pharmacological activation of TMNHA neurons with the H3 receptor antagonist pitolisant significantly improved the social interaction index (P range <0.05-0.001 between groups) and recognition memory (P range <0.01-0.001 between objects). On the other hand, chemogenetic silencing of TMNHA neurons during a 3-day SDS, which normally does not induce maladaptive responses, caused social avoidance (P range <0.05- 0.001 between groups) and recognition memory deficits (P range <0.05-0.0001 between objects). Similar susceptibility to a subthreshold SDS protocol was observed in HDC-/- mice, mice receiving alpha-FMH, or VUF16839. Conclusions These results indicate the full implication of the brain histaminergic system in promoting a coping behaviour toward stress-related dysfunctions. By using different experimental manipulations we show that global activation of histaminergic neurons promotes resilience to SDS-induced behavioural alterations, whereas their silencing triggers susceptibility. These results indicate that pharmacological interventions targeting the histaminergic system as with pitolisant, an effective compound for the treatment of narcolepsy, can promote coping resilience and ultimately normalize the affected systems. References 1.Rani, B., Santangelo, A., Romano, A., Koczwara, J.B., Friuli M., Provensi G., et al. 2021 Brain histamine and oleoylethanolamide restore behavioral deficits induced by chronic social defeat stress in mice Neurobiol Stress 14:100317. doi: 10.1016/j.ynstr.2021.100317. eCollection 2021 May. 2.Endou, M., Yanai, K., Sakurai, E., Fukudo, S., Hongo, M., Watanabe, T. 2001 Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats Brain Res. 891:32-41. 3.Brabant C, Charlier Y, Tirelli E (2013) The histamine H3-receptor inverse agonist pitolisant improves fear memory in mice. Behav Brain Res 243:199–204. 4.Krief, S., Berrebi-Bertrand, I., Nagmar, I., Giret, M., Belliard, S., Perrin, D., et al. 2021 Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol. Pharmacol Res Perspect 9(5):e00855. doi: 10.1002/prp2.855. 5.Rani, B., Silva-Marques, B., Leurs, R., Passani, M.B., Blandina, P., Provensi, G. 2021 Short- and Long-Term Social Recognition Memory Are Differentially Modulated by Neuronal Histamine Biomolecules. 11(4):555. doi: 10.3390/ biom11040555 No conflict of interest