Beneficial effects of prolonged 2-phenylethyl alcohol inhalation on chronic distress-induced anxio-depressive-like phenotype in female mice

Chronic distress-induced hypothalamic-pituitary-adrenal axis deregulations have been associated with the development of neuropsychiatric disorders such as anxiety and depression. Currently available drugs treating such pathological conditions have limited efficacy and diverse side effects, revealing the need of new safer strategies. Aromatic plant-based compounds are largely used in herbal medicine due to their therapeutic properties on mood, physiology, and general well-being. The purpose of this study was to investigate the effects of 2-phenylethyl alcohol (PEA), one of the pharmacologically active constituents of rose essential oil, on chronic corticosterone (CORT)-induced behavioral and neurobiological changes in female mice. Animals followed a prolonged PEA inhalation exposure (30 min per day) for 15 consecutive days prior to behavioral evaluation with open-field, forced swim and novelty-suppressed feeding tests. CORT treatment induced an anxio-depressive-like phenotype, evidenced by a reduced locomotor activity in the open-field, and an increased latency to feed in the novelty-suppressed feeding paradigms. To elucidate the neural correlates of our behavioral results, cerebral cFos expression analysis was further performed to provide a global map of neuronal activity. The altered feeding behavior was accompanied by a significant decrease in the number of cFos-positive cells in the olfactory bulb, and altered brain connectivity as shown by cross-correlation-based network analysis. CORT-induced behavioral and neurobiological alterations were reversed by prolonged PEA inhalation, suggesting a therapeutic action that allows regulating the activity of neural circuits involved in sensory, emotional and feeding behaviors. These findings might contribute to better understand the therapeutic potential of PEA on anxio-depressive symptoms. ### Competing Interest Statement The authors have declared no competing interest. * ACo : anterior cortical amygdaloid area aIC : anterior insular cortex aPirCx : anterior piriform cortex BLA : basolateral amygdala CeA : central amygdala CORT : corticosterone EPM : elevated plus-maze test FST : forced swim test GC : glucocorticoids Hip : hippocampus HPA : hypothalamic-pituitary-adrenal axis LEC : lateral entorhinal cortex MWU : Mann- Whitney U test MCox : log-rank Mantel-Cox test NAcC : nucleus accumbens core subregion NAcS : nucleus accumbens shell subregion NSF : novelty-suppressed feeding task OB : olfactory bulb OF : open-field test PEA : 2-phenylethyl alcohol PLCo : posterolateral cortical amygdaloid area pPirCx : posterior piriform cortex PSTN : parasubthalamic nucleus ROI : region of interest SEM : standard error of the mean VEH : vehicle