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Abstract We investigated whether linoleic acid (LA) supplementation could modulate emotional behavior and microglia-related neuroinflammation. For that, male mice of C57BL/6J genetic background fed either a high-fat diet (HFD) or a standard diet (STD) for 12 weeks, were treated with a vehicle or LA solution for 5 weeks before being evaluated for emotional behavior using a battery of behavioral tests. The animals were subsequently sacrificed and their brains collected and processed for immunofluorescence staining, targeting microglia-specific calcium-binding proteins (IBA-1). Neuroinflammation severity was assessed in multiple hypothalamic, cortical and subcortical brain regions. We show an anxio-depressive-like effect of sustained HFD feeding that was neither alleviated nor worsened with LA supplementation. However, increased IBA-1 expression and microgliosis in the HFD group were largely attenuated by LA supplementation. These observations demonstrate that the anti-neuroinflammatory properties of LA are not restricted to hypothalamic areas but are also evident at the cortical and subcortical levels. This study discloses that neuroinflammation plays a role in the genesis of neuropsychiatric disorders in the context of obesity, and that LA supplementation is a useful dietary strategy to alleviate the impact of obesity-related neuroinflammation.

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, immunohistochemistry was further performed to provide a global map of neural activity based on cerebral cFos expression. The altered feeding behavior was accompanied by a significant decrease in the number of cFos-positive cells in the olfactory bulb, and altered functional 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.

Repeated anodal transcranial direct current stimulation (RA-tDCS) is a neuromodulatory technique consisting of stimulating the cerebral cortex with a weak electric anodal current in a non-invasive manner. RA-tDCS over the dorsolateral prefrontal cortex has antidepressant-like properties and improves memory both in humans and laboratory animals. However, the mechanisms of action of RA-tDCS remain poorly understood. Since adult hippocampal neurogenesis is thought to be involved in the pathophysiology of depression and memory functioning, the purpose of this work was to evaluate the impact of RA-tDCS on hippocampal neurogenesis levels in mice. RA-tDCS was applied for 20 min per day for five consecutive days over the left frontal cortex of young adult (2-month-old, high basal level of neurogenesis) and middle-aged (10-month-old, low basal level of neurogenesis) female mice. Mice received three intraperitoneal injections of bromodeoxyuridine (BrdU) on the final day of RA-tDCS. The brains were collected either 1 day or 3 weeks after the BrdU injections to quantify cell proliferation and cell survival, respectively. RA-tDCS increased hippocampal cell proliferation in young adult female mice, preferentially (but not exclusively) in the dorsal part of the dentate gyrus. However, the number of cells that survived after 3 weeks was the same in both the Sham and the tDCS groups. This was due to a lower survival rate in the tDCS group, which suppressed the beneficial effects of tDCS on cell proliferation. No modulation of cell proliferation or survival was observed in middle-aged animals. Our RA-tDCS protocol may, therefore, influence the behavior of naïve female mice, as we previously described, but its effect on the hippocampus is only transient in young adult animals. Future studies using animal models for depression in male and female mice should provide further insights into RA-tDCS detailed age- and sex-dependent effects on hippocampal neurogenesis.

In humans and mammals, effort-based decision-making for monetary or food rewards paradigms contributes to the study of adaptive goal-directed behaviours acquired through reinforcement learning. Chronic distress modelled by repeated exposure to glucocorticoids in rodents induces suboptimal decision-making under uncertainty by impinging on instrumental acquisition and prompting negative valence behaviours. In order to further disentangle the motivational tenets of adaptive decision-making, this study addressed the consequences of enduring distress on relevant effort and reward-processing dimensions. Experimentally, appetitive and consummatory components of motivation were evaluated in adult C57BL/6JRj male mice experiencing chronic distress induced by oral corticosterone (CORT), using multiple complementary discrete behavioural tests. Behavioural data (from novelty suppressed feeding, operant effort-based choice, free feeding, and sucrose preference tasks) collectively show that behavioural initiation, effort allocation, and hedonic appreciation and valuation are altered in mice exposed to several weeks of oral CORT treatment. Additionally, data analysis from FosB immunohistochemical processing of postmortem brain samples highlights CORT-dependent dampening of neural activation in the anterior insular cortex (aIC) and basolateral amygdala (BLA), key telencephalic brain regions involved in appetitive and consummatory motivational processing. Combined, these results suggest that chronic distress-induced irregular aIC and BLA neural activations with reduced effort production and attenuated reward value processing during reinforcement-based instrumental learning could result in maladaptive decision-making under uncertainty. The current study further illustrates how effort and reward processing contribute to adjust the motivational threshold triggering goal-directed behaviours in versatile environments.