The neuropsychiatric symptoms of multiple sclerosis (MS), such as anxiety and depression, can result from disease activity itself as well as psychological reaction to an unfavorable diagnosis. Accordingly, the literature reports evidence of increased anxiety-like behavior in experimental autoimmune encephalomyelitis (EAE), an accepted MS model. Due to the recently described critical role of platelets in inflammation and autoimmune disease, we examined the relationship between platelets, inflammation, and anxiety-like behavior in EAE. In the elevated plus maze, EAE-induced C57BL/6J mice showed decreased time spent in the open arms relative to vehicle-only controls, demonstrating an increase in anxiety-like behavior. This effect occurred in the presence of platelet–neuron association, but absence of lymphocytic infiltration, in the hippocampal parenchyma. Platelet depletion at the pre-clinical disease stage, using antibody-mediated lysis prevented the EAE-induced increase in anxiety-like behavior, while no significant difference in distance moved was recorded. Furthermore, platelet depletion was also associated with reduction of the pro-inflammatory environment to control levels in the hippocampus and prevention of EAE disease symptomology. These studies demonstrate the high efficacy of a platelet-targeting approach in preventing anxiety-like symptoms and clinical manifestations of EAE and have implications for the treatment of neuropsychiatric symptoms in MS.

Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala.

Study Objectives Sleep is a prominent behavioral and biochemical state observed in all animals studied, including platyhelminth flatworms. Investigations into the biochemical mechanisms associated with sleep – and wakefulness – are important for understanding how these states are regulated and how that regulation changed with the evolution of new types of animals. Unfortunately, beyond a handful of vertebrates, such studies on invertebrates are rare. Methods We investigated the effect of seven neurotransmitters, and one pharmacological compound, that modulate either sleep or wakefulness in mammals, on flatworms (Girardia tigrina). Flatworms were exposed via ingestion and diffusion to four neurotransmitters that promote wakefulness in vertebrates (acetylcholine, dopamine, glutamate, histamine), and three that induce sleep (adenosine, GABA, serotonin) along with the H1 histamine receptor antagonist pyrilamine. Compounds were administered over concentrations spanning three to five orders of magnitude. Flatworms were then transferred to fresh water and video recorded for analysis. Results Dopamine and histamine decreased the time spent inactive and increased distance travelled, consistent with their wake-promoting effect in vertebrates and fruit flies; pyrilamine increased restfulness and GABA showed a non-significant trend towards promoting restfulness in a dose-dependent manner, in agreement with their sleep-inducing effect in vertebrates, fruit flies, and Hydra. Similar to Hydra, acetylcholine, glutamate, and serotonin, but also adenosine, had no apparent effect on flatworm behavior. Conclusions These data demonstrate the potential of neurotransmitters to regulate sleep and wakefulness in flatworms and highlight the conserved action of some neurotransmitters across species.

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Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system, characterized by an unpredictable disease course and a wide range of symptoms. Emotional and cognitive deficits are now recognized as primary disease manifestations and not simply the consequence of living with a chronic condition, raising questions regarding the efficacy of current therapeutics for these specific symptoms. Mechanisms underlying psychiatric sequelae in MS are believed to be similar to those underlying pathogenesis, that is mediated by cytokines and other inflammatory mediators. To gain insight into the pathogenesis of MS depression, we performed behavioral assays in the murine experimental autoimmune encephalomyelitis (EAE) MS model, in the presence or absence of immunomodulation using the drug FTY720, an analogue of the lipid signaling molecule sphingosine-1-phosphate (S1P). Specifically, mice were challenged with the elevated plus maze (EPM) test, a validated experimental paradigm for rodent-specific anxiety-like behavior. FTY720 treatment failed to ameliorate anxiety-like symptoms, irrespective of dosage. On the other hand, it was effective in reducing inflammatory infiltration, microglial reactivity and levels of pro-inflammatory molecules in the hippocampus, confirming the anti-inflammatory capacity of treatment. To explore the absence of FTY720 effect on behavior, we confirmed expression of S1P receptors (S1PR) S1PR1, S1PR3 and S1PR5 in the hippocampus and mapped the dynamics of these receptors in response to drug treatment alone, or in combination with EAE induction. We identified a complex pattern of responses, differing between (1) receptors, (2) dosage and (3) hippocampal sub-field. FTY720 treatment in the absence of EAE resulted in overall downregulation of S1PR1 and S1PR3, while S1PR5 exhibited a dose-dependent upregulation. EAE induction alone resulted in overall downregulation of all three receptors. On the other hand, combined FTY720 and EAE showed generally no effect on S1PR1 and S1PR3 expression except for the fimbrium region, but strong upregulation of S1PR5 over the range of doses examined. These data illustrate a hitherto undescribed complexity of S1PR response to FTY720 in the hippocampus, independent of drug effect on effector immune cells, but simultaneously emphasize the need to explore novel treatment strategies to specifically address mood disorders in MS.