The Role of Dorsal Raphe Nucleus Serotonergic Systems in Emotional Learning and Memory in Male BALB/c Mice.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for a variety of anxiety-, trauma- and stressor-related disorders. Although they are efficacious, therapeutic improvements require several weeks of treatment and are often associated with an initial exacerbation of symptoms. The dorsal raphe nucleus (DR) has been proposed as an important target for the modulation of emotional responses and the therapeutic effects of SSRIs. Using a fear-conditioning paradigm we aimed to understand how SSRIs affect emotional learning and memory, and their effects on serotonergic circuitry. Adult male BALB/c mice were treated with vehicle (n = 16) or the SSRI fluoxetine (18 mg/kg/d) acutely (n = 16), or chronically (21d, n = 16), prior to fear conditioning. Treatment was stopped, and half of the mice (n = 8/treatment group) were exposed to cued fear memory recall 72 h later. Activation of DR serotonergic neurons during fear conditioning (Experiment 1) or fear memory recall (Experiment 2), was measured using dual-label immunohistochemistry for Tph2 and c-Fos. Acute and chronic fluoxetine treatment reduced associative fear learning without affecting memory recall and had opposite effects on anxiety-like behaviour. Acute fluoxetine decreased serotonergic activity in the DR, while chronic treatment led to serotonergic activity that was indistinguishable from that of control levels in DRD and DRV subpopulations. Chronic fluoxetine facilitated fear extinction, which was associated with rostral DRD inhibition. These findings provide further evidence that SSRIs can alter aspects of learning and memory processes and are consistent with a role for discrete populations of DR serotonergic neurons in regulating fear- and anxiety-related behaviours.

Association between dietary factors, symptoms, and psychological factors in adults with dyspepsia: A cross-sectional study.

BACKGROUND: Evidence-based dietary management approaches for symptoms of dyspepsia are lacking. This study aimed to compare dietary factors, symptoms, quality of life (QOL) and salivary cortisol in dyspepsia participants and healthy controls. METHODS: A cross-sectional survey was completed by adults with dyspepsia (n = 121) meeting Rome IV criteria and healthy controls (n = 52). Outcome measures included self-reported questionnaires about dietary habits, triggers, restrictions, dietary management approaches, nutritional intake, psychological variables, QOL, gastrointestinal symptoms, and optional cortisol awakening response (CAR) via saliva samples. Data were analyzed using Chi-square or Mann-Whitney U. Cortisol awakening response data was analyzed using moderated regression controlling for age, gender and distress. KEY RESULTS: Fermentable carbohydrates (FODMAPs) (55%) were the most reported trigger in adults with dyspepsia. The dyspepsia group (88%) followed special diets more than controls (47%; p < 0.001), with a low FODMAP diet being most common (69%). The dyspepsia group consumed less fiber (p = 0.014), calcium (p = 0.015), and total FODMAPs (p < 0.001) than controls. There was a greater prevalence of comorbid anxiety (41%) and depression (31%) in dyspepsia compared to controls (15% and 12%, respectively, p < 0.001 and p = 0.006). The dyspepsia group had poorer QOL and greater gastrointestinal symptom severity than controls (p < 0.001). There was a negative association between anxiety and CAR (p = 0.001) in dyspepsia but not in controls. CONCLUSIONS & INFERENCES: Adults with dyspepsia follow special diets more than controls and perceive FODMAPs as a key dietary trigger. These findings highlight the importance of monitoring nutritional adequacy and QOL, and emphasize mechanisms of depleted stress response in dyspepsia, warranting further exploration.

A Systematic Review and Revised Meta-analysis of the Effort-Reward Imbalance Model of Workplace Stress and Hypothalamic-Pituitary-Adrenal Axis Measures of Stress.

OBJECTIVE: Despite considerable research in the past 20 years into associations between the effort-reward imbalance (ERI) model and various health outcomes, the mechanisms responsible for the association remain unclear. Our meta-analysis assessed the associations of ERI and overcommitment (OC) in the workplace with measures from the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Electronic databases were searched with the phrase "effort * reward * imbalance," which yielded 319 studies leading to 56 full-text studies being screened. Thirty-two studies within 14 articles met the inclusion criteria and were meta-analyzed using mixed- and random-effects models. RESULTS: Greater ERI was associated with increased HPA axis activity (r = 0.05, p = .02, k = 14, n = 2461). The cortisol waking concentrations (r = 0.11, p = .02, k = 6, n = 493) were the only subgroup associated with ERI. Meta-regression revealed that studies that contained more men had stronger ERI to HPA marker associations. When all HPA markers were considered collectively, OC was not associated with greater HPA axis activity (r = 0.01, p = .70, k = 10, n = 1684), with only cortisol (pm) associated with OC (r = -0.24, p = .02, k = 2, n = 95). CONCLUSIONS: ERI and OC were associated with HPA responsivity. Although the cortisol waking concentrations and not the CAR were associated with ERI, this may be due to heterogeneity in the experience of stress between studies. Future studies should consider the concurrent assessment of burnout to better assist the interpretation of ERI with HPA responsivity.

Clinical and Blood Biomarker Trajectories after Concussion: New Insights from a Longitudinal Pilot Study of Professional Flat-Track Jockeys.

There is a recognized need for objective tools for detecting and tracking clinical and neuropathological recovery after sports-related concussion (SRC). Although computerized neurocognitive testing has been shown to be sensitive to cognitive deficits after SRC, and some blood biomarkers have shown promise as indicators of axonal and glial damage, the potential utility of these measures in isolation and combination for assisting SRC diagnosis and tracking recovery is not well understood. To provide new insights, we conducted a prospective study of 64 male and female professional flat-track jockeys (49 non-SRC, 15 SRC), with each jockey undergoing symptom evaluation, cognitive testing using the CogSport battery, and serum biomarker quantification of glial fibrillary acidic protein (GFAP), tau, and neurofilament light (NfL) using a Simoa HD-X Analyzer. Measures were performed at baseline (i.e., pre-injury), and 2 and 7 days and 1 and 12 months after SRC. Symptoms were most pronounced at 2 days and had largely resolved by either 7 days or 1 month. CogSport testing at 2 days revealed cognitive impairments relative to both non-concussed peers and their own pre-injury baselines, with SRC classification utility found at 2 days, and to a slightly lesser extent, at 7 days. Relatively prolonged changes in serum NfL were observed, with elevated levels and classification utility persisting beyond the resolution of SRC symptoms and cognitive deficits. Finally, SRC classification performance throughout the 1st month after SRC was optimized through the combination of cognitive testing and serum biomarkers. Considered together, these findings provide further evidence for a role of computerized cognitive testing and fluid biomarkers of neuropathology as objective measures to assist in the identification of SRC and the monitoring of clinical and neuropathological recovery.

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression.

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.

Within subject rise in serum TNFα to IL-10 ratio is associated with poorer attention, decision-making and working memory in jockeys.

Jockeys work in high-risk environments that rely heavily on attention- and decision-making to perform well and safely. Workplace stress literature has often overlooked the impact of stress on cognition, and designs that include physiological measures are rare. This study assessed the prospective concurrent relationships between workplace stress, depression symptoms and low-grade inflammation with cognitive performance among professional jockeys. Professional jockeys (N = 35, Mage = 32.29) provided information on workplace stress and depression symptoms, with serum levels of inflammatory cytokines (IL-6, IL-10, TNFα) and cytokine balance (IL-6: IL-10, TNFα: IL-10) quantified with SIMOA, and cognitive performance with CogSport computer-based testing battery. These measures were repeated after a twelve-month interval. Increased workplace stress between testing intervals was associated to an increased cytokine imbalance (ß = 0.447, p = .015) after controlling for age and gender. Increases in cytokine imbalance occurred in unison with decreases in attention (ß = 0.516, p = .002), decision-making (ß = 0.452, p = .009) and working memory (ß = 0.492, p = .004). These preliminary findings suggest the underlying mechanisms linking workplace stress and reduced cognitive performance may be influenced by measures of low-grade inflammation and specifically a cytokine imbalance. Our findings suggest a measure of cytokine balance may explain the heterogenous findings in previous studies that have focussed solely on the association of workplace stress with pro-inflammatory cytokines. Future work is needed however, to provide a broader evidence-base for our claims to better inform designs to intervene in the higher workplace stress-poorer cognition relationship.

Neurotransmitters of sleep and wakefulness in flatworms.

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 traveled, consistent with their wake-promoting effect in vertebrates and fruit flies; pyrilamine increased restfulness and GABA showed a nonsignificant 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.

Acute treatment with 5-hydroxytryptophan increases social approach behaviour but does not activate serotonergic neurons in the dorsal raphe nucleus in juvenile male BALB/c mice: A model of human disorders with deficits of sociability.

BACKGROUND: The BALB/c mouse has been proposed as a model of human psychiatric disorders characterised by elevated anxiety and altered sociability. Juvenile BALB/c mice show decreased social exploratory behaviour, increased anxiety, and reduced brain serotonin synthesis compared to other strains including C57BL/6J mice. AIM: To determine whether supplementation of brain serotonin synthesis alters social behaviour and activation of serotonergic neurons across subregions of the dorsal raphe nucleus (DR) in BALB/c mice. METHODS: Juvenile male BALB/c mice were assigned to one of four treatment conditions: vehicle/vehicle, carbidopa (25 mg/kg)/vehicle, vehicle/5-HTP (10 mg/kg), carbidopa (25 mg/kg)/5-HTP (10 mg/kg). Social behaviour was measured using the three-chamber social approach test, followed by immunohistochemical staining for TPH2 and c-Fos to measure activation of serotonergic neurons across subregions of the DR. RESULTS: Mice treated with carbidopa/5-HTP spent more time in the social cage zone and covered more distance in the social approach test compared to other treatment groups. There was no difference between treatment groups in the activation of serotonergic neurons across subregions of the DR. However, the DRD was associated with increased social approach behaviour in carbidopa/5-HTP treated animals. CONCLUSIONS: Supplementation of serotonin synthesis can increase social approach behaviour in juvenile BALB/c mice. An increase in locomotor behaviour was also observed suggesting that increasing central serotonin synthesis may have led to a reduction in state anxiety, manifesting in increased exploratory behaviour. As no effect on serotonergic activation within the DR was found, alternative mechanisms are likely important for the effects of 5-HTP on social behaviour.

Immunomodulation Eliminates Inflammation in the Hippocampus in Experimental Autoimmune Encephalomyelitis, but Does Not Ameliorate Anxiety-Like Behavior.

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.

Involvement of dorsal raphe nucleus serotonergic systems in social approach-avoidance behaviour and in the response to fluoxetine treatment in peri-adolescent female BALB/c mice.

Serotonergic systems are involved in the development and regulation of social behaviour, and drugs that target serotonin neurotransmission, such as selective serotonin reuptake inhibitors (SSRIs), also alter aspects of social approach-avoidance. The midbrain dorsal raphe nucleus (DR), which is a major serotonergic nucleus and main source of serotonergic innervation of the forebrain, has been proposed as an important target for SSRIs, although evidence in females is lacking. In this study, we examined the involvement of the DR serotonergic systems in social behaviour and in response to SSRI treatment, using peri-adolescent female BALB/c mice. Mice were exposed to the SSRI fluoxetine either chronically (18 mg/kg/day, in drinking water, for 12 days) or acutely (18 mg/kg, i.p.), or to vehicle control condition (0.9 % saline, i.p.), prior to being exposed to the three-chambered sociability test. Activation of serotonergic neurons across subregions of the DR were subsequently measured, using dual-label immunohistochemistry for TPH2 and c-Fos. Acute fluoxetine administration increased generalised and social avoidance, while mice exposed to chronic fluoxetine treatment showed levels of social approach behaviour that were comparable to controls. Serotonergic populations across the DR showed reduced activity following acute fluoxetine treatment. Further, activation of serotonergic neurons in the ventral DR correlated with social approach behaviour in vehicle-treated control mice. These data provide some support for the involvement of discrete populations of DR serotonergic neurons in the regulation of social approach-avoidance, although more research is needed to understand the effects and mechanisms of chronic SSRI treatment in females.

Platelets in Multiple Sclerosis: Early and Central Mediators of Inflammation and Neurodegeneration and Attractive Targets for Molecular Imaging and Site-Directed Therapy.

Platelets are clearly central to thrombosis and hemostasis. In addition, more recently, evidence has emerged for non-hemostatic roles of platelets including inflammatory and immune reactions/responses. Platelets express immunologically relevant ligands and receptors, demonstrate adhesive interactions with endothelial cells, monocytes and neutrophils, and toll-like receptor (TLR) mediated responses. These properties make platelets central to innate and adaptive immunity and potential candidate key mediators of autoimmune disorders. Multiple sclerosis (MS) is the most common chronic autoimmune central nervous system (CNS) disease. An association between platelets and MS was first indicated by the increased adhesion of platelets to endothelial cells. This was followed by reports identifying structural and functional changes of platelets, their chronic activation in the peripheral blood of MS patients, platelet presence in MS lesions and the more recent revelation that these structural and functional abnormalities are associated with all MS forms and stages. Investigations based on the murine experimental autoimmune encephalomyelitis (EAE) MS model first revealed a contribution to EAE pathogenesis by exacerbation of CNS inflammation and an early role for platelets in EAE development via platelet-neuron and platelet-astrocyte associations, through sialated gangliosides in lipid rafts. Our own studies refined and extended these findings by identifying the critical timing of platelet accumulation in pre-clinical EAE and establishing an initiating and central rather than merely exacerbating role for platelets in disease development. Furthermore, we demonstrated platelet-neuron associations in EAE, coincident with behavioral changes, but preceding the earliest detectable autoreactive T cell accumulation. In combination, these findings establish a new paradigm by asserting that platelets play a neurodegenerative as well as a neuroinflammatory role in MS and therefore, that these two pathological processes are causally linked. This review will discuss the implications of these findings for our understanding of MS, for future applications for imaging toward early detection of MS, and for novel strategies for platelet-targeted treatment of MS.

Effect of Pleomorphic Adenoma Gene 1 Deficiency on Selected Behaviours in Adult Mice.

The proto-oncogene pleomorphic adenoma gene 1 (Plag1) encodes a zinc finger transcription factor. PLAG1 is part of the high motility group AT hook-2 (HGMA2)-PLAG1-insulin-like growth factor 2 (IGF2) pathway that, when disrupted, leads to Silver-Russell syndrome, a severe form of intrauterine growth restriction. With little known about PLAG1's role in normal physiology, this study is the first to characterise the behavioural phenotype of PLAG1-deficient mice. Mice were tested for differences in circadian locomotor activity and body temperature, sleep-like behaviour, anxiety-like behaviour, cognition, social behaviour, and sensorimotor gating. Overall, the behavioural phenotype of the Plag1 knock-out (KO) mice was mild: no significant differences were seen in circadian activity levels, locomotion, object recognition, spatial memory or sociability compared to wild-type mice. However, the cued test of fear conditioning, prepulse inhibition of the startle response and Preyer's reflex test suggest that Plag1 KO mice may have a hearing impairment. This implies that PLAG1 plays an important role in proper functioning and/or development of the neural circuitry behind the auditory processes or interacts with genes involved in those processes.

Empathy and job resources buffer the effect of higher job demands on increased salivary alpha amylase awakening responses in direct-care workers.

The job demands-resources (JD-R) model has rarely been used in conjunction with physiological indicators of stress and ill-health. This study explored the associations between the JD-R model and physiological indicators of the stress response, while considering potential moderators of this relationship. Across 2 timepoints (summer-winter) direct-care workers completed questionnaires assessing job demands, job resources, empathy and self-efficacy, and provided morning saliva samples to assess physiological indices of stress and ill-health. Changes in job resources and empathy were positively correlated with changes in the cortisol awakening response (CAR). Further, changes in both job resources and empathy independently buffered the impact of higher job demands on increased salivary alpha amylase awakening response (sAA-AR) concentrations. These findings suggest that despite increased job demands, the sAA-AR decreased for direct-care workers that had perceived high job resources or who reported higher empathy. Potentially, job resources and empathy may act as a protective factor against the development of poor health associated with workplace stress.

Trait mindfulness and the Effort-Reward Imbalance workplace stress model: Higher trait mindfulness is associated with increased salivary immunoglobulin A.

Individuals who are high in trait mindfulness are less stressed at work, better adjusted, and healthier than individuals who are low in this trait (Allen et al., 2015; Irving et al., 2009; Lomas et al., 2017) [1-3]. To date, trait mindfulness has not been considered within current, empirically supported, workplace stress models. Therefore, the present study explored if trait mindfulness, when used in conjunction with the Effort-Reward Imbalance model (Siegrist, 1996) (ERI [4]) better explains the links between workplace stress and non-adaptive physiological arousal. Across 2 timepoints (Summer-Winter) direct-care workers completed job stress (ERI), trait mindfulness, and health questionnaires and provided morning saliva samples to assess physiological indices of stress and ill-health. Compared across timepoints, changes in ERI and overcommitment were not associated with changes in the cortisol awakening response, salivary alpha amylase awakening response or secretory immunoglobulin A (sIgA). However, higher trait mindfulness was associated with increased sIgA. Potentially, trait mindfulness may act as a protective factor against ensuing ill-health and further, may be useful in better understanding the underlying mechanisms of the workplace stress-ill-health relationship.

Assessing the association of university stress and physiological reactivity with decision-making among students.

Compared with age-matched employees, university students report higher levels of chronic stress and this may affect their decision-making. The impact of chronic stress and physiological reactivity upon cognitive function is receiving more attention, but few studies have empirically assessed the associations of these variables concurrently. Our aim was to investigate if chronic student stress, as assessed by effort-reward imbalance (ERI) and overcommitment, and physiological reactivity, were related to decision-making. As measures of physiological reactivity, we collected salivary alpha-amylase (sAA) and continuously recorded heart rate variability (HRV) data from male students (n = 79) at pretest and immediately after some computerized decision-making tasks (simple and choice- reaction times). Our findings suggest that students who are higher in overcommitment and who are more physiologically reactive (sAA and HRV indices) at the pretest stage may be more "at-risk" of poor decision-making than others. If others can replicate our findings in more diverse samples, this will contribute to an evidence base for interventions targeted at reducing overcommitment, ERI, and dysregulated autonomic reactivity to improve decision-making.

Mild Closed-Head Injury in Conscious Rats Causes Transient Neurobehavioral and Glial Disturbances: A Novel Experimental Model of Concussion.

Rodent models can provide insights into the most pertinent issues surrounding concussion. Nonetheless, the relevance of some existing models to clinical concussion can be questioned, particularly with regard to the use of surgery and anesthesia and the mechanism and severity of injury. Accordingly, we have co-developed an awake closed-head injury (ACHI) model in rats. Here, we aimed to create a temporal profile of the neurobehavioral and neuropathological effects of a single ACHI. Adolescent male rats were placed in a restraint bag and a steel helmet was positioned over the head such that the impact target was centered over the left parietal cortex. Once positioned on a foam platform, a cortical impactor was used to strike the helmet. Sham animals underwent the same procedure without impact. When compared with sham rats, those given a single ACHI displayed evidence of sensorimotor deficits and reduced exploratory behavior within the first 20 min post-injury; however, these effects were resolved after 24 h. A single ACHI impaired spatial memory on the Y-maze task at both 5 min and 24 h post-ACHI; however, no deficits were apparent at 48 h. Immunostaining revealed region-specific increases in ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein expression at 3 days post-impact, with no differences found at either 1 or 14 days. Taken together, our findings indicate that a single ACHI results in transient neurobehavioral and glial disturbances and as such, this model may be a valuable tool for pre-clinical concussion research.

Platelet Depletion is Effective in Ameliorating Anxiety-Like Behavior and Reducing the Pro-Inflammatory Environment in the Hippocampus in Murine Experimental Autoimmune Encephalomyelitis.

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.

Social approach, anxiety, and altered tryptophan hydroxylase 2 activity in juvenile BALB/c and C57BL/6J mice.

Autism spectrum disorder (ASD) is a heterogeneous and highly heritable condition with multiple aetiologies. Although the biological mechanisms underlying ASD are not fully understood, evidence suggests that dysregulation of serotonergic systems play an important role in ASD psychopathology. Preclinical models using mice with altered serotonergic neurotransmission may provide insight into the role of serotonin in behaviours relevant to clinical features of ASD. For example, BALB/c mice carry a loss-of-function single nucleotide polymorphism (SNP; C1473 G) in tryptophan hydroxylase 2 (Tph2), which encodes the brain-specific isoform of the rate-limiting enzyme for serotonin synthesis, and these mice frequently have been used to model symptoms of ASD. In this study, juvenile male BALB/c (G/G; loss-of-function variant) and C57BL/6 J (C/C; wild type variant) mice, were exposed to the three-chamber sociability test, and one week later to the elevated plus-maze (EPM). Tryptophan hydroxylase 2 (TPH2) activity was measured following injection of the aromatic amino acid decarboxylase (AADC)-inhibitor, NSD-1015, and subsequent HPLC detection of 5-hydroxytryptophan (5-HTP) within subregions of the dorsal raphe nucleus (DR) and median raphe nucleus (MnR). The BALB/c mice showed reduced social behaviour and increased anxious behaviour, as well as decreased 5-HTP accumulation in the rostral and mid-rostrocaudal DR. In the full cohort of mice, TPH2 activity in the mid-rostrocaudal DR was correlated with anxious behaviour in the EPM, however these correlations were not statistically significant within each strain, suggesting that TPH2 activity was not directly associated with either anxiety or sociability. Further research is therefore required to more fully understand how serotonergic systems are involved in mouse behaviours that resemble some of the clinical features of ASD.

Trait Mindfulness Helps Explain the Relationships Between Job Stress, Physiological Reactivity, and Self-Perceived Health.

OBJECTIVE: The aim of this study was to assess, for the first time, the associations among work stress as measured by the job-demands resources (JD-R) model, trait mindfulness, and indices of the physiological stress response. METHOD: Dairy farmers (N = 79) completed job stress (using the JD-R model), trait mindfulness, burnout, and self-reported health questionnaires and provided physiological indices of the stress response. RESULTS: Our findings suggest that those reporting higher mindfulness have better physical and mental health, and that being more mindful may buffer the effects of a large cortisol awakening response on poor physical health. CONCLUSION: Although assessments of both psychological and physiological indicators of stress and ill-health will inform the underlying mechanisms of the associations between work stress and disease, assessing the role of trait mindfulness in this relationship may prove useful.