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    Peripherally Restricted Activation of Opioid Receptors Influences Anxiety-Related Behaviour and Alters Brain Gene Expression in a Sex-Specific Manner.
    (MDPI (Basel, Switzerland), 2024-12-07) Parkar N; Young W; Olson T; Hurst C; Janssen P; Spencer NJ; McNabb WC; Dalziel JE; Szumlinski KK; Shiina T
    Although effects of stress-induced anxiety on the gastrointestinal tract and enteric nervous system (ENS) are well studied, how ENS dysfunction impacts behaviour is not well understood. We investigated whether ENS modulation alters anxiety-related behaviour in rats. We used loperamide, a potent μ-opioid receptor agonist that does not cross the blood-brain barrier, to manipulate ENS function and assess changes in behaviour, gut and brain gene expression, and microbiota profile. Sprague Dawley (male/female) rats were acutely dosed with loperamide (subcutaneous) or control solution, and their behavioural phenotype was examined using open field and elevated plus maze tests. Gene expression in the proximal colon, prefrontal cortex, hippocampus, and amygdala was assessed by RNA-seq and caecal microbiota composition determined by shotgun metagenome sequencing. In female rats, loperamide treatment decreased distance moved and frequency of supported rearing, indicating decreased exploratory behaviour and increased anxiety, which was associated with altered hippocampal gene expression. Loperamide altered proximal colon gene expression and microbiome composition in both male and female rats. Our results demonstrate the importance of the ENS for communication between gut and brain for normo-anxious states in female rats and implicate corticotropin-releasing hormone and gamma-aminobutyric acid gene signalling pathways in the hippocampus. This study also sheds light on sexually dimorphic communication between the gut and the brain. Microbiome and colonic gene expression changes likely reflect localised effects of loperamide related to gut dysmotility. These results suggest possible ENS pharmacological targets to alter gut to brain signalling for modulating mood.
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    Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome.
    (Elsevier B.V., 2019-06-06) Silva MSB; Desroziers E; Hessler S; Prescott M; Coyle C; Herbison AE; Campbell RE
    Background Enhanced GABA activity in the brain and a hyperactive hypothalamic-pituitary-gonadal axis are associated with polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Women with PCOS exhibit elevated cerebrospinal fluid GABA levels and preclinical models of PCOS exhibit increased GABAergic input to GnRH neurons, the central regulators of reproduction. The arcuate nucleus (ARN) is postulated as the anatomical origin of elevated GABAergic innervation; however, the functional role of this circuit is undefined. Methods We employed a combination of targeted optogenetic and chemogenetic approaches to assess the impact of acute and chronic ARN GABA neuron activation. Selective acute activation of ARN GABA neurons and their fiber projections was coupled with serial blood sampling for luteinizing hormone secretion in anesthetized male, female and prenatally androgenised (PNA) mice modelling PCOS. In addition, GnRH neuron responses to ARN GABA fiber stimulation were recorded in ex vivo brain slices. Chronic activation of ARN GABA neurons in healthy female mice was coupled with reproductive phenotyping for PCOS-like features. Findings Acute stimulation of ARN GABA fibers adjacent to GnRH neurons resulted in a significant and long-lasting increase in LH secretion in male and female mice. The amplitude of this response was blunted in PNA mice, which also exhibited a blunted LH response to GnRH administration. Infrequent and variable GABAA-dependent changes in GnRH neuron firing were observed in brain slices. Chronic activation of ARN GABA neurons in healthy females impaired estrous cyclicity, decreased corpora lutea number and increased circulating testosterone levels. Interpretation ARN GABA neurons can stimulate the hypothalamic-pituitary axis and chronic activation of ARN GABA neurons can mimic the reproductive deficits of PCOS in healthy females. Unexpectedly blunted HPG axis responses in PNA mice may reflect a history of high frequency GnRH/LH secretion and reduced LH stores, but also raise questions about impaired function within the ARN GABA population and the involvement of other circuits.
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    Neurobiological impacts of kiwifruit consumption in a pig model and its effects on sleep and mood in young adults : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Sciences at Massey University, Palmerston North, New Zealand
    (Massey University, 2024) Kanon, Alexander Putra
    Kiwifruit (KF) positively impacts gut health, specifically in alleviating gastrointestinal symptoms and improving laxation. Emerging evidence also suggests that consuming KF influences sleep and mood, with most studies indicating improvements in subjective measures of these attributes. Previous research has explored the mechanisms behind these effects using in vitro and rodent models, which have considerable differences to human physiology. This study explores the impact of New Zealand KF on various brain physiological aspects in animal models and humans. It explores the antioxidant neuroprotective potential of KF, examines alterations in the gut microbiome composition and bioamine concentrations, analyses temporal bioamine concentration effects in plasma and brain regions, and assesses the acute effects on human sleep quality and mood. Findings reveal that in one week, consumption of both green and gold KF reduced oxidative potential in plasma, increased concentrations of 5-Hydroxyindoleacetic Acid (5HIAA, a serotonin metabolite), and induced changes in the abundance of specific microbial genera along the colon of adult pigs, a more representative model of human physiology. Furthermore, green KF enhances antioxidant protective potential in plasma and various brain regions, while gold KF elevates plasma vitamin C levels and tends to reduce acetylcholinesterase activity across the entire brain. Temporal effects highlight distinct patterns in metabolite concentrations between green and gold KF, with γ-Aminobutyric Acid (GABA) and serotonin exhibiting notable interactions in different brain regions. Good and poor sleepers consuming KF before sleep had improved sleep quality and mood. Fresh KF facilitates easier sleep onset for good sleepers, while freeze-dried KF leads to increased ease of awakening in the morning for poor sleepers. Notably, both forms of KF increase the urinary excretion of 5HIAA and reduce feelings of sleepiness while increasing alertness. The inclusion of the fruit skin appears to increase improvements in sleep quality, suggesting a more noticeable effect. These studies provide valuable insights into the neurobiological effects of KF and support its potential as a functional food to improve sleep in humans.
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    Metabolome and microbiome profiling of a stress-sensitive rat model of gut-brain axis dysfunction
    (Springer Nature Limited, 2019-10-01) Bassett SA; Young W; Fraser K; Dalziel JE; Webster J; Ryan L; Fitzgerald P; Stanton C; Dinan TG; Cryan JF; Clarke G; Hyland N; Roy NC
    Stress negatively impacts gut and brain health. Individual differences in response to stress have been linked to genetic and environmental factors and more recently, a role for the gut microbiota in the regulation of stress-related changes has been demonstrated. However, the mechanisms by which these factors influence each other are poorly understood, and there are currently no established robust biomarkers of stress susceptibility. To determine the metabolic and microbial signatures underpinning physiological stress responses, we compared stress-sensitive Wistar Kyoto (WKY) rats to the normo-anxious Sprague Dawley (SD) strain. Here we report that acute stress-induced strain-specific changes in brain lipid metabolites were a prominent feature in WKY rats. The relative abundance of Lactococcus correlated with the relative proportions of many brain lipids. In contrast, plasma lipids were significantly elevated in response to stress in SD rats, but not in WKY rats. Supporting these findings, we found that the greatest difference between the SD and WKY microbiomes were the predicted relative abundance of microbial genes involved in lipid and energy metabolism. Our results provide potential insights for developing novel biomarkers of stress vulnerability, some of which appear genotype specific.
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    Modulation of enteric neural activity and its influence on brain function and behaviour : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science at Massey University, Manawatu, New Zealand
    (Massey University, 2024) Parkar, Nabil Jamil
    The gut-brain axis (GBA) facilitates bidirectional communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS). The location of the ENS along the GI tract enables it to serve as a relay station along the GBA. A key regulator of the GBA is the diverse population of microbial communities inhabiting the GI tract, known as the gut microbiota. Due to its proximity to the ENS, gut microbes significantly influence ENS functions, such as gut motility, and also impact brain function and behavior. A diverse and healthy gut microbiota is crucial for normal GI physiology and mental health. Understanding the physiological host factors that influence and control the gut microbiota is essential for grasping its variability in health and states of dysbiosis. Movement of luminal content along the GI tract, primarily driven by rhythmic contractions of GI smooth muscles, affects gut microbiota growth and population dynamics. This research involved a series of ex vivo and behavioral experiments in rodents to better understand ENS control of gut motility and its impact on anxiety-related behavior. Initially, the effect of a specific pharmacological agent on colonic motility patterns was evaluated using ex vivo techniques. Observations from this study provided fundamental insights into ENS function and its regulation of colonic motility, laying the foundation for further research on how altered colonic motility via ENS manipulation affects gut microbiota composition and anxiety-related behavior. The second study investigated whether pharmacological modulation of the ENS, resulting in reduced colonic motility, affected the gut microbiota. Results revealed significant changes in gut microbiota composition, including decreased abundance of certain bacterial species and alterations in community structure. The final study aimed to understand the relationship between ENS manipulation, brain function, and behavior by inducing changes in gut motility. Anxiety-related behavior was assessed in rats using open field and elevated plus maze tests, focusing on those exposed to a pharmacological agent that slowed colonic motility via specific ENS receptors. To determine if behavior changes involved specific neural pathways, brain gene expression in key regions was studied. Additionally, the potential relationship between gut microbiota and brain function was explored, assessing if ENS modulation and behavioral effects correlated with changes in gene expression and microbiota profiles in the large intestine. Findings indicated that ENS modulation altered anxiety-related behavior in a sex-specific manner, with female rats showing increased anxiety and corresponding changes in brain and proximal colon gene expression compared to males. This study highlighted sexually dimorphic gut-brain communication and suggested multiple genes/pathways may influence anxiety-related behavior in females. This comprehensive exploration through three interrelated studies has provided new insights into the regional specificity of ENS receptors in regulating colonic motility, the impact of slowed gut transit on microbiota composition, and the physiological consequences of ENS modulation on brain function and anxiety, with associated sex differences. A combined analysis of these findings discusses their implications for understanding the ENS as a key player in regulating the gut-brain axis.
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    Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis
    (BioMed Central Ltd, 2024-12) Tan WJ; Hawley HR; Wilson SJ; Fitzsimons HL
    BACKGROUND: Dysregulation of nucleocytoplasmic shuttling of histone deacetylase 4 (HDAC4) is associated with several neurodevelopmental and neurodegenerative disorders. Consequently, understanding the roles of nuclear and cytoplasmic HDAC4 along with the mechanisms that regulate nuclear entry and exit is an area of concerted effort. Efficient nuclear entry is dependent on binding of the transcription factor MEF2, as mutations in the MEF2 binding region result in cytoplasmic accumulation of HDAC4. It is well established that nuclear exit and cytoplasmic retention are dependent on 14-3-3-binding, and mutations that affect binding are widely used to induce nuclear accumulation of HDAC4. While regulation of HDAC4 shuttling is clearly important, there is a gap in understanding of how the nuclear and cytoplasmic distribution of HDAC4 impacts its function. Furthermore, it is unclear whether other features of the protein including the catalytic site, the MEF2-binding region and/or the ankyrin repeat binding motif influence the distribution and/or activity of HDAC4 in neurons. Since HDAC4 functions are conserved in Drosophila, and increased nuclear accumulation of HDAC4 also results in impaired neurodevelopment, we used Drosophila as a genetic model for investigation of HDAC4 function. RESULTS: Here we have generated a series of mutants for functional dissection of HDAC4 via in-depth examination of the resulting subcellular distribution and nuclear aggregation, and correlate these with developmental phenotypes resulting from their expression in well-established models of neuronal morphogenesis of the Drosophila mushroom body and eye. We found that in the mushroom body, forced sequestration of HDAC4 in the nucleus or the cytoplasm resulted in defects in axon morphogenesis. The actions of HDAC4 that resulted in impaired development were dependent on the MEF2 binding region, modulated by the ankyrin repeat binding motif, and largely independent of an intact catalytic site. In contrast, disruption to eye development was largely independent of MEF2 binding but mutation of the catalytic site significantly reduced the phenotype, indicating that HDAC4 acts in a neuronal-subtype-specific manner. CONCLUSIONS: We found that the impairments to mushroom body and eye development resulting from nuclear accumulation of HDAC4 were exacerbated by mutation of the ankyrin repeat binding motif, whereas there was a differing requirement for the MEF2 binding site and an intact catalytic site. It will be of importance to determine the binding partners of HDAC4 in nuclear aggregates and in the cytoplasm of these tissues to further understand its mechanisms of action.
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    Shining a light on recovery : investigating the effectiveness of bright light therapy in mitigating fatigue after mild traumatic brain injury : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Clinical Psychology at Massey University, New Zealand
    (Massey University, 2023) Connolly, Kathryn Marie
    Fatigue is a common and debilitating symptom experienced by individuals following a mild traumatic brain injury (mTBI). Despite its prevalence, post-mTBI fatigue remains a challenging, and at times misunderstood condition, with a scarcity of scientifically evidenced treatment approaches. The complexity of fatigue's underlying causes in this population calls for further research. Recognising its significant impact on individuals' quality of life emphasises the need to identify effective interventions and enhance symptom management. This study aims to investigate the potential effectiveness of daily bright light exposure as a non-invasive intervention to alleviate fatigue in the post-mTBI population. While existing research has shown positive outcomes for bright light therapy in managing fatigue in broader traumatic brain injury populations, the current study focuses on individuals with injuries at the mild end of the spectrum, offering valuable insights into the efficacy of this treatment in a more targeted context. The primary objective of the research was to investigate whether daily bright light exposure effectively reduced fatigue symptoms in individuals with mTBI. Additionally, the study aimed to explore the impact of light exposure on secondary outcomes, including daytime sleepiness, sleep quality, depression, anxiety, stress, and circadian rest-activity cycles. To address recruitment challenges, a randomised multiple baseline controlled trial design was adopted. The results revealed that all nine participants consistently experienced significant fatigue throughout the study. Fatigue levels appeared to decrease during the bright light therapy sessions suggesting a potential positive impact of bright light exposure on fatigue, although this reduction was not statistically significant across the group. Due to limitations in data, the ability to confidently demonstrate efficacy was low and this prompted a shift in focus towards assessing the feasibility of conducting research of this nature. Moving forward, future studies can benefit from an understanding of the complexities involved in implementing intensive intervention protocols. The current study demonstrates a need for close collaboration with participants to monitor adherence and potential side effects, alongside coordination with colleagues in the mTBI field to ensure access to a sufficient participant pool for achieving statistically significant results. Overall, this research provides some limited evidence of positive effects from bright light therapy for select individuals and contributes to the expanding body of evidence investigating light as a potential intervention for alleviating fatigue symptoms post-mTBI. More importantly, by shedding light on the hurdles in implementing such interventions among individuals with mTBI, it contributes to the development of targeted and potentially effective interventions for improving the quality of life for individuals affected by this condition. It is hoped that this study contributes to the broader literature aimed at facilitating better outcomes for individuals with mTBI and related fatigue symptoms.
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    Marine Fish-Derived Lysophosphatidylcholine: Properties, Extraction, Quantification, and Brain Health Application
    (MDPI (Basel, Switzerland), 2023-03-30) Ahmmed MK; Hachem M; Ahmmed F; Rashidinejad A; Oz F; Bekhit AA; Carne A; Bekhit AE-DA; Jembrek MJ; Šegota S
    Long-chain omega-3 fatty acids esterified in lysophosphatidylcholine (LPC-omega-3) are the most bioavailable omega-3 fatty acid form and are considered important for brain health. Lysophosphatidylcholine is a hydrolyzed phospholipid that is generated from the action of either phospholipase PLA1 or PLA2. There are two types of LPC; 1-LPC (where the omega-3 fatty acid at the sn-2 position is acylated) and 2-LPC (where the omega-3 fatty acid at the sn-1 position is acylated). The 2-LPC type is more highly bioavailable to the brain than the 1-LPC type. Given the biological and health aspects of LPC types, it is important to understand the structure, properties, extraction, quantification, functional role, and effect of the processing of LPC. This review examines various aspects involved in the extraction, characterization, and quantification of LPC. Further, the effects of processing methods on LPC and the potential biological roles of LPC in health and wellbeing are discussed. DHA-rich-LysoPLs, including LPC, can be enzymatically produced using lipases and phospholipases from wide microbial strains, and the highest yields were obtained by Lipozyme RM-IM®, Lipozyme TL-IM®, and Novozym 435®. Terrestrial-based phospholipids generally contain lower levels of long-chain omega-3 PUFAs, and therefore, they are considered less effective in providing the same health benefits as marine-based LPC. Processing (e.g., thermal, fermentation, and freezing) reduces the PL in fish. LPC containing omega-3 PUFA, mainly DHA (C22:6 omega-3) and eicosapentaenoic acid EPA (C20:5 omega-3) play important role in brain development and neuronal cell growth. Additionally, they have been implicated in supporting treatment programs for depression and Alzheimer's. These activities appear to be facilitated by the acute function of a major facilitator superfamily domain-containing protein 2 (Mfsd2a), expressed in BBB endothelium, as a chief transporter for LPC-DHA uptake to the brain. LPC-based delivery systems also provide the opportunity to improve the properties of some bioactive compounds during storage and absorption. Overall, LPCs have great potential for improving brain health, but their safety and potentially negative effects should also be taken into consideration.
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    Effects of Green and Gold Kiwifruit Varieties on Antioxidant Neuroprotective Potential in Pigs as a Model for Human Adults.
    (MDPI (Basel, Switzerland), 2024-04-09) Kanon AP; Giezenaar C; Roy NC; Jayawardana IA; Lomiwes D; Montoya CA; McNabb WC; Henare SJ; Digiacomo M
    Kiwifruit (KF) has shown neuroprotective potential in cell-based and rodent models by augmenting the capacity of endogenous antioxidant systems. This study aimed to determine whether KF consumption modulates the antioxidant capacity of plasma and brain tissue in growing pigs. Eighteen male pigs were divided equally into three groups: (1) bread, (2) bread + Actinidia deliciosa cv. 'Hayward' (green-fleshed), and (3) bread + A. chinensis cv. 'Hort16A' (yellow-fleshed). Following consumption of the diets for eight days, plasma and brain tissue (brain stem, corpus striatum, hippocampus, and prefrontal cortex) were collected and measured for biomarkers of antioxidant capacity, enzyme activity, and protein expression assessments. Green KF significantly increased ferric-reducing antioxidant potential (FRAP) in plasma and all brain regions compared with the bread-only diet. Gold KF increased plasma ascorbate concentration and trended towards reducing acetylcholinesterase activity in the brain compared with the bread-only diet. Pearson correlation analysis revealed a significant positive correlation between FRAP in the brain stem, prefrontal cortex, and hippocampus with the total polyphenol concentration of dietary interventions. These findings provide exploratory evidence for the benefits of KF constituents in augmenting the brain's antioxidant capacity that may support neurological homeostasis during oxidative stress.
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    Social determinants and lifestyle factors for brain health: implications for risk reduction of cognitive decline and dementia
    (Springer Nature Limited, 2022-07-28) Röhr S; Pabst A; Baber R; Engel C; Glaesmer H; Hinz A; Schroeter ML; Witte AV; Zeynalova S; Villringer A; Löffler M; Riedel-Heller SG
    Substantial evidence indicates a huge potential for risk reduction of cognitive decline and dementia based on modifiable health and lifestyle factors. To maximize the chances for risk reduction, it is useful to investigate associations of social determinants and lifestyle for brain health. We computed the “LIfestyle for BRAin health” (LIBRA) score for baseline participants of the Leipzig Research Centre for Civilization Diseases (LIFE) Adult Study, a population-based urban cohort in Germany. LIBRA predicts dementia in midlife and early late life populations, comprising 12 modifiable risk factors (heart disease, kidney disease, diabetes, obesity, hypertension, hypercholesterolemia, alcohol consumption, smoking, physical inactivity, diet, depression, cognitive inactivity). Associations of social determinants (living situation, marital status, social isolation, education, net equivalence income, occupational status, socioeconomic status/SES, employment) with LIBRA were inspected using age- and sex-adjusted multivariable linear regression analysis. Z-standardization and sampling weights were applied. Participants (n = 6203) were M = 57.4 (SD = 10.6, range 40–79) years old and without dementia, 53.0% were women. Except for marital status, all considered social determinants were significantly associated with LIBRA. Beta coefficients for the association with higher LIBRA scores were most pronounced for low SES (β = 0.80, 95% CI [0.72–0.88]; p < 0.001) and middle SES (β = 0.55, 95% CI [0.47–0.62]; p < 0.001). Social determinants, particularly socioeconomic factors, are associated with lifestyle for brain health, and should thus be addressed in risk reduction strategies for cognitive decline and dementia. A social-ecological public health perspective on risk reduction might be more effective and equitable than focusing on individual lifestyle behaviors alone.