Applications of manganese-enhanced magnetic resonance imaging in neuroscience

xi, 84 leaves ; 29 cmManganese-Enhanced Magnetic Resonance Imaging (MEMRI) has proven itself to be a beneficial technique in the field of Neuroscience. This thesis applies MEMRI to studies in neuroscience by first establishing the limitations concerning the use of MEMRI in live rats. Experiment 1 used an osmotic pump for manganese (Mn) delivery to the lateral ventricles for acquisition of anatomical images using MEMRI. From my knowledge, this was the first method demonstrating slow infusion of Mn to the lateral ventricles. In Experiment 2, MEMRI was used for volumetric analysis the whole brain and hippocampus of prenatally stressed rats. To my knowledge, this study was the first to investigate the effect of generational prenatal stress on the structure of a rat’s brain using MEMRI and histology. Additionally, Experiment 2 investigated the use of a subcutaneous osmotic pump to deliver Mn for MEMRI. A summary on the use of MEMRI in Neuroscience concludes this thesis, with a discussion on the methods used and related technical considerations

Allostatic load and preterm birth

Preterm birth is a universal health problem that is one of the largest unmet medical needs contributing to the global burden of disease. Adding to its complexity is that there are no means to predict who is at risk when pregnancy begins or when women will actually deliver. Until these problems are addressed, there will be no interventions to reduce the risk because those who should be treated will not be known. Considerable evidence now exists that chronic life, generational or accumulated stress is a risk factor for preterm delivery in animal models and in women. This wear and tear on the body and mind is called allostatic load. This review explores the evidence that chronic stress contributes to preterm birth and other adverse pregnancy outcomes in animal and human studies. It explores how allostatic load can be used to, firstly, model stress and preterm birth in animal models and, secondly, how it can be used to develop a predictive model to assess relative risk among women in early pregnancy. Once care providers know who is in the highest risk group, interventions can be developed and applied to mitigate their risk

Investigating the effects of ancestral stress, environmental enrichment and the concept of allostatic load

The stress that our ancestors experienced resonates with us in their stories, and memoires, but does it affect our health? In this thesis, the impact of ancestral stress on offspring was investigated. We hypothesized that ancestral stress has a significant impact on the development of the stress response, neuromorphology, and behaviour. Moreover, as stress is multi-systematic in its effects, this study examined the use of a new stratification tool termed the cumulative animal allostatic load index (CAALM). In addition, we tested the influence of postnatal enriched environment (EE) on ancestral stress-induced deficits. Lastly, we investigated a “two-hit hypothesis” of maternal stress and inflammation on offspring development. Overall, results indicate that ancestral stress is transferred across generations and increases allostatic load, and EE reverses detrimental effects. Moreover, inflammation exacerbates the effect of stress. Altogether, our results shed light on the influence of maternal and ancestral health on offspring development and the benefit of EE

Environmental intervention as a therapy for adverse programming by ancestral stress

Sherpa Romeo green journal. Open access article. Creative Commons Attribution 4.0 International License (CC BY 4.0) appliesAncestral stress can program stress sensitivity and health trajectories across multiple generations. While ancestral stress is uncontrollable to the filial generations, it is critical to identify therapies that overcome transgenerational programming. Here we report that prenatal stress in rats generates a transgenerationally heritable endocrine and epigenetic footprint and elevated stress sensitivity which can be alleviated by beneficial experiences in later life. Ancestral stress led to downregulated glucocorticoid receptor and prefrontal cortex neuronal densities along with precocious development of anxiety-like behaviours. Environmental enrichment (EE) during adolescence mitigated endocrine and neuronal markers of stress and improved miR-182 expression linked to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) regulation in stressed lineages. Thus, EE may serve as a powerful intervention for adverse transgenerational programming through microRNA-mediated regulation of BDNF and NT-3 pathways. The identification of microRNAs that mediate the actions of EE highlights new therapeutic strategies for mental health conditions and psychiatric disease.Ye

Personalised profiling to identify clinically relevant changes in tremor due to multiple sclerosis

Background: There is growing interest in sensor-based assessment of upper limb tremor in multiple sclerosis and other movement disorders. However, previously such assessments have not been found to offer any improvement over conventional clinical observation in identifying clinically relevant changes in an individual's tremor symptoms, due to poor test-retest repeatability. Method: We hypothesised that this barrier could be overcome by constructing a tremor change metric that is customised to each individual's tremor characteristics, such that random variability can be distinguished from clinically relevant changes in symptoms. In a cohort of 24 people with tremor due to multiple sclerosis, the newly proposed metrics were compared against conventional clinical and sensor-based metrics. Each metric was evaluated based on Spearman rank correlation with two reference metrics extracted from the Fahn-Tolosa-Marin Tremor Rating Scale: a task-based measure of functional disability (FTMTRS B) and the subject's self-assessment of the impact of tremor on their activities of daily living (FTMTRS C). Results: Unlike the conventional sensor-based and clinical metrics, the newly proposed ’change in scale’ metrics presented statistically significant correlations with changes in self-assessed impact of tremor (max R2>0.5,p< 0.05 after correction for false discovery rate control). They also outperformed all other metrics in terms of correlations with changes in task-based functional performance (R2=0.25 vs. R2=0.15 for conventional clinical observation, both p< 0.05).Conclusions: The proposed metrics achieve an elusive goal of sensor-based tremor assessment: improving on conventional visual observation in terms of sensitivity to change. Further refinement and evaluation of the proposed techniques is required, but our core findings imply that the main barrier to translational impact for this application can be overcome. Sensor-based tremor assessments may improve personalised treatment selection and the efficiency of clinical trials for new treatments by enabling greater standardisation and sensitivity to clinically relevant changes in symptoms

Prenatal two-hit stress affects maternal and offspring pregnancy outcomes and uterine gene expression in rats : match or mismatch?

Maternal stress and inflammation excesses can lead to adverse pregnancy outcomes and offspring development. We evaluated whether distinct prenatal stressors affect pregnancy, maternal and offspring outcomes, and uterine gene expression differently when combined than either alone. Long-Evans dams were exposed to psychological or/and (two-hit) immune stress (interleukin-1 beta [IL-1 beta]), on gestational days 12-18 and 17-delivery, respectively. Gestational length, maternal weight gain, glycaemia and corticosterone levels, offspring weight, and gender effects were recorded. Maternal and offspring uteri were collected at weaning and on postnatal day 160 correspondingly. Uterine expression of genes involved in local progesterone metabolism, neuroendocrine and immune systems were analyzed using quantitative real-time polymerase chain reaction. Maternal two-hit stress increased gestational length variation and the occurrence of adverse pregnancy outcomes while reducing gestational weight gain. Pup weight was negatively affected by prenatal stressors in a gender-specific way. In dams, IL-1 beta upregulated gene expression of neuroendocrine (Crh, Crhr1) and cytokine genes (Il1b, Il1rn, Il6, and Il10). Conversely, transcriptional patterns in offspring uteri were more variable with gene-specific up- or downregulation by each stressor separately, while exposure to both extensively reduced the expression of neuroendocrine (Hsd11b1), cytokine (Il1a, Il1rn, Il6), and IL-1 receptor genes. In conclusion, maternal stress affects physiological and molecular processes in dams and their offspring; two hits have different effects than single stressors. Outcomes appear generation-, gender-, and stressor-specific. Dampening of offspring uterine gene expression after exposure to multiple stressors could fit within the match/mismatch hypothesis of perinatal programming, with offspring preparing for a stressful life. The combination of two distinct prenatal stressors, psychological and immune stress, induces adverse outcomes and differentially affects expression of genes related to progesterone metabolism, stress and the immune system in the rat uterus

Trans- and Multigenerational Maternal Social Isolation Stress Programs the Blood Plasma Metabolome in the F3 Generation

Metabolic risk factors are among the most common causes of noncommunicable diseases, and stress critically contributes to metabolic risk. In particular, social isolation during pregnancy may represent a salient stressor that affects offspring metabolic health, with potentially adverse consequences for future generations. Here, we used proton nuclear magnetic resonance (1H NMR) spectroscopy to analyze the blood plasma metabolomes of the third filial (F3) generation of rats born to lineages that experienced either transgenerational or multigenerational maternal social isolation stress. We show that maternal social isolation induces distinct and robust metabolic profiles in the blood plasma of adult F3 offspring, which are characterized by critical switches in energy metabolism, such as upregulated formate and creatine phosphate metabolisms and downregulated glucose metabolism. Both trans- and multigenerational stress altered plasma metabolomic profiles in adult offspring when compared to controls. Social isolation stress increasingly affected pathways involved in energy metabolism and protein biosynthesis, particularly in branched-chain amino acid synthesis, the tricarboxylic acid cycle (lactate, citrate), muscle performance (alanine, creatine phosphate), and immunoregulation (serine, threonine). Levels of creatine phosphate, leucine, and isoleucine were associated with changes in anxiety-like behaviours in open field exploration. The findings reveal the metabolic underpinnings of epigenetically heritable diseases and suggest that even remote maternal social stress may become a risk factor for metabolic diseases, such as diabetes, and adverse mental health outcomes. Metabolomic signatures of transgenerational stress may aid in the risk prediction and early diagnosis of non-communicable diseases in precision medicine approaches

Multiple prenatal stresses increase sexual dimorphism in adult offspring behavior

Introduction: Maternal gestational stress and immune activation have independently been associated with affective and neurodevelopmental disorders across the lifespan. We investigated whether rats exposed to prenatal maternal stressors (PNMS) consisting of psychological stress, interleukin (IL)-1 beta or both (two-hit stress) during critical developmental windows displayed a behavioral phenotype representative of these conditions. Methods: Long-Evans dams were exposed to psychological stressors consisting of restraint stress and forced swimming from gestational day (GD)12 to 18 or to no stress (controls). From GD17 until day of delivery, these same animals were injected with saline or IL-1 beta as a second hit and immune stressor (5 mu g/day, intraperitoneally). The behavior of F1 offspring adults was tested on the open field test, elevated plus maze and affective exploration task on postnatal days (P)90, 100 and 110 respectively. Results: The effects of PNMS differed depending on the specific testing environment and potentially the age at assessment, especially in female offspring. Both locomotion and anxiety-like behavioral measures were susceptible to PNMS effects. In females, psychological stress increased anxiety-like behavior, whereas IL-1 beta had an opposite effect, inducing exploration and risk-taking behavior on the open field test and the elevated plus maze. When present, interactions between both stressors limited the anxiogenic effect of psychological stress on its own. In contrast, prenatal psychological stress increased anxiety-like behavior in adult males overall. A similar anxiogenic effect of IL-1 beta was only found on the open field test while the Stress*IL-1 beta interaction appeared to limit the effect of either alone. Contrarily, the PNMS effects on anxiety-like behavior on the affective exploration task were highly similar between both sexes. Analysis of males and females together revealed an additive effect of Stress and IL-1 beta on the number of exits from the refuge, a measure of risk assessment and thus correlated with anxiety. Conclusion: PNMS affected offspring adult behavior in a sex-dependent manner. Effects on females were more variable, whereas psychological stress mostly induced anxiety-like behavior in males. These data highlight the sexual dimorphism in vulnerability to prenatal stressors. Maternal or stress-induced programming of the stress response and neuroinflammation may play an important role in mediating stress effects on offspring adult behavior

Effects of maternal social isolation on adult rodent offspring cognition

Abstract Prenatal experiences can influence offspring physiology and behaviour through the lifespan. Various forms of prenatal stress impair adult learning and memory function and can lead to increased occurrence of anxiety and depression. Clinical work suggests that prenatal stress and maternal depression lead to similar outcomes in children and adolescents, however the long-term effects of maternal depression are less established, particularly in well controlled animal models. Social isolation is common in depressed individuals and during the recent COVID-19 pandemic. Accordingly, for this study we were interested in the effects of maternal stress induced via social isolation on adult offspring cognitive functions including spatial, stimulus–response, and emotional learning and memory that are mediated by different networks centered on the hippocampus, dorsal striatum, and amygdala, respectively. Tasks included a discriminative contextual fear conditioning task and cue-place water task. Pregnant dams in the social isolation group were single housed prior to and throughout gestation. Once offspring reached adulthood the male offspring were trained on a contextual fear conditioning task in which rats were trained to associate one of two contexts with an aversive stimulus and the opposing context remained neutral. Afterwards a cue-place water task was performed during which they were required to navigate to both a visible and invisible platform. Fear conditioning results revealed that the adult offspring of socially isolated mothers, but not controls, were impaired in associating a specific context with a fear-inducing stimulus as assessed by conditioned freezing and avoidance. Results from the water task indicate that adult offspring of mothers that were socially isolated showed place learning deficits but not stimulus-response habit learning on the same task. These cognitive impairments, in the offspring of socially isolated dams, occurred in the absence of maternal elevated stress hormone levels, anxiety, or altered mothering. Some evidence suggested that maternal blood-glucose levels were altered particularly during gestation. Our results provide further support for the idea that learning and memory networks, centered on the amygdala and hippocampus are particularly susceptible to the negative impacts of maternal social isolation and these effects can occur without elevated glucocorticoid levels associated with other forms of prenatal stress

Social Isolation Stress Modulates Pregnancy Outcomes and the Inflammatory Profile of Rat Uterus

Prenatal stressors have been linked to adverse pregnancy outcomes; including preterm birth (PTB). Recent work demonstrates that social isolation in mothers represents a silent stressor contributing to PTB risk. Here; we investigate the association of inflammatory and stress markers with PTB risk in Long–Evans rats exposed to social isolation stress (SIS) during preconception and pregnancy across four generations (F0-F3). Gestational length; blood glucose; corticosterone levels; and maternal and offspring weights were assessed in two SIS paradigms: transgenerational (TG) and multigenerational (MG) exposure. Maternal uterine tissues were collected 21 days after the dams gave birth. Exposure to SIS reduced pregnancy lengths in the parental generation and neonatal birth weights in the F1 and F2 generations. Interleukin (IL)-1β (Il1b) mRNA levels increased in F0 animals but decreased in the offspring of both stress lineages. Protein levels of IL-1β decreased in the TG lineage. Corticotrophin-releasing hormone receptor 1 (Crhr1) expression decreased in SIS-exposed F0 animals and increased in the TG-F2 and MG-F1 offspring. Expression of enzyme 11-β hydroxysteroid dehydrogenase-2 (11bHSD2) was enhanced in F1 animals. These findings suggest SIS has adverse consequences on the F0 mothers; but their F1–F3 progeny may adapt to this chronic stress; thus supporting the fetal programming hypothesis