Adiponectin rescues synaptic plasticity in the dentate gyrus of a mouse model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that Fmr1 knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

The combined effects of corticosterone and brain-derived neurotrophic factor on plasticity-related receptor phosphorylation and expression at the synaptic surface in male Sprague-Dawley rats.

Following acute exercise, a temporal window exists wherein neuroplasticity is thought to be heightened. Although a number of studies have established that pairing this post-exercise period with motor training enhances learning, the mechanisms through which exercise-induced priming occurs are not well understood. Previously, we characterized a rodent model of acute exercise that generates significant enhancement in glutamatergic receptor phosphorylation as a possible mechanism to explain how exercise-induced priming might occur. However, whether these changes are stimulated by peripheral factors (e.g., glucocorticoids), central effects (e.g., brain-derived neurotrophic factor (BDNF), or a combination of the two remains unclear. Herein, we explored the possible individual and/or cumulative contribution corticosterone (CORT) and BDNF may have on glutamate receptor phosphorylation and synaptic surface expression. Tissue slices from the sensorimotor cortex were prepared and acutely (30 min) incubated with either CORT (200 nM), BDNF (20 ng/mL), or the simultaneous application of CORT and BDNF (CORT+BDNF). Immunoblotting with biotinylated synaptoneurosomes (which provide an enrichment of proteins from the synaptic surface) suggested divergent effects between CORT and BDNF. Acute CORT application enhanced NMDA- (GluN2A, B) and AMPA- (GluA1) receptor phosphorylation, whereas BDNF preferentially increased synaptic surface expression of both NMDA- and AMPA-receptor subunits. The combined effects of CORT+BDNF resulted in a unique subset of signaling patterns that favored phosphorylation in the absence of surface expression. Taken together, these data provide a mechanistic framework for how CORT and BDNF may alter glutamatergic synapses during exercise-induced priming.

Serum Orotidine: A Novel Biomarker of Increased CVD Risk in Type 2 Diabetes Discovered Through Metabolomics Studies.

OBJECTIVE: To identify novel biomarkers of cardiovascular disease (CVD) risk in type 2 diabetes (T2D) via a hypothesis-free global metabolomics study, while taking into account renal function, an important confounder often overlooked in previous metabolomics studies of CVD. RESEARCH DESIGN AND METHODS: We conducted a global serum metabolomics analysis using the Metabolon platform in a discovery set from the Joslin Kidney Study having a nested case-control design comprising 409 individuals with T2D. Logistic regression was applied to evaluate the association between incident CVD events and each of the 671 metabolites detected by the Metabolon platform, before and after adjustment for renal function and other CVD risk factors. Significant metabolites were followed up with absolute quantification assays in a validation set from the Joslin Heart Study including 599 individuals with T2D with and without clinical evidence of significant coronary heart disease (CHD). RESULTS: In the discovery set, serum orotidine and 2-piperidinone were significantly associated with increased odds of incident CVD after adjustment for glomerular filtration rate (GFR) (odds ratio [OR] per SD increment 1.94 [95% CI 1.39-2.72], P = 0.0001, and 1.62 [1.26-2.08], P = 0.0001, respectively). Orotidine was also associated with increased odds of CHD in the validation set (OR 1.39 [1.11-1.75]), while 2-piperidinone did not replicate. Furthermore, orotidine, being inversely associated with GFR, mediated 60% of the effects of declining renal function on CVD risk. Addition of orotidine to established clinical predictors improved (P < 0.05) C statistics and discrimination indices for CVD risk (ΔAUC 0.053, rIDI 0.48, NRI 0.42) compared with the clinical predictors alone. CONCLUSIONS: Through a robust metabolomics approach, with independent validation, we have discovered serum orotidine as a novel biomarker of increased odds of CVD in T2D, independent of renal function. Additionally, orotidine may be a biological mediator of the increased CVD risk associated with poor kidney function and may help improve CVD risk prediction in T2D.

The three sisters of fate: Genetics, pathophysiology and outcomes of animal models of neurodegenerative diseases.

Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are neurodegenerative disorders characterized by progressive structural and functional loss of specific neuronal populations, protein aggregation, an insidious adult onset, and chronic progression. Modeling AD, PD, and HD in animal models is useful for studying the relationship between neuronal dysfunction and abnormal behaviours. Animal models are also excellent tools to test therapeutic approaches. Numerous genetic and toxin-induced models have been generated to replicate these neurodegenerative disorders. These differ in the genetic manipulation employed or the toxin used and the brain region lesioned, and in the extent to which they mimic the neuropathological and behavioral deficits seen in the corresponding human condition. Each model exhibits unique advantages and drawbacks. Here we present a comprehensive overview of the numerous AD, PD, and HD animal models currently available, with a focus on their utilities and limitations. Differences among models might underlie some of the discrepancies encountered in the literature and should be taken into consideration when designing new studies and testing putative therapies.

Quantitative analysis of γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline in HeLa cells using UHPLC-MS/MS.

γ-Glutamylpeptides have been identified as potential biomarkers for a number of diseases including cancer, diabetes, and liver disease. In this study, we developed and validated a novel quantitative analytical strategy for measuring γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline, all of which have been previously reported as potential biomarkers for prostate cancer in HeLa cells using ultra-high-performance liquid chromatography-tandem mass spectrometry. A BEH C18 column was used as the stationary phase. Mobile phase A was 99:1 water:formic acid and mobile phase B was acetonitrile. Chemical isotope labeling using benzoyl chloride was used as the internal standardization strategy. Sample preparation consisted of the addition of water to a frozen cell pellet, sonication, derivatization, centrifugation, and subsequent addition of an internal standard solution. The method was validated for selectivity, accuracy, precision, linearity, and stability. The determined concentrations of γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline in HeLa cells were 1.92 ± 0.06, 10.8 ± 0.4, and 1.96 ± 0.04 pmol/mg protein, respectively. In addition, the qualitative analysis of these analytes in human serum was achieved using a modified sample preparation strategy. To the best of our knowledge, this is the first report of the use of benzoyl chloride for chemical isotope labeling for metabolite quantitation in cells.

Do behaviour change techniques increase adherence to home exercises in those with upper extremity musculoskeletal disorders? A systematic review.

OBJECTIVES: To investigate whether behaviour change techniques (BCTs) can influence adherence to home exercise in people with upper extremity musculoskeletal disorders (UEMD). DESIGN: A systematic review of randomised control trials, non-randomised control trials, case-control studies and cohort studies. Results were presented narratively. Participants were those with UEMD. The intervention was any home exercise programme, alongside a BCT designed to increase exercise adherence. Any duration of intervention was accepted. The main outcome sought was adherence to home exercise. A systematic search was performed on four online databases. Grey literature was searched. RESULTS: The search resulted in 28,755 titles. 77 full-text articles were assessed for eligibility. Six studies were included in the qualitative synthesis. Four studies had Some Concern of Bias, whilst two studies had High Risk of Bias. Three studies found statistically significant differences in exercise adherence (p < 0.05) between the Intervention group and Control group. The BCT 'Social Support (unspecified)' was used within all studies that found significant differences in adherence levels at outcome. However, multiple BCTs were received by the Intervention groups within all studies, making it impossible to identify the effects of any single BCT upon adherence levels. CONCLUSION: Social support may be relevant in patients' adherence levels to HEPs. However, confidence in the results is uncertain given the small number of studies found, and their High RoB. Future studies should validate their measurement and definition of adherence, as well as the number of BCTs they use, to provide reproducible evidence.

Sample preparation and fractionation techniques for intact proteins for mass spectrometric analysis.

The analysis of proteins in biological samples is highly desirable, given their connection to myriad biological functions and disease states, as well as the growing interest in the development of protein-based pharmaceuticals. The introduction and maturation of "soft" ionization methods, such as electrospray ionization and matrix-assisted laser desorption/ionization, have made mass spectrometry an indispensable tool for the analysis of proteins. Despite the availability of powerful instrumentation, sample preparation and fractionation remain among the most challenging aspects of protein analysis. This review summarizes these challenges and provides an overview of the state-of-the-art in sample preparation and fractionation of proteins for mass spectrometric analysis, with an emphasis on those used for top-down proteomic approaches. Biological fluids, particularly important for clinical and pharmaceutical applications and their characteristics are also discussed. While immunoaffinity-based methods are addressed, more attention is given to non-immunoaffinity-based methods, such as precipitation, coacervation, size exclusion, dialysis, solid-phase extraction, and electrophoresis. These techniques are presented in the context of a significant number of studies where they have been developed and utilized.

Unlocking the brain: A new method for Western blot protein detection from fixed brain tissue.

BACKGROUND: Aldehyde fixation is a common process used to preserve the complex structure of biological samples ex vivo. This method of fixation relies on the formation of covalent bonds between aldehydes and amines present in the biomolecules of the sample. Aldehyde fixation is routinely performed in histological studies, however fixed tissue samples are rarely used for non-histological purposes as the fixation process is thought to make brain tissue unsuitable for traditional proteomic analyses such as Western blot. Advances in antigen-retrieval procedures have allowed detectable levels of protein to be solubilized from formaldehyde fixed tissue, opening the door for aldehyde-fixed samples to be used in both histological and proteomic approaches. NEW METHOD: Here, we developed a series of antigen-retrieval steps for use on fixed-brain lysates to make them suitable for analysis by Western blot. RESULTS: Prolonged exposure of the tissue homogenate to high temperature (90 °C for 2 h) in the presence of a concentrated formaldehyde scavenger and ionic detergent was sufficient to reveal a variety of synaptic and non-synaptic proteins on membrane blots. CONCLUSION: This protocol has significant utility for future studies using fixed tissue samples in a variety of neuropathological conditions.

Soil from an Abandoned Manganese Mining Area (Hunan, China): Significance of Health Risk from Potentially Toxic Element Pollution and Its Spatial Context.

This study assessed the significance and potential impact of potentially toxic element (PTE) (i.e., Mn, Pb, Cu, Zn, Cr, Cd, and Ni) pollution in the surface soil from an abandoned manganese mining area in Xiangtan City, Hunan Province, China, on the health of residents. The risks were sequentially evaluated using a series of protocols including: the geo-accumulation index (Igeo), pollution load index (PLI), potential ecological risk index (RI), and implications for human health from external exposures using the hazard quotient (HQ), hazard index (HI) and carcinogenic risk (CR). The results revealed that Mn and Cd were the major pollutants in the soil samples. The ecological risk assessment identified moderate risks, which were mainly derived from Cd (82.91%). The results of the health risk assessment revealed that generally across the area, the non-carcinogenic risk was insignificant, and the carcinogenic risk was at an acceptable level. However, due to local spatial fluctuation, some of the sites presented a non-carcinogenic risk to children. The soil ingestion pathway is the main route of exposure through both non-carcinogenic and carcinogenic risks, with Mn being the major contributor to non-carcinogenic risk, with Cr and Cd the major contributors to carcinogenic risk. In addition, three pollution sources were identified through the Pearson correlation coefficient and principal component analysis (PCA), which included: a. mining activities and emissions from related transportation; b. natural background; c. agricultural management practices and municipal sewage discharge. The study provides information on the effects of spatial variation for the development of the abandoned mining areas and a useful approach to the prioritization of locations for the development and utilization of soil in these areas in China.

Ketamine Rescues Hippocampal Reelin Expression and Synaptic Markers in the Repeated-Corticosterone Chronic Stress Paradigm.

Depression is the leading cause of disability worldwide, which necessitates novel therapeutics and biomarkers to approach treatment of this neuropsychiatric disorder. To assess potential mechanisms underlying the fast-acting antidepressant actions of ketamine we used a repeated corticosterone paradigm in adult male rats to assess the effects of ketamine on reelin-positive cells, a protein largely implicated in the pathophysiology of depression. We also assessed the effects of reelin and ketamine on hippocampal and cerebellar synpatosomes, and on serotonin transporter clustering in peripheral lymphocytes to determine reelin and ketamine's impact at the synaptic and peripheral levels. Reelin and ketamine similarly rescue synaptic expression of mTOR and p-mTOR that were decreased by corticosterone. Reelin, but not ketamine, was able to rescue patterns of serotonin transporter clustering in the periphery. These findings display ketamine as a powerful modulator of reelin expression and lend strength to further evaluation of the putative fast antidepressant-like actions of reelin.

Interplay between hormones and exercise on hippocampal plasticity across the lifespan.

The hippocampus is a brain structure known to play a central role in cognitive function (namely learning and memory) as well as mood regulation and affective behaviors due in part to its ability to undergo structural and functional changes in response to intrinsic and extrinsic stimuli. While structural changes are achieved through modulation of hippocampal neurogenesis as well as alterations in dendritic morphology and spine remodeling, functional (i.e., synaptic) changes can be noted through the strengthening (i.e., long-term potentiation) or weakening (i.e., long-term depression) of the synapses. While age, hormone homeostasis, and levels of physical activity are some of the factors known to module these forms of hippocampal plasticity, the exact mechanisms through which these factors interact with each other at a given moment in time are not completely understood. It is well known that hormonal levels vary throughout the lifespan of an individual and it is also known that physical exercise can impact hormonal homeostasis. Thus, it is reasonable to speculate that hormone modulation might be one of the various mechanisms through which physical exercise differently impacts hippocampal plasticity throughout distinct periods of an individual's life. The present review summarizes the potential relationship between physical exercise and different types of hormones (namely sex, metabolic, and stress hormones) and how this relationship may mediate the effects of physical activity during three distinct life periods, adolescence, adulthood, and senescence. Overall, the vast majority of studies support a beneficial role of exercise in maintaining hippocampal hormonal levels and consequently, hippocampal plasticity, cognition, and mood regulation.

Modulation of synaptic plasticity by exercise.

Synaptic plasticity is an experience-dependent process that results in long-lasting changes in synaptic communication. This phenomenon stimulates structural, molecular, and genetic changes in the brain and is the leading biological model for learning and memory processes. Synapses are able to show persistent increases in synaptic strength, or long-term potentiation (LTP), as well as persistent decreases in synaptic strength, known as long-term depression (LTD). Understanding the complex interactions that regulate these activity-dependent processes can provide insight for the development of strategies to improve cognitive function. Twenty years ago, we provided the first evidence indicating that aerobic exercise can reliably enhance LTP, and went on to show that it can also regulate some of the mechanisms involved in LTD induction. Since then, several laboratories have confirmed and expanded these findings, helping to identify different molecular mechanisms involved in exercise-mediated changes in synaptic efficacy. This chapter reviews this material and shows how these experimental findings may prove valuable for alleviating the burden of neurodegenerative diseases in an aging population.

A Single Session of Aerobic Exercise Mediates Plasticity-Related Phosphorylation in both the Rat Motor Cortex and Hippocampus.

A single session of aerobic exercise may offer one means to "prime" motor regions to be more receptive to the acquisition of a motor skill; however, the mechanisms whereby this priming may occur are not clear. One possible explanation may be related to the post-translational modification of plasticity-related receptors and their associated intracellular signaling molecules, given that these proteins are integral to the development of synaptic plasticity. In particular, phosphorylation governs the biophysical properties (e.g., Ca2+ conductance) and the migratory patterns (i.e., trafficking) of plasticity-related receptors by altering the relative density of specific receptor subunits at synapses. We hypothesized that a single session of exercise would alter the subunit phosphorylation of plasticity-related receptors (AMPA receptors, NMDA receptors) and signaling molecules (PKA, CaMKII) in a manner that would serve to prime motor cortex. Young, male Sprague-Dawley rats (n = 24) were assigned to either exercise (Moderate, Exhaustion), or non-exercising (Sedentary) groups. Immediately following a single session of treadmill exercise, whole tissue homogenates were prepared from both the motor cortex and hippocampus. We observed a robust (1.2-2.0× greater than sedentary) increase in tyrosine phosphorylation of AMPA (GluA1,2) and NMDA (GluN2A,B) receptor subunits, and a clear indication that exercise preferentially affects pPKA over pCaMKII. The changes were found, specifically, following moderate, but not maximal, acute aerobic exercise in both motor cortex and hippocampus. Given the requirement for these proteins during the early phases of plasticity induction, the possibility exists that exercise-induced priming may occur by altering the phosphorylation of plasticity-related proteins.

Building your best day for healthy brain aging-The neuroprotective effects of optimal time use.

As the number of older people increases, so too does the prevalence of neurodegenerative disease. Worldwide, health organisations have identified the need for practical, affordable interventions to slow or delay the onset of neurodegenerative diseases such as dementia, for which there are multiple modifiable risk factors. The effects of various interventions on brain health has been investigated, including achieving sufficient physical activity, getting appropriate amounts and quality of sleep, and limiting sedentary behaviours. Few of these studies, though, have taken into account more than one lifestyle behaviour within a single study. Epidemiologists have recently initiated a paradigm shift to move away from studying the independent effects of each physical activity, sleep and sedentary behaviour, and towards an integrated 24-h time-use paradigm. Time is finite, and thus to increase time in one activity (for example physical activity), equal time must be taken away from other activities (sleep and sedentary behaviour). This 24-h time-use paradigm has begun to be used when studying obesity, adiposity and quality of life; however, to the authors' knowledge, it has not yet been adopted by cognitive neuroscientists for the study of cognition or brain function. This narrative review synthesises the evidence for the neurophysiological effects of physical activity, sleep and sedentary behaviour independently, with a particular focus on brain structure, function and neurodegenerative disease risk. Then, we conclude with a call to action, addressing the need for studies to move towards an integrated 24-h time-use paradigm.

Depression in neurodegenerative diseases: Common mechanisms and current treatment options.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder and a major cause of disability worldwide. This neurological condition is commonly associated with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), and has a significant impact on the increasing burden of these neuropathologies. Over the past decades, some of the pathophysiological and molecular mechanisms that contribute to these diseases have been elucidated and these findings indicate that, despite presenting distinct features, there are several similarities between the neurobiological alterations that lead to MDD and neurodegeneration in AD, PD, and HD. For instance, disturbances in monoaminergic transmission and the hypothalamic-pituitary-adrenal (HPA) axis, increased oxidative and neuroinflammatory events, and impaired trophic support are thought to contribute to neuronal atrophy and death in all these diseases. In addition, neuroimaging findings have helped elucidate the structural and functional changes implicated in the relationship between depression and neurodegeneration, thus establishing a neuroanatomical signature to explain, at least in part, the comorbidity between MDD and AD, PD, and HD. The present review summarizes these findings and the current evidence regarding the effectiveness of common antidepressant therapies for the treatment of MDD in patients with these neurodegenerative diseases. This population is particularly vulnerable to the drawdowns of conventional antidepressant therapy (namely inadequate response and high risk of side effects), and the development of emerging therapeutic approaches to treat MDD in patients with AD, PD, and HD is thus of paramount importance to improve the quality of life of these individuals.

Single session, high-intensity aerobic exercise fails to affect plasticity-related protein expression in the rat sensorimotor cortex.

Typical responses in muscle following acute aerobic exercise have been well documented, but the responses in brain have remained relatively unexplored. Recent reports suggest that a single bout of aerobic exercise can prime motor regions of the human brain to experience use-dependent plasticity, however, the mechanisms underlying this priming phenomenon are unclear. As a result, we asked whether a graded test to exhaustion (GXT), the most widely employed test to examine relationships between exercise and integrated responses within the musculoskeletal, cardiopulmonary, and neuropsychological systems, would be able to upregulate the expression of plasticity-related proteins in sensorimotor cortex in rats. We examined immediate responses in animals following either a GXT, or two resting conditions: non-exercising treadmill controls (TC), and acclimatization controls (AC). Young, male Sprague-Dawley rats (n = 20) on a reverse light cycle (12 h/12 h) were exposed to a treadmill acclimatization procedure consisting of 8 days of increasing exercise intensity (10 m/min up to 25 m/min) for 10 min at the same time each day. The acclimatization was followed by 2 days of rest to reduce any carryover effects. On testing day, rats performed either a GXT, or rested (TC and AC), were then sacrificed and sensorimotor cortex dissected. Homogenates were probed for a physiological marker of stress (HSP 70), and plasticity-related proteins (CaMKII, GluN2A, GluN1, GluA1, GluA2) by Western blotting analysis. Both our acclimatization protocol and single event GXT yielded no observable differences in protein expression, suggesting that single session exercise does not prime brain via altered plasticity-related protein expression.

Use of a Continuous Stirred Tank Reactor for the Determination of Electrospray Response Factors and Its Application to Underivatized Sugars Under Various Solvent Parameters.

The relationship between the electrospray ionization (ESI)-mass spectrometric (MS) response of an analyte and its concentration has been well studied for permanently charged and basic analytes in the positive ionization mode, but there has been a lack of research effort for other analytes, and for the negative ionization mode, in general. In this study, this relationship was investigated for various adducts and deprotonated species of glucose, sucrose, and raffinose using a continuous stirred tank reactor (CSTR) coupled with ESI-tandem MS to obtain a continuum of response factors across a wide concentration range in both the positive and negative ionization modes with a single injection under 18 different combinations of solvents and additives. Profiles of response factors vs. concentrations varied widely and were dependent upon the analyte and solvent parameters. The use of ammonium trifluoroacetate resulted in the highest response factors for methanol-based and acetonitrile-based solvents in the positive and negative ionization modes, respectively. Ammonium acetate, ammonium formate, and sodium chloride in 80:20 acetonitrile:water in the negative ionization mode resulted in good linearities, useful for quantitative analysis. In the positive ionization mode, response factors tended to increase with an increase in the molecular weight of the analyte, and acetonitrile was generally found to decrease response factors. We have also demonstrated the ability of CSTR-ESI-MS to visualize ionization suppression in the presence of co-analytes. These data should be useful for liquid chromatography-ESI-MS method development for sugar analysis, to help guide the choice of mobile phase that will result in high sensitivity and linearity. Graphical Abstract.

Effects of solvent parameters on the electrospray ionization tandem mass spectrometry response of glucose.

RATIONALE: The importance of saccharides, the most abundant biomolecules on Earth, extends beyond their biological roles and to consumer products and industrial processes. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) is an attractive tool for the analysis of underivatized saccharides (US), but they tend to have relatively low sensitivities due to their low surface activities and lack of easily protonable or deprotonable chemical groups. An understanding of the influences that solvent parameters have on their signal intensities would enhance the usefulness of ESI-MS/MS for their analysis. METHODS: Solutions of glucose, a model analyte for US, in various combinations of solvent, additive, additive concentration, and pH were analyzed by flow injection analysis ESI-MS/MS in both the positive and negative ionization mode. The blank-corrected signal intensities of the solvent parameter combinations were then compared. RESULTS: The addition of acetonitrile led to severe ionization suppression in the positive ionization mode through its competition with glucose for cation adduction. High signal intensity was achieved under wide pH and concentration ranges for methanol: water solutions containing ammonium trifluoroacetate in the positive ionization mode. The highest signal intensities for acetonitrile: water solutions were those containing ammonium formate or lithium fluoride in the negative ionization mode. CONCLUSIONS: An understanding of the influence of solvent parameters on the signal intensity of a given analyte is useful for guiding the selection process of mobile phases/flow solvents that lead to low limits of detection or the minimization of matrix effects by allowing its detection at high dilution factors.

A maternal diet high in saturated fat impairs offspring hippocampal function in a sex-specific manner.

While a maternal diet high in saturated fat is likely to affect foetal brain development, whether the effects are the same for male and female offspring is unclear. As a result, we randomly assigned female, Sprague-Dawley rats to either a control, or high-fat diet (HFD; 45% of calories from saturated fat) for 10 weeks. A range of biometrics were collected, and hippocampal function was assessed at both the tissue level (by measuring synaptic plasticity) and at the behavioural level (using the Morris water maze; MWM). Subsequently, a subset of animals was bred and remained on their respective diets throughout gestation and lactation. On post-natal day 21, offspring were weaned and placed onto the control diet; biometrics and spatial learning and memory were then assessed at both adolescence and young adulthood. Although the HFD led to changes in the maternal generation consistent with an obese phenotype, no impairments were noted at the level of hippocampal synaptic plasticity, or MWM performance. Unexpectedly, among the offspring, a sexually dimorphic effect upon MWM performance became apparent. In particular, adolescent male offspring displayed a greater latency to reach the platform during training trials and spent less time in the target quadrant during the probe test; notably, when re-examined during young adulthood, the performance deficit was no longer present. Overall, our work suggests the existence of sexual dimorphism with regard to how a maternal HFD affects hippocampal-dependent function in the offspring brain.