Obesogenic diet induces sex-specific alterations of contextual fear memory and associated hippocampal activity in mice.

In addition to metabolic and cardiovascular disorders, obesity is associated with cognitive deficits in humans and animal models. We have previously shown that obesogenic high-fat and sugar diet intake during adolescence (adoHFSD) impairs hippocampus (HPC)-dependent memory in rodents. These results were obtained in males only and it remains to evaluate whether adoHFSD has similar effect in females. Therefore, here, we investigated the effects of adoHFSD consumption on HPC-dependent contextual fear memory and associated brain activation in male and female mice. Exposure to adoHFSD increased fat mass accumulation and glucose levels in both males and females but impaired contextual fear memory only in males. Compared with females, contextual fear conditioning induced higher neuronal activation in the dorsal and ventral HPC (CA1 and CA3 subfields) as well as in the medial prefrontal cortex in males. Also, adoHFSD-fed males showed enhanced c-Fos expression in the dorsal HPC, particularly in the dentate gyrus, and in the basolateral amygdala compared with the other groups. Finally, chemogenetic inactivation of the dorsal HPC rescued adoHFSD-induced memory deficits in males. Our results suggest that males are more vulnerable to the effects of adoHFSD on HPC-dependent aversive memory than females, due to overactivation of the dorsal HPC.

N-3 PUFA deficiency disrupts oligodendrocyte maturation and myelin integrity during brain development.

Westernization of dietary habits has led to a progressive reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental disorders, conditions in which myelination processes are abnormal, leading to defects in brain functional connectivity. Only little is known about the role of n-3 PUFAs in oligodendrocyte physiology and white matter development. Here, we show that lifelong n-3 PUFA deficiency disrupts oligodendrocytes maturation and myelination processes during the postnatal period in mice. This has long-term deleterious consequences on white matter organization and hippocampus-prefrontal functional connectivity in adults, associated with cognitive and emotional disorders. Promoting developmental myelination with clemastine, a first-generation histamine antagonist and enhancer of oligodendrocyte precursor cell differentiation, rescues memory deficits in n-3 PUFA deficient animals. Our findings identify a novel mechanism through which n-3 PUFA deficiency alters brain functions by disrupting oligodendrocyte maturation and brain myelination during the neurodevelopmental period.

Bidirectional modulation of hippocampal and amygdala synaptic plasticity by post-weaning obesogenic diet intake in male rats: Influence of the duration of diet exposure.

Obesity is a chronic condition associated with adverse memory and emotional outcomes in humans and animal models. We have recently demonstrated that post-weaning (i.e., periadolescent) high-fat diet (HFD)-induced obesity has opposite effect on hippocampal and amygdala-dependent memory in rodents: while HFD consumption impairs spatial and relational memory, it enhances cue-dependent emotional memory. However, it is still not clear whether this bidirectional HFD effect on memory is related to bidirectional alterations of hippocampal and amygdala synaptic plasticity and if it is influenced by the duration of diet intake. In the current study, we compared in male rats the impact of 2-3 and 6-7 months of HFD intake starting at weaning, thus covering adolescence, on in vivo long-term potentiation (LTP) recorded simultaneously in the hippocampal area CA1 and the basolateral amygdala (BLA). As expected, 6-7 months of HFD intake abolished LTP in the CA1 and enhanced LTP in the BLA. However, 2-3 months of of HFD exposure enhanced LTP in both CA1 and BLA suggesting a transient compensatory mechanism in hippocampus. These results indicate that post-weaning HFD intake progressively leads to bidirectional modulation of hippocampal and amygdala synaptic plasticity, as we previously demonstrated for related memory processes, yet with a different temporal dynamic.

Chemogenetic silencing of hippocampus and amygdala reveals a double dissociation in periadolescent obesogenic diet-induced memory alterations.

In addition to numerous metabolic comorbidities, obesity is associated with several adverse neurobiological outcomes, especially learning and memory alterations. Obesity prevalence is rising dramatically in youth and is persisting in adulthood. This is especially worrying since adolescence is a crucial period for the maturation of certain brain regions playing a central role in memory processes such as the hippocampus and the amygdala. We previously showed that periadolescent, but not adult, exposure to obesogenic high-fat diet (HFD) had opposite effects on hippocampus- and amygdala-dependent memory, impairing the former and enhancing the latter. However, the causal role of these two brain regions in periadolescent HFD-induced memory alterations remains unclear. Here, we first showed that periadolescent HFD induced long-term, but not short-term, object recognition memory deficits, specifically when rats were exposed to a novel context. Using chemogenetic approaches to inhibit targeted brain regions, we then demonstrated that recognition memory deficits are dependent on the activity of the ventral hippocampus, but not the basolateral amygdala. On the contrary, the HFD- induced enhancement of conditioned odor aversion specifically requires amygdala activity. Taken together, these findings suggest that HFD consumption throughout adolescence impairs long-term object recognition memory through alterations of ventral hippocampal activity during memory acquisition. Moreover, these results further highlight the bidirectional effects of adolescent HFD on hippocampal and amygdala functions.

An explanation of the pathophysiology of adverse neurodevelopmental outcomes in iron deficiency.

Iron deficiency (ID) is a major public health problem worldwide among children aged 0-12 months. Several factors seem to contribute to the iron-deficient state in infancy, including insufficient antenatal and neonatal iron supplementation, exclusive breastfeeding, and early umbilical cord clamping after birth. The most concerning complications of ID, except for anemia, are related to altered long-term neurodevelopment. Clinical studies have shown a negative impact of ID anemia on fetal and neonatal behavior including impairments of motor maturity, autonomic response, memory/learning, and mood. ID-induced defects during infancy seem to persist later in life, even after ID treatment. The underlying mechanisms involve dysfunctional myelination, neurotransmission alterations, and altered synaptogenesis and/or dendritogenesis. The purpose of the present review is to summarize these mechanisms and to provide recommendations for future clinical research in the field.

Retention of cervical cerclage after preterm premature rupture of the membranes: a critical appraisal.

PURPOSE: The present meta-analysis aims to assess the efficacy of cervical cerclage retention after the occurrence of preterm premature rupture of the membranes by analyzing the observed maternal and neonatal perinatal outcomes. METHODS: We searched Medline (1966-2014), Scopus (2004-2014), Clinicaltrials.org (1997-2014), Cochrane Central Register of Controlled Trials (CENTRAL) (1999-2014) and Google Scholar (2004-2014) search engines, as well as reference lists from all included studies. The statistical analysis was performed using the RevMan software. RESULTS: Six studies were finally included in the present review, involving 293 parturient. Cerclage retention did not significantly prolong the gestational latency period (MD 2.56 days, 95% CI - 1.06, 6.71). It did, however, increased the rates of delivery after the first 48 h (OR 6.27, 95% CI 1.08, 36.24). As a technique, it did not significantly increase the rates of neonatal sepsis (OR 1.42, 95% CI 0.65, 3.12) or the neonatal death rates (OR 1.09, 95% CI 0.48, 2.47).Maternal chorioamnionitis was, however, significantly more prevalent among women offered cerclage retention (OR 1.78, 95% CI 1.02, 3.12), although the same was not observed in the case of postpartum endometritis (REM OR 4.73, 95 % CI 0.74, 30.09). CONCLUSIONS: Current evidence is insufficient to support the retention of cervical cerclage after the occurrence of PPROM, therefore, its implementation should be exceptionally instituted in everyday clinical practice, until further evidence becomes available.

Fetal alcohol spectrum disorders and cognitive functions of young children.

Fetal alcohol spectrum disorder (FASD) is one of the main causes of mental retardation worldwide. Nearly 1% of children in North America are affected from antenatal exposure to ethanol. Its economic burden in industrialized countries is increasing. It is estimated that, in the United States, 4.0 billion dollars are annually expended in the treatment and rehabilitation of these patients. As a pathologic entity, they present with a broad symptomatology. Fetal alcohol syndrome (FAS) is the most readily recognized clinical manifestation of these disorders. Various factors seem to contribute in the pathogenesis of FASD-related cognitive disorders. During the last 20 years, several potential pretranslational and posttranslational factors have been extensively studied in various experimental animal models. Research has specifically focused on several neurotransmitters, insulin resistance, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, abnormal glycosylation of several proteins, oxidative stress, nutritional antioxidants, and various epigenetic factors. The purpose of the present review is to summarize the clinical manifestations of this disorder during childhood and adolescence and to summarize the possible pathophysiologic and epigenetic pathways that have been implicated in the pathophysiology of FASD.

Obesogenic diet induces circuit-specific memory deficits in mice.

Obesity is associated with neurocognitive dysfunction, including memory deficits. This is particularly worrisome when obesity occurs during adolescence, a maturational period for brain structures critical for cognition. In rodent models, we recently reported that memory impairments induced by obesogenic high-fat diet (HFD) intake during the periadolescent period can be reversed by chemogenetic manipulation of the ventral hippocampus (vHPC). Here, we used an intersectional viral approach in HFD-fed male mice to chemogenetically inactivate specific vHPC efferent pathways to nucleus accumbens (NAc) or medial prefrontal cortex (mPFC) during memory tasks. We first demonstrated that HFD enhanced activation of both pathways after training and that our chemogenetic approach was effective in normalizing this activation. Inactivation of the vHPC-NAc pathway rescued HFD-induced deficits in recognition but not location memory. Conversely, inactivation of the vHPC-mPFC pathway restored location but not recognition memory impairments produced by HFD. Either pathway manipulation did not affect exploration or anxiety-like behaviour. These findings suggest that HFD intake throughout adolescence impairs different types of memory through overactivation of specific hippocampal efferent pathways and that targeting these overactive pathways has therapeutic potential.

Pathway specific interventions reveal the multiple roles of ventral hippocampus projections in cognitive functions.

Since the 1950s study of Scoville and Milner on the case H.M., the hippocampus has attracted neuroscientists' attention. The hippocampus has been traditionally divided into dorsal and ventral parts, each of which projects to different brain structures and mediates various functions. Despite a predominant interest in its dorsal part in animal models, especially regarding episodic-like and spatial cognition, recent data highlight the role of the ventral hippocampus (vHPC), as the main hippocampal output, in cognitive processes. Here, we review recent studies conducted in rodents that have used advanced in vivo functional techniques to specifically monitor and manipulate vHPC efferent pathways and delineate the roles of these specific projections in learning and memory processes. Results highlight that vHPC projections to basal amygdala are implicated in emotional memory, to nucleus accumbens in social memory and instrumental actions and to prefrontal cortex in all the above as well as in object-based memory. Some of these hippocampal projections also modulate feeding and anxiety-like behaviours providing further evidence that the "one pathway-one function" view is outdated and future directions are proposed to better understand the role of hippocampal pathways and shed further light on its connectivity and function.

A human-relevant mixture of endocrine disrupting chemicals induces changes in hippocampal DNA methylation correlating with hyperactive behavior in male mice.

Humans are ubiquitously exposed to endocrine disrupting chemicals (EDCs), substances that interfere with endogenous hormonal signaling. Exposure during early development is of particular concern due to the programming role of hormones during this period. A previous epidemiological study has shown association between prenatal co-exposure to 8 EDCs (Mixture N1) and language delay in children, suggesting an effect of this mixture on neurodevelopment. Furthermore, in utero exposure to Mixture N1 altered gene expression and behavior in adult mice. In this study, we investigated whether epigenetic mechanisms could underlie the long term effects of Mixture N1 on gene expression and behavior. To this end, we analyzed DNA methylation at regulatory regions of genes whose expression was affected by Mixture N1 in the hippocampus of in utero exposed mice using bisulfite-pyrosequencing. We show that Mixture N1 decreases DNA methylation in males at three genes that are part of the hypothalamus-pituitary-adrenal (HPA) axis: Nr3c1, Nr3c2, and Crhr1, coding for the glucocorticoid receptor, the mineralocorticoid receptor, and the corticotropin releasing hormone receptor 1, respectively. Furthermore, we show that the decrease in Nr3c1 methylation correlates with increased gene expression, and that Nr3c1, Nr3c2, and Crhr1 methylation correlates with hyperactivity and reduction in social behavior. These findings indicate that an EDC mixture corresponding to a human exposure scenario induces epigenetic changes, and thus programming effects, on the HPA axis that are reflected in the behavioral phenotypes of the adult male offspring.

Endocrine-disrupting chemicals and behaviour: A high risk to take?

Early life exposure to endocrine-disrupting chemicals (EDCs) is considered a potential risk factor for aberrant brain development and the emergence of behavioral deficits. The purpose of this review is to summarize the toxic effects of bisphenol-A (BPA) and phthalate exposure during pre-, -post- or perinatal life on different types of behaviour in male and female rodents. Despite results not being always consistent, most probably due to methodological issues, it is highly probable that early life exposure to BPA or/and phthalates, affects various aspects of behaviour in the offspring. Adverse effects include: Increased levels of anxiety, altered exploratory behaviour, reduced social interaction or increased aggression and deficits in spatial or recognition learning and memory. These effects have been observed with a wide range of doses, in some cases even below the currently employed Tolerable Daily Intake dose for either BPA or phthalates.

Phytochemicals and cognitive health: Are flavonoids doing the trick?

Flavonoids constitute a large group of polyphenolic compounds with numerous effects on behaviour and cognition. These effects vary from learning and memory enhancement to an improvement of general cognition. Furthermore, flavonoids have been implicated in a) neuronal proliferation and survival, by acting on a variety of cellular signalling cascades, including the ERK/CREB/BDNF and PI3K/Akt pathway, b) oxidative stress reduction and c) relief from Alzheimer's disease-type symptoms. From an electrophysiological aspect, they promote long term potentiation in the hippocampus, supporting the hypothesis of synaptic plasticity mediation. Together, these actions reveal a neuroprotective effect of flavonoid compounds in the brain. Therefore, flavonoid intake could be a potential clinical direction for prevention and/or attenuation of cognitive decline deterioration which accompanies various brain disorders. The purpose of the current review paper was to summarise all these effects on cognition, describe the possible pathways via which they may act on a cellular level and provide a better picture for future research towards this direction.