Induced pluripotent stem cell-derived mesenchymal stem cells enhance acellular nerve allografts to promote peripheral nerve regeneration by facilitating angiogenesis.

Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells. However, adult tissue-derived mesenchymal stem cells encounter various obstacles, including limited tissue sources, invasive acquisition methods, cellular heterogeneity, purification challenges, cellular senescence, and diminished pluripotency and proliferation over successive passages. In this study, we used induced pluripotent stem cell-derived mesenchymal stem cells, known for their self-renewal capacity, multilineage differentiation potential, and immunomodulatory characteristics.

Shared and unique transcriptomic signatures of antidepressant and probiotics action in the mammalian brain.

Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we examine the transcriptomic effects of bupropion (NDRI), desipramine (SNRI), fluoxetine (SSRI) and a probiotic formulation (Lacidofil®) on 10 regions across the mammalian brain. These treatments massively alter gene expression (on average, 2211 differentially expressed genes (DEGs) per region-treatment combination), highlighting the biological complexity of AD and probiotic action.

Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing.

Background: There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established.

Methods: In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n = 22-24 per group/region).

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling.

Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI.

Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress.

The multifactorial etiology of stress-related disorders necessitates a constant interrogation of the molecular convergences in preclinical models of stress that use disparate paradigms as stressors spanning from environmental challenges to genetic predisposition to hormonal signaling. Using RNA-sequencing, we investigated the genomic signatures in the ventral hippocampus common to mouse models of stress. Chronic oral corticosterone (CORT) induced increased anxiety- and depression-like behavior in wild-type male mice and male mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met, a variant associated with genetic susceptibility to stress.

Oxytocin receptor expression and epigenetic regulation in the anterior cingulate cortex of individuals with a history of severe childhood abuse.

Childhood abuse significantly increases the lifetime risk of negative mental health outcomes. The oxytocinergic system, which plays a role in complex social and emotional behaviors, has been shown to be sensitive to early-life experiences. While previous studies have investigated the relationship between early-life adversity and oxytocin, they did so with peripheral samples.

Brain-Derived Neurotrophic Factor in the Nucleus Accumbens Mediates Individual Differences in Behavioral Responses to a Natural, Social Reward.

BDNF-oxytocin interactions in the brain are implicated in mammalian maternal behavior. We found that BDNF gene expression is increased in the hippocampus of rat mothers that show increased pup licking/grooming (high LG mothers) compared to low LG mothers. High LG mothers also showed increased BDNF protein levels in the nucleus accumbens (nAcc).

Estrogen receptor α drives pro-resilient transcription in mouse models of depression.

Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress.

Environmental enrichment increases transcriptional and epigenetic differentiation between mouse dorsal and ventral dentate gyrus.

Early life experience influences stress reactivity and mental health through effects on cognitive-emotional functions that are, in part, linked to gene expression in the dorsal and ventral hippocampus. The hippocampal dentate gyrus (DG) is a major site for experience-dependent plasticity associated with sustained transcriptional alterations, potentially mediated by epigenetic modifications. Here, we report comprehensive DNA methylome, hydroxymethylome and transcriptome data sets from mouse dorsal and ventral DG.

Maternal care associates with differences in morphological complexity in the medial preoptic area.

The medial preoptic area (MPOA) is implicated in the expression of maternal behavior including the frequency of pup licking/grooming (LG) in the rat. Cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB) is a transcription factor that regulates the expression of many genes. We found that lactating rats that are more maternal towards their pups showing increased licking/grooming (i.

The methylated-DNA binding protein MBD2 enhances NGFI-A (egr-1)-mediated transcriptional activation of the glucocorticoid receptor.

Variations in maternal care in the rat influence the epigenetic state and transcriptional activity of glucocorticoid receptor (GR) gene in the hippocampus. The mechanisms underlying this maternal effect remained to be defined, including the nature of the relevant maternally regulated intracellular signalling pathways. We show here that increased maternal licking/grooming (LG), which stably enhances hippocampal GR expression, paradoxically increases hippocampal expression of the methyl-CpG binding domain protein-2 (MBD2) and MBD2 binding to the exon 17 GR promoter.

Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat.

Variations in maternal care in the rat affect hippocampal morphology and function as well as performance on hippocampal-dependent tests of learning and memory in the offspring. Preliminary genome-wide analyses of gene transcription and DNA methylation of the molecular basis for such maternal effects suggested differences in the epigenetic state and transcriptional activity of the Grm1 gene in the rat as a function of maternal care. Grm1 encodes the type I metabotropic glutamate receptor (mGluR1), and we found increased mGluR1 mRNA and protein in hippocampus from the adult offspring of mothers showing an increased frequency of pup licking/grooming (i.

Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans.

Parental care influences development across mammals. In humans such influences include effects on phenotypes, such as stress reactivity, which determine individual differences in the vulnerability for affective disorders. Thus, the adult offspring of rat mothers that show an increased frequency of pup licking/grooming (ie, high LG mothers) show increased hippocampal glucocorticoid receptor (GR) expression and more modest hypothalamic-pituitary-adrenal responses to stress compared with the offspring of low LG mothers.

Environmental regulation of the neural epigenome.

Parental effects are a major source of phenotypic plasticity. Moreover, there is evidence from studies with a wide range of species that the relevant parental signals are influenced by the quality of the parental environment. The link between the quality of the environment and the nature of the parental signal is consistent with the idea that parental effects, whether direct or indirect, might serve to influence the phenotype of the offspring in a manner that is consistent with the prevailing environmental demands.

Adult hippocampal glucocorticoid receptor expression and dentate synaptic plasticity correlate with maternal care received by individuals early in life.

Maternal care in mammals is the prevailing environmental influence during perinatal development. The adult rat offspring of mothers exhibiting increased levels of pup licking/grooming (LG; High LG mothers), compared to those reared by Low LG dams, show increased hippocampal glucocorticoid receptor expression, complex dendritic tree structure, and an enhanced capacity for synaptic potentiation. However, these data were derived from studies using the total amount of maternal care directed toward the entire litter, thus ignoring possible within-litter variation.

Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus.

Parenting and the early environment influence the risk for various psychopathologies. Studies in the rat suggest that variations in maternal care stably influence DNA methylation, gene expression, and neural function in the offspring. Maternal care affects neural development, including the GABAergic system, the function of which is linked to the pathophysiology of diseases including schizophrenia and depression.

Oxytocin-dopamine interactions mediate variations in maternal behavior in the rat.

Variations in maternal behavior among lactating rats associate with differences in estrogen-oxytocin interactions in the medial preoptic area (mPOA) and in dopamine levels in the nucleus accumbens (nAcc). Thus, stable, individual differences in pup licking/grooming (LG) are abolished by oxytocin receptor blockade or treatments that eliminate differences in the nAcc dopamine signal. We provide novel evidence for a direct effect of oxytocin at the level of the ventral tegmental area (VTA) in the regulation of nAcc dopamine levels.

Epigenetics and the environmental regulation of the genome and its function.

There are numerous examples in psychology and other disciplines of the enduring effects of early experience on neural function. In this article, we review the emerging evidence for epigenetics as a candidate mechanism for these effects. Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in nucleotide sequence.

Impairments in water maze learning of aged rats that received dextromethorphan repeatedly during adolescent period.

Rationale: Dextromethorphan (DM), an over-the-counter cough suppressant, has been recently used as a drug of abuse by teenage groups in some countries, such as the United States, Canada, and Korea. We previously showed that repeated administration of DM, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, impairs spatial learning performance in adolescent rats.

Objectives: In the present study, long-term adverse effects of repetitive DM use at adolescence were examined in rats.

Maternal programming of defensive responses through sustained effects on gene expression.

There are profound maternal effects on individual differences in defensive responses and reproductive strategies in species ranging literally from plants to insects to birds. Maternal effects commonly reflect the quality of the environment and are most likely mediated by the quality of the maternal provision (egg, propagule, etc.), which in turn determines growth rates and adult phenotype.

Maternal programming of individual differences in defensive responses in the rat.

This paper describes the results of a series of studies showing that variations in mother-pup interactions program the development of individual differences in behavioral and endocrine stress responses in the rat. These effects are associated with altered expression of genes in brain regions, such as the amygdala, hippocampus, and hypothalamus, that regulate the expression of stress responses. Studies from evolutionary biology suggest that such "maternal effects" are common and often associated with variations in the quality of the maternal environment.

Peripubertal environmental enrichment reverses the effects of maternal care on hippocampal development and glutamate receptor subunit expression.

Maternal care in the rat influences the development of cognitive function in the offspring through neural systems known to mediate activity-dependent synaptic plasticity. The offspring of mothers that exhibit increased levels of pup licking/grooming (high-LG mothers) show increased hippocampal N-methyl-D-aspartate (NMDA) subunit mRNA expression, enhanced synaptogenesis and improved hippocampal-dependent spatial learning in comparison with animals reared by low-LG mothers. The effects of reduced maternal care on cognitive function are reversed with peripubertal environmental enrichment; however, the neural mechanisms mediating this effect are not known.