Maternal brain resting‐state connectivity in the postpartum period

In the postpartum period, the maternal brain experiences both structural and functional plasticity. Although we have a growing understanding of the responses of the human maternal brain to infant stimuli, little is known about the intrinsic connectivity among those regions during the postpartum months. Resting‐state functional connectivity (rsFC) provides a measure of the functional architecture of the brain based upon intrinsic functional connectivity (ie, the temporal correlation in blood oxygenation level dependent signal when the brain is not engaged in a specific task). In the present study, we used resting‐state functional magnetic resonance imaging to examine how later postpartum months are associated with rsFC and maternal behaviours. We recruited a sample of 47 socioeconomically diverse first‐time mothers with singleton pregnancies. Because the amygdala has been shown to play a critical role in maternal behaviours in the postpartum period, this was chosen as the seed for a seed‐based correlation analysis. For the left amygdala, later postpartum months were associated with greater connectivity with the anterior cingulate gyrus, left nucleus accumbens, right caudate and left cerebellum (P < 0.05, false discovery rate corrected). Furthermore, in an exploratory analysis, we observed indications that rsFC between the left amygdala and left nucleus accumbens was positively associated with maternal structuring during a mother child‐interaction. In addition, later postpartum months were associated with greater connectivity between the right amygdala and the bilateral caudate and right putamen. Overall, we provide evidence of relationships between postpartum months and rsFC in the regions involved in salience detection and regions involved in maternal motivation. Greater connectivity between the amygdala and nucleus accumbens may play a role in positive maternal behaviours.     

Flexibility and adaptation of the neural substrate that supports maternal behavior in mammals

Maternal behavior is species-specific and expressed under different physiological conditions, and contexts. It is the result of neural processes that support different forms (e.g. postpartum, cycling sensitized and spontaneous maternal behavior) and modalities of mother–offspring interaction (e.g. maternal interaction with altricial/precocious young; selective/non-selective bond). To understand how the brain adapts to and regulates maternal behavior in different species, and physiological and social conditions we propose new neural models to explain different forms of maternal expression (e.g. sensitized and spontaneous maternal behavior) and the behavioral changes that occur across the postpartum period. We emphasize the changing role of the medial preoptic area in the neural circuitry that supports maternal behavior and the cortical regulation and adjustment of ongoing behavioral performance. Finally, we discuss how our accumulated knowledge about the psychobiology of mothering in animal models supports the validity of animal studies to guide our understanding of human mothering and to improve human welfare and health.     

Novel methods for integration and visualization of genomics and genetics data in Alzheimer's disease

IntroductionNumerous omics studies have been conducted to understand the molecular networks involved in Alzheimer's disease (AD), but the pathophysiology is still not completely understood; new approaches that enable neuroscientists to better interpret the results of omics analysis are required.MethodsWe have developed advanced methods to analyze and visualize publicly-available genomics and genetics data. The tools include a composite clinical-neuropathological score for defining AD, gene expression maps in the brain, and networks integrating omics data to understand the impact of polymorphisms on AD pathways.ResultsWe have analyzed over 50 public human gene expression data sets, spanning 19 different brain regions and encompassing three separate cohorts. We integrated genome-wide association studies with expression data to identify important genes in the pathophysiology of AD, which provides further insight into the calcium signaling and calcineurin pathways.DiscussionBiologists can use these freely-available tools to obtain a comprehensive, information-rich view of the pathways in AD.     

Thyroid hormone of maternal origin regulates the expression of RC3/neurogranin mRNA in the fetal rat brain

Recent clinical studies indicate that thyroid hormone plays essential roles in fetal brain development. However, the mechanism by which thyroid hormone affects fetal brain development is poorly studied. We recently identified several genes expressed in the fetal cortex whose abundance is affected by thyroid hormone of maternal origin. However, it is unclear whether these genes are directly regulated by thyroid hormone. Because these are the first genes known to be regulated by thyroid hormone during fetal development, we sought to expand our investigation to genes known to be regulated directly by thyroid hormone. We now report that the well-known thyroid hormone-responsive gene RC3/neurogranin is expressed in the fetal brain and is regulated by thyroid hormone of maternal origin. These findings support the concept that maternal thyroid hormone exerts a direct action on the expression of genes in the fetal brain that are important for normal neurological development.     

Functional mapping of the neural circuitry of rat maternal motivation: effects of site-specific transient neural inactivation

The present review focuses on recent studies from our laboratory examining the neural circuitry subserving rat maternal motivation across postpartum. We employed a site-specific neural inactivation method by infusion of bupivacaine to map the maternal motivation circuitry using two complementary behavioural approaches: unconditioned maternal responsiveness and choice of pup- over cocaine-conditioned incentives in a concurrent pup/cocaine choice conditioned place preference task. Our findings revealed that, during the early postpartum period, distinct brain structures, including the medial preoptic area, ventral tegmental area and medial prefrontal cortex infralimbic and anterior cingulate subregions, contribute a pup-specific bias to the motivational circuitry. As the postpartum period progresses and the pups grow older, it is further revealed that maternal responsiveness becomes progressively less dependent on the medial preoptic area and medial prefrontal cortex infralimbic activity, and more distributed in the maternal circuitry, such that additional network components, including the medial prefrontal cortex prelimbic subregion, are recruited with maternal experience, and contribute to the expression of late postpartum maternal behaviour. Collectively, our findings provide strong evidence that the remarkable ability of postpartum females to successfully care for their developing infants is subserved by a distributed neural network that carries out efficient and dynamic processing of complex, constantly changing incoming environmental and pup-related stimuli, ultimately allowing the progression of appropriate expression and waning of maternal responsiveness across the postpartum period.     

Imprinted gene expression in the brain

In normal mammals, autosomal genes are present in duplicate (i.e. two alleles), one inherited from the father, and one from the mother. For the majority of genes both alleles are transcribed (or expressed) equally. However, for a small subset of genes, known as imprinted genes, only one allele is expressed in a parent-of-origin dependent manner (note that the 'imprint' here refers to the epigenetic mechanism through which one allele is silenced, and is completely unrelated to classical 'filial imprinting' manifest at the behavioural level). Thus, for some imprinted genes expression is only (or predominantly) seen from the paternally inherited allele, whilst for the remainder, expression is only observed from the maternally inherited allele. Early work on this class of genes highlighted their importance in gross developmental and growth phenotypes. Recent studies in mouse models and humans have emphasised their contribution to brain function and behaviour. In this article, we review the literature concerning the expression of imprinted genes in the brain. In particular, we attempt to define emerging organisation themes, especially in terms of the direction of imprinting (i.e. maternal or paternal expression). We also emphasise the likely role of imprinted genes in neurodevelopment. We end by pointing out that, so far as discerning the precise functions of imprinted genes in the brain is concerned, there are currently more questions than answers; ranging from the extent to which imprinted genes might contribute to common mental disorders, to wider issues related to how easily the new data on brain may be accommodated within the dominant theory regarding the origins and maintenance of imprinting, which pits the maternal and paternal genomes against each other in an evolutionary battle of the sexes.     

Cocaine treatment alters oxytocin receptor binding but not mRNA production in postpartum rat dams

Gestational cocaine treatment in rat dams results in decreased oxytocin (OT) levels, up-regulated oxytocin receptor (OTR) binding density and decreased receptor affinity in the whole amygdala, all concomitant with a significant increase in maternal aggression on postpartum day six. Rat dams with no gestational drug treatment that received an infusion of an OT antagonist directly into the central nucleus of the amygdala (CeA) exhibited similarly high levels of maternal aggression towards intruders. Additionally, studies indicate that decreased OT release from the hypothalamic division of the paraventricular nucleus (PVN) is coincident with heightened maternal aggression in rats. Thus, it appears that cocaine-induced alterations in OT system dynamics (levels, receptors, production, and/or release) may mediate heightened maternal aggression following cocaine treatment, but the exact mechanisms through which cocaine impacts the OT system have not yet been determined. Based on previous studies, we hypothesized that two likely mechanisms of cocaine's action would be, increased OTR binding specifically in the CeA, and decreased OT mRNA production in the PVN. Autoradiography and in situ hybridization assays were performed on targeted nuclei in brain regions of rat dams on postpartum day six, following gestational treatment twice daily with cocaine (15 mg/kg) or normal saline (1 ml/kg). We now report cocaine-induced reductions in OTR binding density in the ventromedial hypothalamus (VMH) and bed nucleus of the stria terminalis (BNST), but not the CeA. There was no significant change in OT mRNA production in the PVN following cocaine treatment.     

Maternally responsive neurons in the bed nucleus of the stria terminalis and medial preoptic area: Putative circuits for regulating anxiety and reward

Postpartum neuropsychiatric disorders are a major source of morbidity and mortality and affect at least 10% of childbearing women. Affective dysregulation within this context has been identified in association with changes in reproductive steroids. Steroids promote maternal actions and modulate affect, but can also destabilize mood in some but not all women. Potential brain regions that mediate these effects include the medial preoptic area (mPOA) and ventral bed nucleus of the stria terminalis (vBNST). Herein, we review the regulation of neural activity in the mPOA/vBNST by environmental and hormonal concomitants in puerperal females. Such activity may influence maternal anxiety and motivation and have significant implications for postpartum affective disorders. Future directions for research are also explored, including physiological circuit-level approaches to gain insight into the functional connectivity of hormone-responsive maternal circuits that modulate affect.     

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

To more rapidly identify candidate genes located within chromosomal regions of interest defined by genome scan studies in Alzheimer's disease (AD), we have developed a customized microarray containing all the ORFs (n=2741) located within nine of these regions. Levels of gene expression were assessed in total RNA from brain tissue of 12 controls and 12 AD patients. Of all genes showing differential expression, we focused on the ornithine transcarbamylase (OTC) gene on Xp21.1., a key enzyme of the urea cycle which we found to be expressed in AD brains but not in controls, as confirmed by RT-PCR. We also detected mRNA expression of all the other urea cycle enzymes in AD brains. Immunochemistry experiments revealed that the OTC expression was strictly restricted to vascular endothelial cells in brain. Furthermore, OTC activity was 880% increased in the CSF of probable AD cases compared with controls. We analysed the association of the OTC -389 G/A and -241 A/G promoter polymorphisms with the risk of developing AD. We observed that rare haplotypes may be associated with the risk of AD through a possible modulation of the methylation of the OTC promoter. In conclusion, our results suggest the involvement of a new pathway in AD brains involving the urea cycle.     

Gene array profiling of large hypothalamic CNS regions in lactating and randomly cycling virgin mice

A dramatic example of neuronal and physiological plasticity in adult mammals occurs during the transition from a non-maternal to a maternal, lactating state. In this study, we compared gene expression within a large continuous region of the CNS involved in maternal behaviors (hypothalamus, preoptic regions, and nucleus accumbens) between lactating (L) (postpartum Day 7) and randomly cycling virgin (V) outbred mice. Using high-density oligonucleotide arrays representing 11,904 genes, two statistical algorithms were used to identify significant differences in gene expression: robust multiarray (P < 0.001) (n = 92 genes) and significance analysis of microarrays using a 10% false discover rate (n = 114 genes). 27 common genes were identified as significant using both techniques. A subset of genes (n = 5) were selected and examined by real-time PCR. Our findings were consistent with previous published work. For example, neuropeptide Y (NPY) and proenkephalin were elevated in L mice, whereas POMC was decreased. Increased levels of NPY Y2 receptor and polo-like kinase and decreased levels of endothelin receptor type b in L mice are examples of novel gene expression changes not previously identified. Expression differences occurred in broad classes. Together, our findings provide possible new material on gene expression changes that may support maternal behaviors. The advantages and drawbacks of sampling large CNS regions using arrays are discussed.     

A functional neuroanatomical investigation of the role of the medial preoptic area in neural circuits regulating maternal behavior

The medial preoptic area (MPOA) is essential for normal maternal behavior in the rat. Hormone stimulation of the MPOA facilitates the behavior and lesions of the MPOA and the adjoining ventral part of the bed nucleus of the stria terminalis (vBST) disrupt the behavior. The MPOA/vBST also show increases in Fos protein expression during maternal behavior. The present study examines the larger neural circuitry within which the MPOA/vBST might operate to influence maternal behavior. Combining Fos immunocytochemistry with unilateral excitotoxic amino acid lesions or lateral knife cuts of the MPOA/vBST, we sought to identify brain regions which might be under the influence of Fos expressing neurons in the MPOA/vBST. Two brain regions, the shell of the nucleus accumbens (NAs), and the intermediate part of the lateral septum (LSi) were identified. Both the NAs and LSi exhibited elevated Fos expression during maternal behavior, while unilateral MPOA/vBST damage resulted in an ipsilateral reduction of maternal behavior-induced Fos expression in each area, suggesting that MPOA/vBST neurons modulate Fos expression and associated neural activity in both of these structures during maternal behavior. Importantly, these unilateral preoptic lesions also depressed maternal behavior-induced Fos expression in the ipsilateral MPOA and vBST. The effects of these lesions on Fos expression in the periaqueductal gray (PAG) and other brain regions are also presented.     

Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents

Basic and clinical studies demonstrate that stress and depression are associated with atrophy and loss of neurons and glia, which contribute to the decreased size and function of limbic brain regions that control mood and depression, including the prefrontal cortex and hippocampus. Here, we review findings that suggest that opposing effects of stress and/or depression and antidepressants on neurotrophic factor expression and signaling partly explain these effects. We also discuss recent reports that suggest a possible role for glycogen synthase kinase 3 and upstream wingless (Wnt)-frizzled (Fz) signaling pathways in mood disorders. New studies also demonstrate that the rapid antidepressant actions of NMDA receptor antagonists are associated with activation of glutamate transmission and induction of synaptogenesis, providing novel targets for a new generation of fast-acting, more efficacious therapeutic agents.     

Running-induced epigenetic and gene expression changes in the adolescent brain

Physical exercise is associated with positive neural functioning. Here we examined the gene expression consequences of 1 week of voluntary wheel running in adolescent male mice. We assayed expression levels of genes associated with synaptic plasticity, signaling pathways, and epigenetic modifying enzymes. Two regions were examined: the hippocampus, which is typically examined in exercise studies, and the cerebellum, an area directly involved in motor control and learning. After 1 week of exercise, global acetylation of histone 3 was increased in both brain regions. Interestingly this was correlated with increased brain derived neural growth factor in the hippocampus, as noted in many other studies, but only a trend was found in cerebellum. Differences and similarities between the two areas were noted for genes encoding functional proteins.     

The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus

The dentate gyrus (DG) of the hippocampus plays a crucial role in learning and memory. This subregion is unique in its ability to generate new neurons throughout life and integrate these new neurons into the hippocampal circuitry. Neurogenesis has further been implicated in hippocampal plasticity and depression. Exposure to chronic stress affects DG function and morphology and suppresses neurogenesis and long-term potentiation (LTP) with consequences for cognition. Previous studies demonstrated that glucocorticoid receptor (GR) blockade by a brief treatment with the GR antagonist mifepristone (RU486) rapidly reverses the stress and glucocorticoid effects on neurogenesis. The molecular pathways underlying both the stress-induced effects and the RU486 effects on the DG are, however, largely unknown. The aim of this study was therefore (1) to investigate by microarray analysis which genes and pathways in the DG are sensitive to chronic stress and (2) to investigate to what extent blockade of GR can normalize these stress-induced effects on DG gene expression. Chronic stress exposure affected the expression of 90 genes in the DG (P < 0.01), with an overrepresentation of genes involved in brain development and morphogenesis and synaptic transmission. RU486 treatment of stressed animals affected expression of 107 genes; however, mostly different genes than those responding to stress. Interestingly, we found CREBBP to be normalized by RU486 treatment to levels observed in control animals, suggesting that CREB-signaling may play a central role in mediating the chronic stress effects on neurogenesis, LTP and calcium currents. The identified genetic pathways provide insight into the stress-induced adaptive plasticity of the hippocampal DG that is so central in learning and memory and will direct future studies on the functional outcome and modulation of these stress effects.     

Steroid hormones and maternal experience interact to induce glial plasticity in the cingulate cortex

Neocortical plasticity is not usually associated with changes in reproductive function. However, we have shown a six to 10-fold increase in the number of astrocytes labeled with glial fibrillary acidic protein (GFAP) and astrocytic basic fibroblast growth factor or FGF-2 (bFGF) in the cingulate cortex area 2 (Cg2) in postpartum rats, indicative of changes in connectivity in this area. In the present studies, we investigated the necessary and sufficient stimuli for these changes to occur. We show that 3 h of maternal experience combined with a hormonal treatment that mimics late pregnancy induces the astrocytic changes in Cg2 in virgin rats. The extent of these changes was similar to those of postpartum females. Sensitized virgin females did not show any astrocytic changes after 3 h of maternal behavior, suggesting that a similar amount of maternal experience alone is not sufficient to increase astrocytic bFGF- and GFAP-immunoreactivity in Cg2. Consistent with these data, eliminating early maternal experience by removing pups immediately postpartum abolishes the increased bFGF and GFAP protein expression in the cingulate cortex. These results suggest that maternal experience and hormonal state interact to produce astrocytic remodeling in the Cg2. The current results are consistent with a role for the cingulate cortex in maternal responsivity as suggested by early lesion studies in rats and more recent imaging studies in humans.     

Transcriptome profiling of five brain regions in a 6‐hydroxydopamine rat model of Parkinson’s disease

BackgroundParkinson''s disease (PD) is a neurodegenerative disease, and its pathogenesis is unclear. Previous studies mainly focus on the lesions of substantia nigra (SN) and striatum (Str) in PD. However, lesions are not limited. The olfactory bulb (OB), subventricular zone (SVZ), and hippocampus (Hippo) are also affected in PD.AimTo reveal gene expression changes in the five brain regions (OB, SVZ, Str, SN, and Hippo), and to look for potential candidate genes and pathways that may be correlated with the pathogenesis of PD.Materials and methodsWe established control group and 6‐hydroxydopamine (6‐OHDA) PD model group, and detected gene expressions in the five brain regions using RNA‐seq and real‐time quantitative polymerase chain reaction (RT‐qPCR). We further analyzed the RNA‐seq data by bioinformatics.ResultsWe identified differentially expressed genes (DEGs) in all five brain regions. The DEGs were significantly enriched in the “dopaminergic synapse” and “retrograde endocannabinoid signaling,” and Gi/o‐GIRK is the shared cascade in the two pathways. We further identified Ephx2, Fam111a, and Gng2 as the potential candidate genes in the pathogenesis of PD for further studies.ConclusionOur study suggested that gene expressions change in the five brain regions following exposure to 6‐OHDA. The “dopaminergic synapse,” “retrograde endocannabinoid signaling,” and Gi/o‐GIRK may be the key pathways and cascade of the synaptic damage in 6‐OHDA PD rats. Ephx2, Fam111a, and Gng2 may play critical roles in the pathogenesis of PD.