Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats

Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS ("PRS rats") showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.     

Stress downregulates hippocampal expression of the adhesion molecules NCAM and CHL1 in mice by mechanisms independent of DNA methylation of their promoters

Stress is an important physiological regulator of brain function in young and adult mammals. The mechanisms underlying regulation of the consequences of stress, and in particular severe chronic stress, are thus important to investigate. These consequences most likely involve changes in synaptic function of brain areas being part of neural networks that regulate responses to stress. Cell adhesion molecules have been shown to regulate synaptic function in the adult and we were thus interested to investigate a regulatory mechanism that could influence expression of three adhesion molecules of the immunoglobulin superfamily (NCAM, L1 and CHL1) after exposure of early postnatal and adult mice to repeated stress. We hypothesized that reduction of adhesion molecule expression after chronic stress, as observed previously in vivo, could be due to gene silencing of the three molecules by DNA methylation. Although adhesion molecule expression was reduced after exposure of C57BL/6 mice to stress, thus validating our stress paradigm as imposing changes in adhesion molecule expression, we did not observe differences in methylation of CpG islands in the promoter regions of NCAM, L1 and CHL1, nor in the promoter region of the glucocorticoid receptor in the hippocampus, the expression of which at the protein level was also reduced after stress. We must therefore infer that severe stress in mice of the C57BL/6 strain downregulates adhesion molecule levels by mechanisms that do not relate to DNA methylation.Key words: stress, immunoglobulin superfamily, adhesion molecules, promoter, DNA methylation, hippocampus, glucocorticoid receptor     

The early life environment and the epigenome

Several lines of evidence point to the early origin of adult onset disease. A key question is: what are the mechanisms that mediate the effects of the early environment on our health? Another important question is: what is the impact of the environment during adulthood and how reversible are the effects of early life later in life? The genome is programmed by the epigenome, which is comprised of chromatin, a covalent modification of DNA by methylation and noncoding RNAs. The epigenome is sculpted during gestation, resulting in the diversity of gene expression programs in the distinct cell types of the organism. Recent data suggest that epigenetic programming of gene expression profiles is sensitive to the early-life environment and that both the chemical and social environment early in life could affect the manner by which the genome is programmed by the epigenome. We propose that epigenetic alterations early in life can have a life-long lasting impact on gene expression and thus on the phenotype, including susceptibility to disease. We will discuss data from animal models as well as recent data from human studies supporting the hypothesis that early life social-adversity leaves its marks on our epigenome and affects stress responsivity, health, and mental health later in life.     

Impact of High-Fat Diet and Early Stress on Depressive-Like Behavior and Hippocampal Plasticity in Adult Male Rats

During development, the brain goes through fundamental processes, including organization of neural networks and plasticity. Environmental interventions may change initial brain programming, leading to long-lasting effects and altering the susceptibility to psychopathologies, including depression disorder. It is known that depression is a psychiatric disorder with a high prevalence worldwide, including high rates among adolescents. In this study, we evaluated whether social isolation in the prepubertal period and chronic use of high-fat diet (HFD) may induce depressive-like behavior in male adult rats. We also investigated hippocampal plasticity markers and neurotransmitter systems. We found both social isolation and HFD induced a depressive-like behavior in the forced swimming task. Moreover, chronic HFD reduced synaptic markers in hippocampus, demonstrated by reductions in βIII-tubulin (neuronal marker), PSD-95, SNAP-25, and neurotrophin-3. The HFD group also presented decreased glutamatergic and GABAergic receptors subunits. On the other hand, stress affected hippocampal brain-derived neurotrophic factor (BDNF) signaling pathways, and increased expression of subunit of the NMDA receptor (NR2A). Both factors (stress and diet) decreased GR in the hippocampus without affecting plasma corticosterone at basal levels. Interactions between early stress and HFD access were observed only in the BNDF receptor (tropomyosin receptor kinase B; TrkB) and synaptophysin. In summary, these findings showed that a brief social isolation and chronic HFD, during a sensitive developmental period, cause depressive-like behavior in adulthood. The mechanisms underlying these behavioral effects may involve changes in the levels of synaptic proteins in hippocampus: HFD consumption appears to affect synaptic markers, while social isolation affected BDNF signaling more significantly.     

Stress downregulates hippocampal expression of the adhesion molecules NCAM and CHL1 in mice by mechanisms independent of DNA methylation of their promoters

Stress is an important physiological regulator of brain function in young and adult mammals. The mechanisms underlying regulation of the consequences of stress, and in particular severe chronic stress, are thus important to investigate. These consequences most likely involve changes in synaptic function of brain areas being part of neural networks that regulate responses to stress. Cell adhesion molecules have been shown to regulate synaptic function in the adult and we were thus interested to investigate a regulatory mechanism that could influence expression of three adhesion molecules of the immunoglobulin superfamily (NCAM, L1 and CHL1) after exposure of early postnatal and adult mice to repeated stress. We hypothesized that reduction of adhesion molecule expression after chronic stress, as observed previously in vivo, could be due to gene silencing of the three molecules by DNA methylation. Although adhesion molecule expression was reduced after exposure of C57BL/6 mice to stress, thus validating our stress paradigm as imposing changes in adhesion molecule expression, we did not observe differences in methylation of CpG islands in the promoter regions of NCAM, L1 and CHL1, nor in the promoter region of the glucocorticoid receptor in the hippocampus, the expression of which at the protein level was also reduced after stress. We must therefore infer that severe stress in mice of the C57BL/6 strain downregulates adhesion molecule levels by mechanisms that do not relate to DNA methylation.     

The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis

The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell division, migration, growth, and differentiation. Although there are several examples of MT‐stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of MT‐destabilizing proteins. Stathmin is such a MT‐destabilizing protein largely restricted to the CNS, and in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone of the mouse hippocampus. After carefully mapping stathmin expression in the adult dentate gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki‐67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA‐NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore, our data suggest that migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early postmitotic neurons. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 1226–1242, 2014     

Early Maternal Alcohol Consumption Alters Hippocampal DNA Methylation,Gene Expression and Volume in a Mouse Model

The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.     

Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes

Nutrition during early mammalian development permanently influences health of the adult, including increasing the risk of type 2 diabetes and coronary heart disease. However, the molecular mechanisms underlying such programming are poorly defined. Here we demonstrate that programmed changes in miRNA expression link early-life nutrition to long-term health. Specifically, we show that miR-483-3p is upregulated in adipose tissue from low-birth-weight adult humans and prediabetic adult rats exposed to suboptimal nutrition in early life. We demonstrate that manipulation of miR-483-3p levels in vitro substantially modulates the capacity of adipocytes to differentiate and store lipids. We show that some of these effects are mediated by translational repression of growth/differentiation factor-3, a target of miR-483-3p. We propose that increased miR-483-3p expression in vivo, programmed by early-life nutrition, limits storage of lipids in adipose tissue, causing lipotoxicity and insulin resistance and thus increasing susceptibility to metabolic disease.     

Effect of prenatal hypoxia on heat stress-mediated cardioprotection in adult rat heart

Fetal programming has profound effects on cardiovascular function in later adult life. We tested the hypothesis that chronic hypoxic exposure during fetal development downregulates endogenous cardioprotective mechanisms in adult rats. Time-dated pregnant rats were divided between normoxic and hypoxic (10.5% O2 from days 15 to 21 of gestation) groups. The male progeny were studied at 2 mo of age. Rats were subjected to heat stress (42 degrees C for 15 min). After 24 h, hearts were excised and subjected to 30 min of global ischemia and 1 h of reperfusion. Prenatal hypoxia did not change adult rat body weight and heart weight, but significantly increased the cross-sectional area of a left ventricular (LV) myocyte. Heat stress significantly improved postischemic recovery of LV function in normoxic control rats, but not in prenatally hypoxic rats. The infarct size in the LV resulting from ischemia-reperfusion was reduced by the heat stress pretreatment in control rats, but not in prenatally hypoxic rats. In accordance, heat stress significantly increased LV myocardial content of heat shock protein 70 only in normoxic control rats. In addition, there was a significant decrease in the LV myocardial content of the PKC-epsilon isoform in prenatally hypoxic rats compared with control rats. We conclude that prenatal hypoxia causes in utero programming of hsp70 gene in the LV, leading to an inhibition of its response to heat stress and a loss of cardioprotection in later adult life.     

Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus

Exposure to stressful life events during pregnancy exerts profound effects on neurodevelopment and increases the risk for several neurodevelopmental disorders including major depression. The mechanisms underlying the consequences of gestational stress are complex and remain to be elucidated. This study investigated the effects of gestational stress on depressive-like behavior and epigenetic modifications in young adult offspring. Gestational stress was induced by a combination of restraint and 24-hour light disturbance to pregnant dams throughout gestation. Depressive-like and anxiety-like behaviors of young adult offspring were examined. The expression and promoter methylation of brain derived neurotrophic factor (BDNF) were measured using RT-qPCR, Western blot, methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation (ChIP). In addition, the expressions of histone deacetylases (HDACs) and acetylated histone H3 lysine 14 (AcH3K14) were also analyzed. Our results show that offspring from gestational stress dams exhibited depressive-like and anxiety-like behaviors. Biochemically, stress-offspring showed decreased expression of BDNF, increased expression of DNMT1, HDAC1, and HDAC2, and decreased expression of AcH3K14 in the hippocampus as compared to non-stress offspring. Data from MeDIP and ChIP assays revealed an increased methylation as well as decreased binding of AcH3K14 on specific BDNF promoters. Pearson analyses indicated that epigenetic changes induced by gestational stress were correlated with depressive-like and anxiety-like behaviors. These data suggest that gestational stress may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with depression.     

Genipin normalizes depression-like behavior induced by prenatal stress through inhibiting DNMT1

Synthetic antidepressants in current use for the complex etiopathogeneses of depression have slow response and remission as well as various unpleasant side effects. As a result, it is imperative to develop new antidepressants with more effectiveness and less severe side effects. Recent studies demonstrated that genipin, the aglycon of geniposide, extracted from Gardenia jasminoides Ellis has antidepressive effects. However, knowledge regarding the molecular mechanisms of its antidepressant effects remains limited. Employing a depression-like mouse model, we confirmed that genipin is capable of correcting depressions-like behaviors induced by prenatal stress in offspring from prenatally stressed dams (defined as PRS mice). In further experiments, we found that the effect of genipin on PRS mice occurs through DNA demethylation by inhibiting DNA methyltransferase 1 (DNMT1), normalizing the expression of reduced brain-derived neurotrophic factor (BDNF) in the hippocampus.     

La dépression et le traitement antidépresseur: de la neurotoxicité à la neurogenèse

Major depressive disorder is characterized by structural and neurochemical changes in limbic structures, including the hippocampus that regulates mood and cognitive functions. Hippocampal atrophy is observed in patients with depression: structural changes in the hippocampus associated with depression include dendritic atrophy, decreased adult neurogenesis and reduced volume. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, episodic verbal memory and emotions are altered in depression. Chronic stress exposure and depression leads to hippocampal atrophy and cell loss as well as to decreased expression of neurotrophic growth factors. All types of antidepressant drugs reverse or block the effects of stress. Chronic antidepressant administration upregulates neurogenesis and neuroplasticity in the adult hippocampus and these cellular responses are required for the effects of antidepressants in animal models of depression.     

Wogonin preventive impact on hippocampal neurodegeneration,inflammation and cognitive defects in temporal lobe epilepsy

Previous studies demonstrated that the pathophysiological changes after temporal lobe epilepsy (TLE) such as oxidative stress, inflammatory reaction contribute to cognitive defect and neuronal damage. The present study was conducted to evaluate the anticonvulsant effect of wogonin ameliorates kainate-induced TLE, and to investigate the mechanism underlying these effects. Rats were divided into control, wogonin, kainate, and wogonin-pretreated kainate groups. The rat model of TLE was induced by unilateral intrahippocampal injection of 0.4 ug/ul of kainate. The results showed that the cognitive function in TLE rats was significantly impaired, and wogonin treatment improved cognitive function in the Morris water maze (MWM). H & E staining and TUNEL staining showed obvious damage in the hippocampus of TLE rats, and wogonin alleviated the damage. To evaluate the oxidative stress, the expression of MDA and GSH in plasma were detected. Nrf-2 and HO-1 mRNA expression in the hippocampus were detected. The levels of MDA in plasma increased in TLE rats, and the levels of GSH in plasma and Nrf-2, HO-1 in the brain decreased. Treatment with wogonin alleviated these changes. We also detected the mRNA expression of inflammatory mediators like IL-1β, TNF-α, and NF kB in the brain. The inflammatory reaction was significantly activated in the brain of TLE rats, and wogonin alleviated neuroinflammation. We detected the mRNA expression of Bcl-2, Bax, caspase-3, in the hippocampus. The levels of Bcl-2 decreased in TLE rats, Bax and caspase-3 increased, while wogonin alleviated these changes. The present study indicated that wogonin exerted a noticeable neuroprotective effect in kainate-induced TLE rats.     

Pheasant sexual ornaments reflect nutritional conditions during early growth.

Differences in growth conditions during early life have been suggested to cause long-lasting effects on morphology and quality of adult birds. We experimentally investigated the effect of early growth conditions on the expression of sexual ornaments later in life in male ring-necked pheasants (Phasianus colchicus). We also investigated the effects on immune function, as it could be a functional link between early nutrition and ornament expression. We manipulated the dietary protein intake during the first eight weeks post hatching. Males receiving fodder with 27% protein during the first three weeks of life grew larger and more colourful wattles when sexually mature than males receiving a low-protein diet (20.5% protein). Spur length was unaffected by diet treatment. Manipulation of food protein levels during weeks 4-8 after hatching had no effect on the development of ornaments. The different protein treatments had no long-term effect on either humoral or cell-mediated immune responses. There was, however, a positive relationship between spur length and cell-mediated immune responsiveness. Our study shows that expression of a sexual ornament in adult pheasants reflects nutritional conditions early in life. Because the expression of secondary sexual ornaments is affected by conditions during early growth, by selecting more ornamented males, females would choose mates that are superior at handling early nutritional stress. If the susceptibility to early nutritional stress also has a hereditary basis, females may benefit by obtaining 'good genes'.     

Prenatal Stress Inhibits Hippocampal Neurogenesis but Spares Olfactory Bulb Neurogenesis

The dentate gyrus (DG) and the olfactory bulb (OB) are two regions of the adult brain in which new neurons are integrated daily in the existing networks. It is clearly established that these newborn neurons are implicated in specific functions sustained by these regions and that different factors can influence neurogenesis in both structures. Among these, life events, particularly occurring during early life, were shown to profoundly affect adult hippocampal neurogenesis and its associated functions like spatial learning, but data regarding their impact on adult bulbar neurogenesis are lacking. We hypothesized that prenatal stress could interfere with the development of the olfactory system, which takes place during the prenatal period, leading to alterations in adult bulbar neurogenesis and in olfactory capacities. To test this hypothesis we exposed pregnant C57Bl/6J mice to gestational restraint stress and evaluated behavioral and anatomic consequences in adult male offspring.We report that prenatal stress has no impact on adult bulbar neurogenesis, and does not alter olfactory functions in adult male mice. However, it decreases cell proliferation and neurogenesis in the DG of the hippocampus, thus confirming previous reports on rats. Altogether our data support a selective and cross-species long-term impact of prenatal stress on neurogenesis.     

Induction of Hsp27 and Hsp32 Stress Proteins and Vimentin in Glial Cells of the Rat Hippocampus Following Hyperthermia

In response to stressful stimuli, cells respond by inducing a set of heat shock (stress) proteins (hsps) that play important roles in repair and protective mechanisms. The present study investigates the expression patterns of Hsp27 and Hsp32 in the adult rat hippocampus following whole body hyperthermia. A pronounced induction of these low-molecular-weight stress proteins was apparent in populations of glial cells such as astrocytes and microglia that were identified Using cell-specific markers (GFAP for astrocytes and the lectin GSA I-B4 for microglia). Hyperthermia also resulted in a robust induction of the intermediate filament protein, vimentin, in glial cells in the adult rat hippocampus. Interestingly, a rapid induction of both Hsp27 and vimentin was observed in the microvasculature, suggesting that hyperthermic stress may compromise the blood-brain barrier.     

Effects of an Early Experience of Reward through Maternal Contact or its Denial on Laterality of Protein Expression in the Developing Rat Hippocampus

Laterality is a basic characteristic of the brain which is detectable early in life. Although early experiences affect laterality of the mature brain, there are no reports on their immediate neurochemical effects during neonatal life, which could provide evidence as to the mechanisms leading to the lateralized brain. In order to address this issue, we determined the differential protein expression profile of the left and right hippocampus of 13-day-old rat control (CTR) pups, as well as following exposure to an early experience involving either receipt (RER) or denial (DER) of the expected reward of maternal contact. Proteomic analysis was performed by 2-dimensional polyacrylamide gel electrophoresis (PAGE) followed by mass spectroscopy. The majority of proteins found to be differentially expressed either between the three experimental groups (DER, RER, CTR) or between the left and right hemisphere were cytoskeletal (34%), enzymes of energy metabolism (32%), and heat shock proteins (17%). In all three groups more proteins were up-regulated in the left compared to the right hippocampus. Tubulins were found to be most often up-regulated, always in the left hippocampus. The differential expression of β-tubulin, β-actin, dihydropyrimidinase like protein 1, glial fibrillary acidic protein (GFAP) and Heat Shock protein 70 revealed by the proteomic analysis was in general confirmed by Western blots. Exposure to the early experience affected brain asymmetry: In the RER pups the ratio of proteins up-regulated in the left hippocampus to those in the right was 1.8, while the respective ratio was 3.6 in the CTR and 3.4 in the DER. Our results could contribute to the elucidation of the cellular mechanisms mediating the effects of early experiences on the vulnerability for psychopathology, since proteins shown in our study to be differentially expressed (e.g. tubulins, dihydropyrimidinase like proteins, 14-3-3 protein, GFAP, ATP synthase, α-internexin) have also been identified in proteomic analyses of post-mortem brains from psychiatric patients.     

Life-Long Effects of Perinatal Asphyxia on Stress-Induced Proteins and Dynamin 1 in Rat Brain

In previous work, we have shown that perinatal asphyxia (PA) in the rat leads to life-long neurotransmitter deficits and impairment of cognitive functions and behavior. This observation made us examine protein expression in hippocampus of rats with PA at the end of the life span. We applied a well-documented and characterized animal model of PA. Pups, normoxic and asphyxiated for 20 min, were brought up until the age of 24 months and then were sacrificed. Hippocampal tissue was dissected from the brains, and proteins were run on two-dimensional gel electrophoresis with in-gel digestion and subsequent identification of proteins by MALDI-TOF followed by quantification of protein spots by specific software. In hippocampus of rats with PA, the stress proteins protein disulfide isomerase A3 precursor and stress-induced phosphoprotein-1 were significantly increased, whereas the microtubule-associated protein dynamin-1 was significantly reduced. Increased stress protein levels may represent long-term effects of PA or, alternatively, could reflect conditioning of the stress protein machinery known to occur as a neuroprotective principle following hypoxic-ischemic conditions. Decreased dynamin-1 levels may be considered as a long-term effect on the exocytotic system possibly reflecting or leading to impaired neuronal transport and vesicle-trafficking in PA of the rat of advanced age.     

BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (trkB) influence neuronal survival, differentiation, synaptogenesis, and maintenance. Using in situ hybridization we examined the spatial and temporal expression of mRNAs encoding these proteins during diverse stages of life in the human hippocampus and inferior temporal cortex. We examined six postnatal time points: neonatal (1-3 months), infant (4-12 months), adolescent (14-18 years), young adult (20-24 years), adult (34-43 years), and aged (68-86 years). Within the hippocampus, levels of BDNF mRNA did not change significantly with age. However, levels of both the full-length form of trkB (trkB TK+) mRNA and the truncated form of trkB (trkB TK-) decreased over the life span (p < 0.05). In the temporal cortex, BDNF and trkB TK+ mRNA levels were highest in neonates and decreased with age (r = -0.4 and r = -0.7, respectively, both p < 0.05). In contrast, TrkB TK- mRNA levels remained constant across the life span in the temporal cortex. The peak in both BDNF and trkB TK+ mRNA expression in the neonate temporal cortex differs from that previously described for the frontal cortex where both mRNAs peak in expression during young adulthood. The increase in BDNF and trkB TK+ mRNA in the temporal cortex of the neonate suggests that neurotrophin signaling is important in the early development of the temporal cortex. In addition, since BDNF and both forms of its high affinity receptor are expressed throughout the development, maturation, and aging of the human hippocampus and surrounding neocortex they are likely to play roles not only in early growth but also in maintenance of neurons throughout life.     

Programming of the adult psychoneuroendocrine qualities by gene expression early-life

Ontogeny of the mechanisms of physiological functions and behavior are adjusted --"programmed" during early development to match predicted conditions of future life environment. The discrepancies between anticipated and actual environmental conditions provoke endocrine, cardiovascular, metabolic and psychiatric pathologies. Alterations in gene expression and of subsequent regulation of the gene activities, as well as morphogenetic abnormalities due to changes in cell migration and apoptosis could be the mechanisms of this phenomenon. Inhibition of a targeted-gene expression by short interfering RNA in the developing mammalian brain in vivo have revealed programming of the adult animal psychophysiological qualities by the neurogene during critical period of the brain development. Mechanism of early-life programming evidently has adaptive evolutionary-genetic basis and is capable of transmitting effects of adverse treatments endued by ancestors to subsequent generations.