Chronic stress during the peripartum period: Implications for mother and offspring

Neuroendocrine, neuronal and behavioural peripartum adaptations are essential for the female`s successful adaptive response when becoming maternal. Despite these adjustive mechanisms, the period around birth represents a time with high risk for women to develop mood and anxiety disorders that include a severe confinement of mother-infant interactions. Unfortunately, the aetiology of postpartum mood and anxiety disorders is largely unknown. However, chronic stress during the peripartum period is one major risk factor of such mental illnesses. Therefore, my thesis centered on the premise that by assessing the consequences of peripartum stress, I can provide insight into the mechanisms underlying postpartum mood and anxiety disorders. In order to demonstrate the specificity of such effects to the peripartum period it is necessary to include controls such as males and, particularly, virgin females. In this thesis, I demonstrated that chronic stress during either pregnancy or lactation prevented a number of the above mentioned peripartum adaptations. Thus, I could show that chronic stress during pregnancy induces an increase in active maternal care with a concurrent increase in anxiety-related behaviour. Although, chronic stress and increased levels of anxiety are often associated with an increase in depression-like behaviour, I did not observe an effect of chronic stress in this direction. However, using the antidepressant imipramine, I revealed that chronic stress prevented the lactation-associated decrease in the noradrenergic system activity, which in general underlies the observed passive stress-coping behaviour in the FST. Furthermore, I could show that chronic pregnancy stress prevented the lactation-associated basal hypercorticism and the elevation in the OXT system within the PVN. Illustrating the specificity of the stress-induced changes to the peripartum period, most of the parameters were not affected in stressed virgin females. Given the fact that several postpartum psychiatric disorders have been linked to changes in basal ACTH and cortisol levels in humans, the results of the present thesis provide further important evidence that HPA axis dysregulation may be one major mechanism involved in the development of postpartum mood and anxiety disorders. Naturally, males and females differ in their sensitivity to stress and their stress responsiveness to several stressors. Using chronic restraint as the stress paradigm and adult hippocampal neurogenesis as the readout parameter, I could demonstrate that sex differences do not only occur in the basal HPA axis activity and pattern of hippocampal neurogenesis, but moreover that cell proliferation, cell survival, cell differentiation and stem cell quiescence are differentially affected by chronic stress in male and female rats. These results are of importance for various reasons. First, there is a correlation between chronic stress, neurogenesis and depression and second, females have twice a higher risk to develop depressive disorders compared to males. Thus, the results provide evidence that sex differences in hippocampal neurogenesis may underlie the increased depression-susceptibility in females. Taking these findings, I next assessed the effect of this RS paradigm on the altered neurogenesis that occurs in the peripartum period. Here, I revealed that chronic stress during lactation prevents lactation-associated changes in cell proliferation and survival, but moreover, I showed for the first time that differentiation patterns and stem cell quiescence are altered after chronic lactation stress. The lactation period is a time when the bigger part of metabolic resources is needed to insure healthy survival of the offspring. Therefore, reducing growth processes like neurogenesis and simultaneously increasing efficiency might be an important adaptive mechanism of the lactation period. Beside the effects of chronic stress on the mother, I provided a wide-ranging of basic knowledge about the effect of early life stress on the adult emotional and social behaviour in the offspring. Importantly, I demonstrated that not only the timing of the stressor plays a pivotal role, but moreover that postnatal maternal-infant interaction in the form of maternal care is seminal for the adult behavioural outcome of the offspring. While prenatal stress induced an anxiety-related and depression-like phenotype in adulthood, postnatal stress rather led to deficits in social behaviour. Although an increase in active maternal care was effective to restore the effect of postnatal stress on social behaviour, it did not restore prenatal induced stress effects. Thus, it seems that regulatory mechanisms that are fundamental for adult affective behaviour undergo a critical stage of development during the prenatal stage and a disruption of these processes might not be rescued by increased amounts of maternal care. However, a high quantity of maternal care might be able to restore deficits in social behaviour when occurring simultaneously with postnatal stress exposure. The neurobiological mechanisms underlying the observed time-dependent differences in behaviour have not been subject of investigation in this thesis. However, future studies will concentrate to identify mechanism that are involved in the regulation of adult affective and social behaviours that might also underlie psychopathologies like anxiety disorders, autism, attention deficit hyperactivity disorders and schizophrenia, which have all been associated with early life stress exposure

From Stress to Postpartum Mood and Anxiety Disorders: How Chronic Peripartum Stress Can Impair Maternal Adaptations

The peripartum period, in all mammalian species, is characterised by numerous adaptations at neuroendocrine, molecular and behavioural levels that prepare the female for the challenges of motherhood. These changes have been well characterised and, while they are necessary to ensure the survival and nurturance of the offspring, there is growing belief that they are also required for maternal mental health. Thus, while increased calmness and attenuated stress responsivity are common characteristics of the peripartum period, it also represents a time of increased susceptibility to mood disorders. While a number of risk factors for these disorders are known, their underlying aetiology remains poorly understood, due at least in part to a lack of appropriate animal models. One translatable risk factor is stress exposure during the peripartum period. In the following review we first describe common peripartum adaptations and the impact postpartum mood disorders have on these. We then discuss the known consequences of peripartum stress exposure on such maternal adaptations that have been described in basic research

Differential Contribution of Hypothalamic MAPK Activity to Anxiety-Like Behaviour in Virgin and Lactating Rats

The c-Raf – MEK1/2 – ERK1/2 mitogen-activated protein kinase (MAPK) intracellular signalling cascade in neurons plays important roles in the control of a variety of behaviours, including social behaviours and anxiety. These roles partially overlap with those described for oxytocin (OXT), and it has been shown that OXT activates the MAPK pathway in the hypothalamus (of male), and hippocampus (of female) rats. Here, by combining behavioural (light/dark box) and biochemical analyses (western blotting), we tested two hypotheses: (i) that OXT is anxiolytic within the hypothalamus of females, and (ii) that this effect, as well as that of lactation-associated anxiolysis, depends on the recruitment of the MAPK pathway. We found that, when injected bilaterally into the hypothalamic paraventricular nucleus (PVN), OXT decreased anxiety-like behaviour in virgins, and that this effect depended on phosphorylation of MEK1/2. MAPK pathway activation in lactation was evident by high phosphorylated (p) MEK1/2 levels, and nuclear translocation of ERK1. The high pMEK1/2 levels were necessary for the anxiolytic phenotype typically observed during lactation. Interestingly, exogenous OXT in lactating rats reduced pMEK1/2 levels without a concomitant effect on anxiety, indicating that OXT receptor activation can lead to recruitment of additional intracellular pathways to modulate MEK activity. Still other pathways could include MEK, but without subsequent activation of ERK, as we did not observe any increase in OXT-induced ERK phosphorylation. Together the results demonstrate that the MAPK pathway, especially MEK1/2, is critically involved in the regulation of anxiety-like behaviour in female rats

Differences in navigation performance and postpartal striatal volume associated with pregnancy in humans.

Pregnancy is accompanied by prolonged exposure to high estrogen levels. Animal studies have shown that estrogen influences navigation strategies and, hence, affects navigation performance. High estrogen levels are related to increased use of hippocampal-based allocentric strategies and decreased use of striatal-based egocentric strategies. In humans, associations between hormonal shifts and navigation strategies are less well studied. This study compared 30 peripartal women (mean age 28 years) to an age-matched control group on allocentric versus egocentric navigation performance (measured in the last month of pregnancy) and gray matter volume (measured within two months after delivery). None of the women had a previous pregnancy before study participation. Relative to controls, pregnant women performed less well in the egocentric condition of the navigation task, but not the allocentric condition. A whole-brain group comparison revealed smaller left striatal volume (putamen) in the peripartal women. Across the two groups, left striatal volume was associated with superior egocentric over allocentric performance. Limited by the cross-sectional study design, the findings are a first indication that human pregnancy might be accompanied by structural brain changes in navigation-related neural systems and concomitant changes in navigation strategy

H Magnetic Resonance Spectroscopy of the Lentiform Nucleus in Idiopathic Focal Hand Dystonia

Die Pathogenese der idiopathischen Handdystonie ist bis heute nicht abschließend geklärt. Verschiedene Befunde sprechen für eine Läsion der Basalganglien, insbesondere des Linsenkerns. Insbesondere bildgebende Verfahren wie MRT, Sonographie, PET oder SPECT, und Untersuchungen bei sekundären Dystonieformen weisen in diese Richtung. Trotz vielfacher Anstrengungen, den zugrunde liegenden Pathomechanismus aufzudecken, ist es bis heute noch nicht gelungen, ein einheitliches anatomisches oder biochemisches Korrelat für die Störung verantwortlich zu machen: So bieten einige pathoanatomische Studien Hinweise auf Zellverlust und Gliose im Striatum, andere zeigten Veränderungen in der Konzentration verschiedener Neurotransmitter. Jüngere Untersuchungen lassen einen gestörten Komplex I der mitochondrialen Atmungskette vermuten. Da die Ätiologie der Dystonien bisher letztlich nicht geklärt ist, bietet die Protonenspektroskopie die Möglichkeit, Stoffwechselveränderungen sowie Änderungen der Gewebszusammensetzung und der Konzentrationen darin enthaltener Stoffe zu untersuchen und so Hypothesen zur Genese der idiopathischen Dystonie herauszuarbeiten. Wir untersuchten 14 Patienten mit idiopathischem Schreibkrampf und 11 gesunde, altersentsprechende Probanden, die nachweislich an keiner zentral-neurologischen Erkrankung litten. Zur Messung wurde eine Standard-Kopfspule ( 1,5 T Ganzkörper MR-Tomograph, Siemens Magnetom Vision, Erlangen) verwendet. Die Spektrenerhebung erfolgte mit Hilfe einer PRESS-Sequenz (TR= 1365 ms, TE= 135 ms), das Voxel war auf das Gebiet des Linsenkerns zentriert. Die anhand der Spektren ermittelten Metabolitenverhältnisse von NAA:Cho, NAA:Crea, Cho:Crea und Lac:Crea ergaben keine statistisch signifikante Seitendifferenz innerhalb der Patientengruppe, auch ein Vergleich zwischen Patienten- und Kontrollgruppe blieb ohne statistische Differenz (p>0,05). Somit konnten durch die Protonenspektroskopie keine Veränderungen der Metabolitenkonzentrationen bei der idiopathischen Handdystonie festgestellt werden. Es ergibt sich damit kein Hinweis darauf, daß idiopathischen Dystonien ein meßbarer Verlust von Neuronen, eine damit einhergehende sekundäre Gliose oder eine meßbare Störung des Energiehaushalts, sei es durch erhöhte Umsatzraten oder eine fehlerhafte oxidative Phosphorylierung, zugrunde liegt. Eine mögliche Erklärung dieser unauffälligen Befunde bei Dystoniepatienten könnte die Annahme einer Störung des Stoffwechsels in nur wenigen Neuronen bieten, was sich der Sensitivität der Methode entziehen kann. Denkbar sind auch Konzentrationsänderungen von Neurotransmittern, Einlagerungen von Schwermetallen (z.B.Kupfer), Veränderungen der oxidativen Phosphorylierung oder Änderungen der Rezeptordichte. Generalisierte Dystonien müßten eine eventuell vorhandene Pathologie am deutlichsten aufweisen und wären deshalb ebenfalls ein interessantes Krankheitsbild. Die spektroskopische Untersuchung gestaltet sich aber wegen des bei dieser Form zu erwartenden erhöhten Auftretens von Bewegungsartefakten schwierig. Auch das Verwenden veränderter Meßparameter (TE, TR) oder einer höheren Tesla-Zahl bei einem größeren Patientenkollektiv wäre zur weiteren Abklärung anzustreben. Insbesondere sollten Schreibkrampf-Patienten mit Hilfe der funktionellen MR-Spektroskopie während des Auftretens dystoner Verkrampfungen oder auch während der Durchführung willkürlicher Fingerbewegungen untersucht werden. Bisher latente Veränderungen könnten sich dann, unter der so erzeugten motorischen Aktivierung, manifestieren.The pathogenesis of primary focal hand dystonia is still unknown. Several radiologic findings and also findings by studies in patients with secondary dystonia point toward the basal ganglia, especially the lentiform nucleus as a possible site of the lesion. There are also abnormalities in histopathologic and biochemical examinations: cell loss and gliosis in the striatum are described as well as an imbalance of neurotransmitters or defects of the complex I of the respiratory chain. But all these results are inconsistent, so the question is open as to whether neurodegeneration occurs in basal ganglia of primary dystonia. H-magnetic resonance spectroscopy (MRS) in vivo is a non-invasive technique for the examination of brain metabolites. It has proved helpful to assess neuronal degeneration and loss or changes in the tissue composition in various basal ganglia disorders, but data of dystonia patients is lacking so far. We have examinated 14 patients with primary focal hand dystonia and 11 healthy control subjects. For the examination a standard quadrature head coil was used (1.5-T MR whole body imager, Siemens AG, Erlangen, Germany). Single volume spectra were obtained using a PRESS sequenz (TR=1365ms, TE=135ms). The voxels (3.375 or 8.0 cm³) were centered on the lentiform nucleus. No statistically significant difference of the measured metabolite ratios of N-acetylaspartate (NAA)/creatine, NAA/choline, choline/creatine or lactate/creatine were found, neither by the intraindividual comparison between the left and right sided lentiform nucleus of the patient group nor by the comparison between patient and control group. So we found no evidence that primary focal dystonia is associated with a conspicuous loss of neurons with secondary gliosis or a marked disturbance of the energy metabolism caused by defects of the respiratory chain or an increased turnover. A possible reason for the normal findings is the limited sensitivity of the method, so minor abnormalities cannot be excluded. For future investigations it will be interesting to examinate patients with generalised dystonia or patients with focal dystonia at the time of a dystonic contraction or active finger movement, because if there are just small changes in the metabolite ratios, it should be recognizable in this cases first. Also changes in the study protocol (p.e. other TE or TR) or examinations with a 3-T imager could bring a benefit

Neurobiological mechanisms underlying sex-related differences in stress-related disorders: effects of neuroactive steroids on the hippocampus

Men and women differ in their vulnerability to a variety of stress-related illnesses, but the underlying neurobiological mechanisms are not well understood. This is likely due to a comparative dearth of neurobiological studies that assess male and female rodents at the same time, while human neuroimaging studies often don’t model sex as a variable of interest. These sex differences are often attributed to the actions of sex hormones, i.e. estrogens, progestogens and androgens. In this review, we summarize the results on sex hormone actions in the hippocampus and seek to bridge the gap between animal models and findings in humans. However, while effects of sex hormones on the hippocampus are largely consistent in animals and humans, methodological differences challenge the comparability of animal and human studies on stress effects. We summarise our current understanding of the neurobiological mechanisms that underlie sex-related differences in behavior and discuss implications for stress-related illnesses

The Maternal Brain: An Organ with Peripartal Plasticity

The time of pregnancy, birth, and lactation, is characterized by numerous specific alterations in several systems of the maternal body. Peripartum-associated changes in physiology and behavior, as well as their underlying molecular mechanisms, have been the focus of research since decades, but are still far from being entirely understood. Also, there is growing evidence that pregnancy and lactation are associated with a variety of alterations in neural plasticity, including adult neurogenesis, functional and structural synaptic plasticity, and dendritic remodeling in different brain regions. All of the mentioned changes are not only believed to be a prerequisite for the proper fetal and neonatal development, but moreover to be crucial for the physiological and mental health of the mother. The underlying mechanisms apparently need to be under tight control, since in cases of dysregulation, a certain percentage of women develop disorders like preeclampsia or postpartum mood and anxiety disorders during the course of pregnancy and lactation. This review describes common peripartum adaptations in physiology and behavior. Moreover, it concentrates on different forms of peripartum-associated plasticity including changes in neurogenesis and their possible underlying molecular mechanisms. Finally, consequences of malfunction in those systems are discussed

Gating of the neuroendocrine stress responses by stressor salience in early lactating female rats is independent of infralimbic cortex activation and plasticity

<p>In early lactation (EL), stressor salience modulates neuroendocrine stress responses, but it is unclear whether this persists throughout lactation and which neural structures are implicated. We hypothesized that this process is specific to EL and that the infralimbic (IL) medial prefrontal cortex (mPFC) might provide a critical link between assessment of threat and activation of the hypothalamo-pituitary-adrenal (HPA) axis in EL. We measured neuroendocrine responses and neuronal Fos induction to a salient (predator odor) or non-salient (tail pinch) psychogenic stressor in EL and late lactation (LL) females. We found that EL females exhibited a large response to predator stress only in the presence of pups, while responses to tail pinch were reduced independently of pup presence. In LL, HPA axis responses were independent of pup presence for both stressors and only responses to tail pinch were modestly reduced compared to virgins. Intracerebral injection of the local anesthetic bupivacaine (BUP) (0.75%; 0.5 µl/side) in the IL mPFC did not differentially affect neuroendocrine responses to predator odor in virgin and EL females, suggesting that lactation-induced changes in this structure might not regulate stressor salience for the HPA axis. However, the IL mPFC displayed morphological changes in lactation, with significant increases in dendritic spine numbers and density in EL compared to LL and virgin females. EL females also showed improved performance in the attention set-shifting task (AST), which could reflect early plasticity in the IL mPFC at a time when rapid adaptation of the maternal brain is necessary for pup survival.</p