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«DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTEN (DR. RER. NAT.) DER FAKULTÄT FÜR BIOLOGIE UND VORKLINISCHEN MEDIZIN DER ...»

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Chronic stress during the peripartum period:

Implications for mother and offspring

DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES

DER NATURWISSENSCHAFTEN (DR. RER. NAT.)

DER FAKULTÄT FÜR BIOLOGIE UND VORKLINISCHEN MEDIZIN

DER UNIVERSITÄT REGENSBURG

vorgelegt von Katharina Hillerer

aus Passau

im Jahr 2011

Das Promotionsgesuch wurde eingereicht am: 18.11.2011 Die Arbeit wurde angeleitet von Prof. Dr. Inga D. Neumann

Unterschrift:

Prologue “At first I thought what I was feeling was just exhaustion, but with it came an overriding sense of panic that I had never felt before. Rowan kept crying, and I began to dread the moment when Chris would bring her back to me. I started to experience a sick sensation in my stomach; it was if a vise were tightening around my chest. Instead of the nervous anxiety that often accompanied panic, a feeling of devastation overcame me. I hardly moved. Sitting on my bed, I let out a deep, slow, guttural wail. It wasn`t simply emotional or weepy, like I had been told I might be. This was something quite different. This was sadness of a shocking different magnitude. It felt as if it would never go away.” Brook Shields “Down Came the Rain” What the American actress Brooke Shields describes here in her book “Down Came the Rain”, is what about 10-22% of mothers experience after the birth of their child- postpartum depression.

Although, the peripartum period is a time of reduced stress responsivity and increased calmness, for a large percentage of mothers it can represent a time of increased susceptibility to mood disorders. Although, the underlying aetiology of peripartumassociated mood and anxiety disorders is poorly understood, stress exposure during the peripartum period has been shown to be one important risk factor for their development.

Interestingly, both stress and lactation have been associated with alterations in neurogenesis, and this in turn has been shown to be implicated in mood and anxiety disorders.

Therefore, the major aim of my thesis was to assess the effect of chronic peripartum stress on common neuroendocrine and behavioural adaptations and on adult hippocampal neurogenesis. Furthermore, I was interested to determine the effects of early life stress on the behavioural outcome of the offspring in adulthood in dependence on the effects stress exposure had on the mother.

Content Chapter 1

General Introduction Chapter 2

Exposure to chronic pregnancy stress reverses peripartum-associated adaptations:

implications for postpartum mood and anxiety disorders42 Chapter 3

Hippocampal neurogenesis is differentially regulated under basal and chronic stress conditions in male and female rats Chapter 4

Reversal of lactation-induced reduction in hippocampal neurogenesis by chronic stress Chapter 5

Prenatal versus postnatal stress: Differential effects on adult affective- and socialbehaviour Chapter 6

General Discussion Summary in German

References

Abbreviations

Acknowledgements

CV and publications

List of Figures and Tables Chapter 1: General Introduction

Table 1: Examples of neuroendocrine and behavioural alterations observed in pregnancy and lactation assessed in rodent and human studies

Figure 1: Schematic representation of the different stages of adult hippocampal neurogenesis

Table 2: Overview of how chronic stress affects hippocampal neurogenesis in male and female rats

Chapter 2: Exposure to chronic pregnancy stress reverses peripartum-associated adaptations: implications for postpartum mood and anxiety disorders

Figure 2: Schematic representation of the chronic pregnancy stress paradigm.................. 48 Figure 3: Chronic stress effects on physiological parameters

Figure 4: Chronic stress effect on plasma ACTH and CORT levels

Figure 5: Chronic stress effects on hypothalamic AVP, CRH and OXT mRNA expression..... 59 Figure 6: Chronic stress effects on maternal care, anxiety-related and depression-like behaviour

Chapter 3: Hippocampal neurogenesis is differentially regulated under basal and chronic stress conditions in male and female rats

Figure 7: Schematic representation of the temporal designs used in the present studies... 83 Figure 8: Effect of sex and chronic stress on cell proliferation and stem cell quiescence in the DG

Figure 9: Effect of sex and chronic stress on immature neuron production and survival of cells

Figure 10: Effect of sex and chronic stress on differentiation patterns

Figure 11: Effect of sex and chronic stress exposure on basal CORT levels

Figure 12: Effect of sex and chronic stress on spatial working memory in the Y-maze....... 90 Chapter 4: Reversal of lactation-induced reduction in hippocampal neurogenesis by chronic stress

Figure 13: Schematic representation of the temporal designs used in the studies............ 109 Figure 14: Effect of reproductive status and chronic stress on cell proliferation and stem cell quiescence

Figure 15: Effect of reproductive status and chronic stress on immature neuron production and survival of cells





Figure 16: Effect of reproductive status and chronic stress on differentiation patterns.... 114 Figure 17: Effect of chronic stress on plasma CORT levels

Chapter 5: Prenatal versus postnatal stress: Differential effects on adult affective- and social-behaviour

Figure 18: Effect of stress and pup separation on maternal behaviour

Figure 19: Effect of early life stress on body weight gain

Figure 20: Effect of early life stress on social preference

Figure 21: Effect of early life stress on anxiety-related behaviour

Figure 22: Effect of early life stress on depression-like behaviour

Chapter 1

General IntroductionContent

1. Peripartum-related adaptations and psychiatric disorders

1.1 Neuroendocrine and molecular adaptations in the peripartum period

1.2 Behavioural adaptations during the peripartum period

1.3 Postpartum mood and anxiety disorders

2. Consequences of chronic stress on peripartum-related adaptations

2.1 Stress-effects on neuroendocrine adaptations

2.2 Stress-effects on maternal behaviour

2.3 Stress-effects on maternal anxiety

2.4 Stress-effects on maternal depression-like behaviour

2.5 Stress-effects on the maternal OXT system

3. Adult hippocampal neurogenesis under physiological conditions

3.1 Cell types and specific markers of hippocampal neurogenesis

3.2 Functional importance of hippocampal neurogenesis

3.3 Sex differences in hippocampal neurogenesis

3.4 Neurogenesis during the peripartum period

4. Consequences of chronic stress on adult hippocampal neurogenesis

5. Consequence of early life stress on physiological and behavioural outcomes in adulthood

6. Aim of the present thesis

–  –  –

1. Peripartum-related adaptations and psychiatric disorders Throughout all mammalian species the peripartum period represents a time when a host of changes occur in order to prepare the female for the challenges of motherhood (Walker et al., 1995; Neumann, 2001; Russell et al., 2001). Beside the onset of lactogenesis, milk ejection and maternal behaviours, such as maternal care and aggression, there are numerous other alterations at physiological, cellular and molecular levels that act in concert to ensure the healthy survival and nurturance of the offspring (Brunton et al., 2008; Slattery and Neumann, 2008) (see also summary of findings in Table 1). Moreover, there is growing evidence that these changes are required for maternal mental health (Slattery and Neumann, 2008). Thus, the peripartum period represents a time of high risk for women to develop mood and anxiety disorders (Robertson et al., 2004; Beck, 2006; Lonstein, 2007;

Bridges, 2008). Here, I describe common peripartum-related adaptations followed by the four most common postpartum psychiatric disorders.

1.1 Neuroendocrine and molecular adaptations in the peripartum period Towards the end of pregnancy, and into lactation, the response of the hypothalamicpituitary-adrenal (HPA) axis to a variety of stressors is severely attenuated in mothers (Altemus et al., 1995; Heinrichs et al., 2001). In spite of this, circulating basal glucocorticoid levels are elevated in lactating dams compared with the respective levels in nulliparous females / virgins (Kammerer et al., 2002). Such basal hypercortisolism and concomitant

–  –  –

in numerous other species including rats, mice and sheep (Stern et al., 1973; Barlow et al., 1975; Keller-Wood, 1995; Neumann et al., 1998b; Johnstone et al., 2000; Neumann et al., 2000a; Lightman et al., 2001). The heightened basal activity of the HPA axis in lactation might be due, at least in part, to an increased expression of the neuropeptide vasopressin (AVP) in parvocellular paraventricular nucleus (PVN) neurons of the hypothalamus (Walker et al., 2001b), accompanied by an enhanced sensitivity of the pituitary to AVP (Toufexis et al., 1999). In turn, animal studies have shown that the reduced peak in HPA axis activity predominantly results from a markedly reduced corticotropin-releasing hormone (CRH) mRNA expression in the PVN (Windle et al., 1997; Shanks et al., 1999; Walker et al., 2001b), as well as reduced CRH binding in the adenohypophysis during pregnancy (Neumann et al., 1998b) and lactation (Toufexis et al., 1999). Taken together, these alterations lead to reduced CRH production and release by PVN neurons, which is also accompanied by a decreased secretory response of the adrenocorticotropic hormone (ACTH) to CRH (Neumann et al., 1998a; Toufexis et al., 1999). Further central changes, which occur to attenuate the HPA axis responsiveness, include an altered pattern of the excitatory inputs to the hypothalamus (Douglas et al., 1998). During the peripartum period, a decreased noradrenergic tone within the PVN and a reversed opiodergic system inhibit the HPA axis activity around birth (Douglas et al., 1998; Toufexis et al., 1998; Wigger et al., 1999;

Kammerer et al., 2002). In parallel with the reduction of these excitatory inputs to the hypothalamus, inhibitory pathways, including those of oxytocin (OXT) and prolactin (PRL), are highly activated. These two neuropeptide systems mediate key roles in reproductive functions, such as the promotion of labour, lactogenesis, milk ejection and maternal behaviour (Pedersen and Prange, 1985; Bridges, 2008; Bosch, 2011), but moreover,

–  –  –

oxytocinergic system within the hypothalamus undergoes fundamental structural and functional reorganization in the peripartum period. This is reflected by altered size and branching patterns of dendritic trees within the PVN and supraoptic nucleus (SON) (Stern and Armstrong, 1998) and increased synaptic and neuronal-glial interaction (Theodosis and Poulain, 1993; Hatton, 1997). Further, OXT mRNA, OXT receptor (OXT-R) expression in the PVN (Zingg et al., 1995; Figueira et al., 2008) and central OXT release (Neumann et al., 1993;

Neumann et al., 2000a; Neumann et al., 2000b) are increased in the peripartum period. The changes in the OXT system are accompanied by an upregulation of the PRL system. PRL receptors (PRL-Rs) in the PVN, SON and the medial preoptic area are increased during the peripartum period (Grattan et al., 2001; Kokay et al., 2006), which plays an important role in the parallel reduction in stress-responsiveness (Torner et al., 2001; Torner et al., 2002).

Given the similarity in the actions of OXT and PRL, it is not surprising that there is substantial evidence for an interaction between these two neuropeptides. Thus, PRL-Rs have been described on OXT (and AVP) magnocellular PVN neurons (Grattan et al., 2001; Kokay et al.,

2006) and PRL administration has been shown to increase OXT release and OXT mRNA in vitro (Ghosh and Sladek, 1995b, a). On the other hand, OXT administration can increase PRL release from the pituitary of oestrogen-primed ovariectomised rats (Samson et al., 1986).



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