Research
Research
Projects
1. Towards a better understanding of maternal mental health: Stress and diet effects on peripartum adaptations (Judith Thomas)
(in collaboration with Prof. Stefan Reber (Unversity of Ulm), Dr Kathi Hillerer and Prof. Ludwig Aigner (both Paracelus University, Salzburg))
Across all mammalian species the peripartum period is characterised by behavioural, neuroendocrine and neuronal adaptations, which prepare a mother for the impending birth and nurturance of the offspring (Brunton and Russell 2008; Slattery and Neumann 2008). While these adaptations are essential to ensure the survival and health of the offspring (Carter et al 2001), we hypothesize that they are also required for maternal mental health (Neumann 2003; Slattery and Neumann 2008). Although anxiolysis, enhanced calmness and attenuated stress-responses of the hypothalamic-pituitary adrenal (HPA) axis are observed in the majority of mothers, a significant percentage display increased vulnerability to mood disorders, such as postpartum anxiety (5-12%; Lonstein 2007), postpartum depression (PPD; 5-25%; Beck 2006) or the much rarer postpartum psychosis (0.1%; Bridges 2008; Jones et al 2008).? Despite the high incidence of these disorders, and detrimental outcome for both mother and child, their aetiology remains poorly understood, due in part to the lack of appropriate animal models.?
It is feasible that alterations to these normal peripartum adaptations (for more details see Slattery and Neumann, 2008 and Figure 1) caused, for example, by exposure to chronic stress in pregnancy or maternal obesity may underlie postpartum mood disorders.
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Figure 1: Adapted from Slattery and Neumann, 2008 (J. Physiol)
Figure 2: Data demonstrating the effectiveness of the chronic psycho-social stress paradigm
A) Schematic representation of the chronic stress procedure to be applied to pregnant and virgin rats. B) The effect of chronic stress on body weight gain during pregnancy. C) The relative adrenal weight in virgins, late pregnant (PD 20) or lactation day 8 non-stressed and stressed females.
Therefore, the first aim of the project is to characterise the effects of a novel chronic psychosocial stress paradigm (Figure 2) during pregnancy and and high-fat diet exposure throughout the peripartum period on established peripartum adaptations. As such, we hypothesize that exposure to chronic stress in pregnancy will, at least partly, prevent behavioural, neurogenesis, neuroendocrine and/or neuronal adaptations and result in alterations specific to the reproductive status of the female and, therefore, include males/virgins as controls.? We will then determine whether genetic differences in anxiety-related behaviour (see Figure 1 in project 2) can protect (low-anxiety females) or worsen (high-anxiety females) the observed consequences of these manipulations. ?The project is also being extended to reveal the consequences of stress and high-fat diet on adrenal morphology and function.? Finally, we will attempt to reverse the detrimental effects of stress exposure via chronic application of antidepressants or selected neuropeptides.
Overall, the research objectives aim to demonstrate a causal link between pregnancy stress and/or diet and postpartum mood and anxiety disorders and to show that innate anxiety levels and key neuropeptides can protect against such stress exposure.? The results will also provide novel targets that may be involved in the aetiology and treatment of postpartum mood and anxiety disorders.
These studies are supported by the Deutsche Forschungsgemeinschaft (DFG Ne465/16 and DFG SL141/4-1)
2. Assessment of the contribution of the Neuropeptide S (NPS) system in an animal model of high anxiety-related behaviour
(in collaboration with Dr Gregers Wegener: Aarhus University, Prof. Aleksander Mathe; Karolinska Institute, and Prof. Rainer Landgraf; MPI Munich)
Psychiatric disorders are the most common mental illness with anxiety disorders having a lifetime prevalence of 28.8 % {Kessler et al., 2007). While a number of pharmacotherapies are available, the lack of truly novel-acting compounds has lead in recent years to a more endophenotype-based research approach and a focus on the development of non-GABAergic compounds (Cryan and Slattery, 2007; 2010; Hasler et al., 2006). The large number of neuropeptides, characterized by discrete synthesis sites and widespread receptor distribution, represent likely research candidates for novel therapeutic targets {Landgraf and Neumann, 2004; Slattery and Neumann, 2010).
Neuropeptide S (NPS), originally described in mice, is an example of such a neuropeptide {Xu et al., 2004). Central administration of NPS has been shown to elicit potent anxiolytic and arousal effects in rodents (Pape et al., 2010). In addition to these effects on innate anxiety, direct NPS infusion into the endopiriform nucleus (Meis et al., 2008), or the basolateral amygdala (Jungling et al., 2008), has been demonstrated to facilitate extinction from contextual and conditioned fear, respectively. Intriguingly, human studies have revealed that a single nucleotide polymorphism (SNP) in the NPS receptor (Npsr) is associated with increased risk of panic disorder and over-interpretation of fear (Domschke et al., 2010; Donner et al., 2010; Okamura et al, 2007; Raczka et al., 2010). This A to T polymorphism (rs324981) results in an amino acid substitution from Asn to Ile at position 107 and was originally associated with increased susceptibility for asthma (Laitinen et al, 2004). Although animal studies show that acute NPS application is anxiolytic, the human studies suggest that increased NPS potency is detrimental. It has been suggested that this supposed paradox could be due to an increased level of arousal and over-interpretation of stimuli, which is known to increase the possibility of panic disorder (Domschke et al., 2010).
In order to assess such a hypothesis, it has become apparent that it is important to test novel strategies, and examine the underlying neural mechanisms, in appropriate animal models, which attempt to mimic the human situation. These models generally fall into two main categories; chronic stress paradigms and animals bred for extreme behavioral traits (Cryan and Slattery, 2007). The selective breeding of Wistar (NAB) rats for anxiety-related behavior on the elevated-plus maze (EPM) has resulted in breeding lines of high (HAB) and low (LAB) anxiety-related behaviour, confirmed in numerous tests and laboratories (Figure 1; Neumann, 2010). These in-born differences make these HAB and LAB rodents attractive models to assess the underlying aetiology of affective disorders including the involvement of novel neurotransmitter / neuropeptide systems. Indeed, the differences in anxiety behaviour have been related to SNPs in the vasopressin gene (Murgatroyd et al., 2004). However, whether NPS may also contribute to the anxiety phenotypes of these rodents, or differentially alter behaviour acutely is unknown.
Figure 1: Adapted from Neumann et al., in press (Progress in Neuro-Psychopharmacology & Biological Psychiatry)
Therefore, the aim of the project is to determine whether intracerebral administration of NPS results in differential responses in these lines. Further, we intend to determine if receptor or peptide expression differences, or genetic polymorphisms exist between the lines. Taken together, these studies will reveal the contribution of the NPS system in rodents displaying extremes in anxiety-related behaviour and whether NPS can acutely exert its anxiolytic effects in animals with a genetically-determined psychopathology.
3. Behavioural and central consequences of chronic psychosocial stress
(Anna Schmidtner)
(in collaboration with Prof. Stefan Reber (Universitty of Ulm))
Despite substantial research effort in the last decades, the aetiology of stress-based disorders such as major dep