Periodic Reporting for period 2 - PregnantBrain (Neural adaptations during pregnancy)
Período documentado: 2021-06-01 hasta 2022-11-30
This project addresses the fundamental question of how the hormonal milieu of pregnancy affects the brain to generate adaptive behavioural changes. It has long been observed that virgin females and mothers behave quite differently: for instance, when presented with infants, virgin female mice typically ignore them, whereas mothers are intensely attracted to infants and will spend most of their waking hours caring for them. It has generally been assumed that the hormonal changes and experiences of giving birth are primarily responsible for this onset of full maternal behaviour, but several observations suggest that these changes might in fact occur earlier, during pregnancy. However, how pregnancy affects the brain to orchestrate changed to behaviours such as parenting, feeding or aggression remains unknown. This project will use state-of-the-art approaches from systems neuroscience to address this question. Our overarching objective is to understand how pregnancy hormones change the form and function of specific neurons and circuits in the brain, esp. those mediating parenting, feeding and aggression, using an approach that can be described as 'Systems Neuroendocrinology', i.e. the use of systems neuroscience approaches to study neuroendocrinological questions Understanding how pregnancy hormones affect the female brain is quite fundamental, since the peripartum period in humans - during which dramatic hormonal fluctuations occur - is associated with a drastically increased risk of postpartum conditions such as depression, anxiety or psychosis. Since the overall mechanisms and hormonal changes are preserved between mice and humans, we hope that our project will eventually lead to translational outcomes.
During the first half of this project, we have made the following progress in several areas:
• Aim 1: Profiling infant-directed behaviours of test animals before, during and after pregnancy, we have identified which behavioural parameters are affected by pregnancy, and when this occurs. Importantly, we have used several control groups to segregate hormonal from experiential factors.
• Aim 2: Via ex vivo MRI imaging from brains of females at different stages of pregnancy and brain-wide mapping of pregnancy hormone receptors, we have identified several brain areas that undergo volumetric remodelling in late pregnancy. In particular, we have found that the medial preoptic area, an area critical for parental behaviour, is a promising target. We now also have a complete dataset of pregnancy hormone expression across the brain.
• Aim 3: We have fully established cellular resolution calcium imaging in behaving mice, and have used this technique to record pregnancy-induced functional changes of MPOA neurons.
• Aim 4: Using in vitro whole-cell recordings from individual neurons in the medial preoptic area across pregnancy, we have shown that genetically specified neurons in this brain region undergo pregnancy-induced physiological and morphological changes. We have also discovered that estrogen- and progesterone receptor expression is necessary for these pregnancy-induced adaptations.
• Aim 4: We have used transgenic mouse lines with conditional deletion alleles of ovarian pregnancy hormone receptors to demonstrate that hormone-sensitivity of specific MPOA neurons is necessary for the pregnancy-induced onset of parental behaviour.
• Aim 1: Profiling infant-directed behaviours of test animals before, during and after pregnancy, we have identified which behavioural parameters are affected by pregnancy, and when this occurs. Importantly, we have used several control groups to segregate hormonal from experiential factors.
• Aim 2: Via ex vivo MRI imaging from brains of females at different stages of pregnancy and brain-wide mapping of pregnancy hormone receptors, we have identified several brain areas that undergo volumetric remodelling in late pregnancy. In particular, we have found that the medial preoptic area, an area critical for parental behaviour, is a promising target. We now also have a complete dataset of pregnancy hormone expression across the brain.
• Aim 3: We have fully established cellular resolution calcium imaging in behaving mice, and have used this technique to record pregnancy-induced functional changes of MPOA neurons.
• Aim 4: Using in vitro whole-cell recordings from individual neurons in the medial preoptic area across pregnancy, we have shown that genetically specified neurons in this brain region undergo pregnancy-induced physiological and morphological changes. We have also discovered that estrogen- and progesterone receptor expression is necessary for these pregnancy-induced adaptations.
• Aim 4: We have used transgenic mouse lines with conditional deletion alleles of ovarian pregnancy hormone receptors to demonstrate that hormone-sensitivity of specific MPOA neurons is necessary for the pregnancy-induced onset of parental behaviour.
At the halfway point of this project, we have been successful in using systems neuroscience approaches to tackle a key question in behavioural neuroendocrinology, namely how pregnancy affects the brain to generate adaptive behavioural changes. Specifically, we have identified - through unbiased, brain-wide mapping of (1) pregnancy-associated brain volume changes and (2) hormone receptor expression - candidate brain areas that are likely remodelled during this period. While these resources will be broadly useful for our future research in this area, as well as for the wider community of researchers in this area, we have already used these data to home in on a specific node in the neural circuits controlling parental behaviour. We have been able to show that neurons in this area are remodelled by pregnancy hormones, and that these neurons being hormone-sensitive is in fact critical for the pregnancy-induced onset of parental behaviour in mice. We are currently preparing this work for publication.
The comprehensive datasets generated in this first phase of the project will now also allow us to address pregnancy-associated functional changes to other circuits, e.g. those mediating feeding and aggression. We are also currently investigating whether, and if yes, how other parts of parenting circuits are affected by pregnancy, and whether hormonal and experience-dependent changes have equivalent effects in these circuits. We expect to submit 2-3 more manuscripts on these topics before the end of this grant's lifetime. Altogether, these investigations will allow us to obtain a comprehensive picture of key neural effects of pregnancy.
The comprehensive datasets generated in this first phase of the project will now also allow us to address pregnancy-associated functional changes to other circuits, e.g. those mediating feeding and aggression. We are also currently investigating whether, and if yes, how other parts of parenting circuits are affected by pregnancy, and whether hormonal and experience-dependent changes have equivalent effects in these circuits. We expect to submit 2-3 more manuscripts on these topics before the end of this grant's lifetime. Altogether, these investigations will allow us to obtain a comprehensive picture of key neural effects of pregnancy.