Behavioural Neurogenetics Group

Long term biochemical changes in SERT compromised rats

When studying the role of serotonin in mood disorders there is an obvious paradox. We know that one of the most effective treatment for depression and anxiety disorders is blocking the SERT through selective serotonin reuptake inhibitors (SSRIs), leading to an increase in extracellular 5-HT. On the other hand, a genetic reduction in the SERT, which equally leads to increases in extracellular 5-HT, actually increased the risk of depression and anxiety disorder.

One possible explanation for this apparent paradox lies in the timing of the increases in extracellular 5-HT. Thus, in the case of a genetic reduction in SERT, 5-HT levels are increased already at a very early age. We know that 5-HT is critically involved in the development of the nervous system. It is therefore conceivable that the brain (and body) of genetically compromised SERT animals is fundamentally different from normal (so-called Wildtype) rats. However, since 5-HT plays such as broad role in development it is very hard to predict exactly what has changed in the SERT compromised animals.

In this project we therefore take a so-called “hypothesis-free” approach. So rather than setting a hypothesis a-priori about what may have changed, we aim to investigate as many changes as we can possible find. For that we take two different approaches: MALDI-MS and metabolomics. With MALDI-MS we carefully scan entire brain sections for regional changes in small molecules such as neurotransmitters and neurotransmitter metabolites. In metabolomics, we use brain or blood serum samples to investigate many different metabolites.

This project is in part supported by a grant from the Wellington Medical Research Foundation and is a collaboration with Drs Robert Keyzers and Bill Jordan.

The SERT & synaptic plasticity

While 5-HT is best known for its role in mood, cognition and reward, it also plays an important role in the development of the central nervous system. Several studies have found that different serotonin receptors can affect developmental processes such as axon and dendrite maturation, axon guidance and spine formation. This latter is very important, as dendritic spines are essential hubs for neuronal connections, especially excitatory connections that use glutamate as a neurotransmitter. Moreover, dendritic spine changes do not only occur during development, they are also a central element in adult synaptic plasticity.

Serotonin transporter (SERT) knock-out rats have much higher extracellular levels of 5-HT from very early on. Given its important role in neurodevelopment, we hypothesize these animals to show changes in neuronal connectivity. In this project we aim to investigate this with a variety of different techniques, such as Western Blot, quantitative PCR, immunohistochemistry and RNAscope. We will also grow neuronal cell cultures as it is easier to visualize dendritic spines in such culture than in normal brain tissues. To evaluate the changes over time we will study analyse the brain of young (first two weeks after birth) as well as adult rat brain tissues.

This project is a collaboration with Dr Darren Day from the School of Biological Sciences.

THE SEROTONIN TRANSPORTER (SERT) IN HEALTH AND DISEASE

Much of the research within the Behavioural Neurogenetics group focusses around investigating how genetic and/or environmental factors shape our brain and behaviour. With respect to the genetic factor, we are fortunate to have several genetic models in our group that we developed over the years. One of these is the serotonin transporter knock-out rat (SERT KO). The SERT is a protein that is specifically involved in the removal of serotonin (5—hydroxytryptamine, 5-HT) from the extracellular space back into the neurons. Thus, a reduction in SERT activity will lead to an increase in extracellular 5-HT. Importantly, many genetic studies in humans have found that a genetic reduction in SERT activity enhances the risk for different psychiatric disorders, such as major depression, anxiety disorders, autism spectrum disorder and drug addiction. Unfortunately, it is very difficult to assess from studies in humans whether a genetic change is causally linked to a disorder, as individuals often have multiple other genetic changes as well. Moreover, we know that environmental factors interact with genetic components, and of course people have different life histories. With animal research, on the other hand, we can ensure a similar genetic and environmental background thus allowing us to investigate the causality between genetic factor and behavioural/brain changes.

We have several different projects comparing normal (so-called wildtype, WT) rats with both heterozygous (SET HET) and homozygous (SERT HOM) knock-out rats. The SERT HET rats have about 50% of the SERT proteins compared to the WT, which is a similar reduction to that seen in humans with the genetic alteration in the SERT. The SERT HOM rats, on the other hand, have no SERT proteins at all. While this has not been observed in humans, it is often useful to investigate both SERT HET and SET HOM rats to see whether the effects get more intense with fewer SERT molecules (i.e. a so-called gene-dose effect).

26.4.19 : Research for Life grant

A bit of good news at the end of the week. Darren and I submitted a grant to the Research for Life Foundation to investigate the serotonylation of Rho GTPases in our SERT KO rats, a project very close to Liv McGifford‘s project. And we just got the good news that it was successful.

The SERT & Heart Disease

People with psychiatric disorders such as major depression and anxiety disorders are much more likely to also suffer from with heart problems than the general population. Likewise, individuals suffering from heart problems are more likely to develop major depression or anxiety disorders. In other words, there seems to a causal link between depression, anxiety and heart disease.

In this project we investigate the hypothesis that high levels of serotonin (5-HT) early in life may be this causal link. The reasoning behind this is that genetic reductions in the SERT are a vulnerability factor for major depression, anxiety disorders and heart disease and leads to high levels of 5-HT already very early on in life. From studies in rats and mice, we have learned that 5-HT, during development, plays an important role in shaping the structure and function of the brain as well as the heart.

For this project we will change the extracellular levels of 5-HT early in life through pharmacological means and subsequently investigate whether this leads to changes in the body and behaviour. Behaviourally, we will investigate depressive and anxiety-like symptoms. We will also assess changes in heart rate and especially heart rate variability. In addition, we will investigate changes in the structure and functioning of the brain and heart using immunohistochemistry.

This project is supported by a grant from the New Zealand Heart Foundation

02 October 2017: New Grant


With great pleasure I can announce that we just obtained a substantial grant from the Heart Foundation of NZ for investigating the link between depression, anxiety and heart problems. For more details, see: https://www.victoria.ac.nz/news/2017/09/unravelling-the-link-between-mental-illness-and-heart-disease

Towards a new rat model for autism spectrum disorder

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Bart

Bart studied Chemistry at the Radboud University in Nijmegen and after his Master’s degree spent one year in Saudia Arabia and one year at the Max Planck Institute in Goettingen (Germany) before moving back to Nijmegen for his PhD. From 1988 to 2006 he was assistant and associate professor at the department of psychoneuropharmacology, specialising in animal models for psychiatric disorder. In 2006 he moved to Evotec, a biotech company in Hamburg (Germany) where he was group leader and vice-president of neuropharmacology. He joined Victoria in 2011 and since January 2014 he is professor for behavioural neurosciences in the school of Psychology.

You can view Bart’s staff profile on the Victoria University of Wellington website.

Linda

My identity as a problem solver

How would you ‘define’ yourself?   

How much time do you have 🙂 ?  Well, most of all, I see myself as a problem solver and I’m driven to find solutions.

While preparing for this interview, I had a look at your LinkedIn page, and I was really impressed with the comments there by your former colleagues and employers. One said: “It’s really incredible to see her work. She doesn’t stop until the goal is achieved and even then she just…keeps…going. And with such precision. And accuracy. Leaving no stone unturned. No option unexplored. Nothing left to chance.”

I spent many years in the corporate world; in the private as well as the public sector. The knowledge I gained there helps me tackle my current project. I am especially grateful for my experience as a project manager and the ability to look at a project and scope it, looking at what the requirements are, what has to be achieved, and how to get there.

Using previous work experience for my PhD project  

Can you think of any concrete example where your experience as a project manager benefitted your academic work?

Absolutely. While planning my PhD project I realised that, if I wanted to do everything I originally planned, I’d spend three years just in the lab collecting data… I could see that the plan didn’t take into account the time necessary for brain analysis or writing, so my ability to look at the big picture and then de-scope some of the components helped a lot. Maybe that’s also one of the advantages of being a mature student.

I should mention that a number of students mentioned that they are learning a lot from you, especially in regard to time management.  Bart also commented on your meticulous OneNote.

That’s nice to hear. Bart never told me that! One trick I use to focus on a conversation and be present is to voice-record the meeting (with the other person’s permission) rather than take notes.  It allows me to focus on the conversation at the time, and play it back later for my notes.

The challenges

Are there any challenges you have because of the stark differences between the corporate world the academia?

In the corporate world, there are also long term projects, so that’s a similarity. What’s different is that I’m used to having a team of people working fulltime on my project with me, with each person responsible for aspects of the work. That frees me up to focus on the management/production side of things. In academia, that’s different i.e. it’s mostly on me. I have a few helpers, but I have to manage the project and do the delivery work myself. So that’s definitely a challenge, but also very rewarding.

In my research, I have several work streams going on simultaneously. I’ve planned it all out, but the plan can easily get disrupted and a small delay might have a big impact, because testing needs to happen on certain days. Having it so finely tuned means any disruption is a challenge. The way around that is to factor in a bit of extra time to allow for things to crop up.

There are also no predefined work and break schedules like there are for staff. When I’m in the lab for 12 hours with only the animals for company, it’s easy to miss cues like morning tea or lunch breaks that you get when working around others.

Changing my career

I got the impression that you were very successful in your former life. So what made you start studying again?

Earlier in my career, when I was working at big agencies in NZ, I realised that I’d lost the enthusiasm for the work; every job was “just another website/web banner/execution”. In 2013, I enrolled in Psychology because I had always been fascinated by behaviour. I was driven by questions like: Why are people so different? I knew early on that I wanted to do a PhD, so I mapped out the pathway. Because I hadn’t majored in psychology (I have a Bachelor in Communication from Germany), I had to do a graduate diploma first, followed by my Honours. I was working and studying at the same time, which allowed me to “live in both worlds” and get a sense for academia.

Do you have any advice for people who are considering a similar career change?

As a mature student, you will be a lot more conscious about your choices in terms of how much time you spend on things. You have to pay to do a PhD and, if you are doing it fulltime, you are not earning, which is quite a lifestyle adjustment. I think educating yourself is always a good idea, but don’t forget to have a life as well. Balance is important. It is understandable that you devote yourself to your project, after all, it’s your baby, but I can totally see how relationships can break in this environment. So for people who are in relationships, I would advise that whatever you do, don’t ever neglect that. Because in the end, once you have your PhD, you want to make sure you also still have your partner.

Finding the meaning

I might never make the same kind of money that I used to; it’s not all about money though. The thing is, if I can give something back, if I can make a difference to one person’s life with the work I’ve been doing, that would make it all worthwhile for me.

It’s also amazing to see the rats in the enriched cages and how their personalities come out i.e. how different they are when compared to those in standard housing. While that’s just a small part of my research, it’s the part that gives me the most joy at this stage of the journey. If I need some happy time after a rough day, I just go there and spend some time with the rats.

What kind of future do you envision after your PhD ?

I would like to keep doing research, but I guess I might have to go to overseas. Maybe to the States or Germany for a postdoc. But after that, I’m hoping to come back to Wellington and do research.

Tell us more about your research interests

I am fascinated by the brain. Any behaviour–human or animal–is an expression of the underlying neural structural, but behaviour is incredibly prone to external influences. Like, for example, with the rats. If the night-light settings play up, it might impact the animal’s performance during testing that day/the next day, but it won’t change, for example, the number of dendritic spines. The set-up of the individual brain structures doesn’t change just because the animal had a “bad day”. There’s no need for interpretations when comparing physiological differences and I like that. These differences explain the behaviour, so it’s a way of getting to the bottom of it and that’s what enables scientists to bring it all together to tell one big story.