Brainstorms IV - stress, how does it work?

Hi everyone! Yes, I am back… after a stressful start to the year with moving and shameful WiFi connection, I’ve managed to get my life in order (the COVID quarantine has helped, I have to admit) and once again I have time to write. Home office can be tough; after reading papers for the whole day my brain felt like it had been fried on a grill. So I decided to transform all the knowledge I had accumulated into a comprehensible summary of my (very broadly speaking) research topic: stress and mental health. Work and entertainment all in one ;) I found so many interesting facts about stress and our health that I decided to make this entry a bit broader and briefly include other brain disorders.

So let’s get to it. I guess that most people, upon seeing the word "stress", started stressing. Most of us are familiar with what stress feels like. It’s not a pleasant feeling. The word itself can remind us of all the things we are (sub)consciously stressing about. From those who worry about meeting their tight deadlines at work or school to those who suffer full-blown panic attacks, we would all be happy to avoid the tightening feeling in our chest, the cold sweat or the sleepless nights. Unfortunately, stress seems unavoidable in today’s world. But stress is a necessary feeling, something we aren’t meant to avoid: in the times in which humans had to combat nature one to one, it was a feeling that served to prime us to fight or escape from a threat, for example, a tiger. The problem is that this uneasy feeling is supposed to be temporary. It’s supposed to last enough to get us to a safe place and then fade. But where is our safe space now?

Stress is a mightier enemy than we might think. It can hit us not only when we are in front of the danger itself (i.e. the tiger, or maybe our boss in a more “modern world” scenario), but also when we imagine that danger. And yes, thinking about our future when we aren’t sure if we’ll get a job, if we’ll be able to provide for our kids or if we’ll pass the next exam, is stressful. Add to that that our present is already stressful enough, balancing work and life, and you have a state of constant anxiety.

We have turned “positive” stress (temporary stress that alerts us of an immediate danger and increases our performance) into constant, “negative” stress (chronic stress, a stress that stays for long periods and ends up reducing our productivity and affecting our health). It’s as if we were being chased by a relentless tiger which never leaves us alone. If we had to run for ages to get away from the tiger, many of us would die of exhaustion along the way. That’s what happens to our brain when it’s running on high alert for a long time. This high activity state ends up changing the wirings of our brain. There are many links between chronic stress and mental illness. And it’s not only psychiatric disorders, but it can also predispose to dementia, cardiovascular disease or diabetes.

But how can stress change our brain, when it’s such an abstract feeling? Well, here is where we get into what inspired me to study psychiatry: disentangling the abstract and the concrete, which are so deeply intertwined in the brain. The abstract can seem too complicated to approach, but when we reduce it to specific molecules, proteins, pathways, etc., we can reduce the problem to tiny pieces of a puzzle that we can put together more easily. And who wouldn’t want to understand the organ which defines us as the human species, but also gives us our individuality?

Let’s get back to the matter at hand, though. There are two sides to the way our body reacts to stress: the physiological and the behavioural response to stress. Although they both have molecules in common, little is known about the behavioural response compared to the physiological response. They are both linked, however, through these common molecules, so that when one begins, the other one starts too. Here is how it goes:

When there is a stressful event (real or imagined) there is a region in the brain, called the hypothalamus, which is activated. This is the first step for the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is the central pathway for stress signalling. The hypothalamus secretes "corticotropin-releasing hormone " (CRH), a hormone that is very famous in stress research and that mediates multiple effects of stress, including some in the behavioural part of the stress response. I won't bore you with all the details of the signalling pathway (you can see the whole process on the next image, if you are interested). It ends with the production of glucocorticoids, which are the hormones that produce the changes in our body that we typically associate with stress, like increased heart rate and breathing. Glucocorticoids can also travel back to the brain and stop the HPA axis so that the body goes back to its resting state.

The inactivation of the stress system is as important as its activation, but it’s here that chronic stress messes with our balance. When we suffer from chronic stress, our stress HPA axis doesn’t switch off. In the end, this causes changes in our basal state in terms of hormones, neuronal health and even inflammation in the brain. It is those changes that cause the negative effects that eventually appear if we are constantly stressed.

Okay, so until now what we know is that stress makes the body produce hormones that change how our body works, in theory only while the stress is there. If it doesn’t stop, those hormones are produced at levels that our body is not able to tolerate, so it adapts to cope with them. This should make us tolerate stress better, right? Unfortunately, this is not always the case. So how do the stress hormones end up messing with our brain?

During my master thesis, I researched a particular effect that CRH – the first stress hormone of the HPA axis, if you remember – has on the properties of neurons in the hippocampus. The hippocampus is the main brain region for memory formation. It is also a key region in spatial memory and orientation (to see an explanation of how neurons in the hippocampus code space, watch the video below – you can skip to minute 1:21 – or watch “The Mind Explained, Episode 1”).

Therefore, changes in cells in the hippocampus could have bad consequences for memory, learning and spatial orientation. As far as research has found, CRH reduces the number of the thin protrusions from hippocampal neurons, which indicate young connections with other neurons. Therefore, fewer protrusions could mean fewer connections. Thin protrusions are the first ones to be formed when a new flow of information between two neurons is set. They can then turn into thicker connections, which embody consolidated contact points. The consequences of the disappearance of the thin protrusions, called thin "spines", could manifest as trouble making new memories. This happens to me when I have a lot of stress: I can’t remember my daily schedule or the details of what people told me over the phone unless I write down all the important points. And it’s not only me: for example, in the lab, chronically stressed mice show problems remembering how to do tasks that unstressed mice had managed to learn.

But more things can go wrong in the hippocampus when we stress too much. Four important factors change in the hippocampus during stress, which are exaggerated if the stress becomes chronic. Stress causes less renewal of neurons. Even though you might have heard a million times that neurons are the only cell type that doesn’t regenerate, this is not entirely true: in humans, new neurons are produced in a part of the hippocampus through a process called neurogenesis, but this is very limited compared to other animals and other parts of the body. Stress also changes the activity of neurons by regulating neurotransmitter receptors and other proteins in the cells, it decreases the number of connections between neurons and it reduces the size of the hippocampus. This means that in the hippocampus, after chronic stress, there is less neuronal renewal in stressful conditions, i.e. the neurons that remain will be older than they should be. Since the hippocampus is the key region for new memory formation, it makes sense that stress messes up our capability to remember new things. And, at least for mice, it takes weeks to recover something like normal functioning.

The hippocampus is not the only part of the brain that is affected by stress. It also reduces the number of connections between neurons in the prefrontal cortex (PFC), a brain region that is related, among other things, to self-control and planning. Additionally, it powers up the amygdala, a small brain region in charge of regulating fear and fear-induced memories, as well as other aspects of human behaviour. Because of this, frightening memories (and fear is a kind of stress, right?) are easily remembered.

Okay, so we generally can’t remember things well when we are stressed, but can we get sick because of stress? We'll continue with stress and it's effects on the brain in my next post, so stay tuned!

Finally, because today I brought a lot of complex info to the table, I’ve summed up the take-home messages below:

• Peaks of stress are normal, but constant stress is damaging for our body and our brain.
• Chronic stress affects memory, cognition and mental health and can predispose to other diseases.
• The hippocampus (memory), the prefrontal cortex (planning) and the amygdala (fear) are the regions most affected by stress.

References:

1. Chen, Y., Dube, C. M., Rice, C. J. & Baram, T. Z. Rapid Loss of Dendritic Spines after Stress Involves Derangement of Spine Dynamics by Corticotropin-Releasing Hormone. J. Neurosci. (2008).

2. Chen, Y. et al., Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc. Natl. Acad. Sci (2010).

3. Chen, Y., Andres, A. L., Frotscher, M. & Baram, T. Z. Tuning synaptic transmission in the hippocampus by stress: the CRH system. Front. Cell. Neurosci. (2012).

4. Chen, Y. et al., Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol. Psychiatry (2013).

5. Chen, Y. et al., Converging, Synergistic Actions of Multiple Stress Hormones Mediate Enduring Memory Impairments after Acute Simultaneous Stresses. J. Neurosci. (2016).

6. Chidambaram, S. B. et al., Dendritic spines: Revisiting the physiological role. Prog. Neuro-Psychopharmacology Biol. Psychiatry 92, 161–193 (2019).

7. Kasai, H. et al., Learning rules and persistence of dendritic spines. Eur. J. Neurosci. 32, 241–249 (2010).

8. McEwen, B. S. Brain on stress: How the social environment gets under the skin. Proc. Natl. Acad. Sci. 109, 17180–17185 (2012).

9. The Mind, Explained. S1:E1 Memory.

10. Box 10-2: Place cells, grid cells, and representation of space by Sean Hamill