What is going on in the brain

Stafford Lightman, Professor of Medicine at the University of Bristol, examines the hormonal patterns of our brain and their effects.

Stafford Lightman

Professor of Medicine

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Stafford Lightman

Professor of Medicine

02 Jul 2021

Key Points

The brain allows us to adapt to changes by sensing and anticipating what is going on in the environment around us.
If we alter the amount and the pattern of cortisol that the brain sees at different times of day, the hippocampus responds in a different way.
The pattern of cortisol is extremely important in memory response and emotional response.
The problems of neurodegeneration are becoming a major problem of human life, especially with longer lifespans.

Our brain anticipates what’s going on

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My particular interest is in how the environment affects the brain and how it allows us to adapt to changes by sensing what is going on in the environment around us. What’s fascinating about the brain is that it anticipates what’s going on in the world, and it adapts to the idea of what it is expecting to happen in the future. That means that it is in the best position to function in its optimal state when a particular situation arises. One of the most obvious aspects of this is the fact that when you wake up in the morning, your brain is functioning well. If you are woken up at about two in the morning and somebody asks you a complicated mathematical question, it might take more effort to answer as your brain wouldn’t be working at maximum function. But the second you wake up, your brain is functioning quite well.

The question of why at that particular time it can function well is very interesting to me. Along with my colleagues, I have studied the way synapses work – the way nerve cells talk to each other in areas of the brain which are important for memory, such as the area called the hippocampus. As rats are nocturnal, these studies would be done in the late afternoon, when a rat is normally waking up. We found that the synaptic plasticity at that time of day is very different from the time of day when a rat would normally be asleep.

Changing hormonal patterns in animals

We have been able to take apart what is going on in this situation by altering the amount of cortisol and the pattern of cortisol that the brain sees at different times of day. What we find is that if we change these patterns of cortisol, the hippocampus responds in a different way. Late at night before you wake up, great surges in cortisol are preparing your brain to be ready for all the things that it’s going to need to do during the next day, so that whatever you’re going to be using your brain for, it is better prepared. This interaction of the brain with the hormone axis is critical for making sure that your brain is doing the right thing for you at the right time. We find that if we disrupt that, if we artificially change your pattern of hormones, the brain doesn’t like it at all and then functions very badly.

Changing hormonal patterns in animals is quite easy. We just change their hormone profiles. When we do this, we can test how well they can remember mazes and how they respond to different stimuli. What we find is that the pattern of cortisol is extremely important in the way they respond. At a molecular level, we can even see that the cells within the hippocampus are functioning in a different way.

Changing hormonal patterns in humans

In human beings, we can block the ordinary production of cortisol and we can give them different patterns of the hormone. We can give them back their normal pattern of cortisol – large pulses of cortisol which usually happen early in the morning – or we can flatten it out. Then, we can look at how well they remember things and how they respond to things emotionally. If we iron out the oscillation, creating a totally smooth pattern of cortisol throughout the day, and then we test people’s memory and how they function, we find several things. Firstly, the fact that they sleep less well. Secondly, when we assess how good their memory is, we find that if we do simple memory tests, they do well. However, in more complex memory tests, people who have lost their oscillating level of cortisol don’t function as well. Their memory isn’t as good as it should be.

Cortisol is also very important for your emotional responses. If we get rid of our fluctuating levels of cortisol, we find people’s emotional responses are much poorer. Interestingly, we see a very similar pattern to what happens in depression. When we change from a very smooth to a normal oscillating response, people have a much better emotional response to stimuli. For instance, they recognise happy faces much better. They interpret them in a much better way. So we find, generally, that people who have oscillating hormone levels interpret things in a much more positive manner.

Studying our aging process

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The question about what happens in aging is a very interesting one, and it’s something we’re actively beginning to investigate at the moment. The bottom line is that we don’t know. We have designed equipment which can measure the oscillations of hormone levels in normal people going about their ordinary life, but nobody’s ever done this before, so we don’t know the answer. There is some evidence that the older you get, your response to stress is different and you have a rather more prolonged pulse of cortisol. Similarly, there is some evidence that people who have dementia or Alzheimer’s disease have a change in their oscillating levels of hormones. Again, this is only preliminary data, but there is some suggestion that your levels of cortisol at night may be a bit higher and that your oscillations may not be as good if you’ve got dementia. If this is the case, then it might well be possible that we could improve the cognitive status of some patients with dementia by changing their cortisol rhythms. This is quite an early stage now, but it’s a very interesting level to look at.

We’ve also been looking at neurogenesis. It used to be thought that the brain cells we were born with were the only brain cells we have throughout our life, but there’s now evidence that we are actually producing new brain cells all the time. Some of these may be important for memory and our emotional responses, and we have some evidence now in animal studies that the pattern of your cortisol is important in the formation of these new brain cells. If that’s the case, changing our pattern of cortisol may determine the fate and the number of these new brain cells that are being formed and may enable us to manipulate our ability to maintain the best memory function during later life.

Moving forward

Technology is moving forward incredibly fast at two major levels. At the human level, there’s the technology of scanning patients, of doing magnetoencephalography, of understanding what’s going on in a human being’s brain during the day. Our ability to understand physiologically what’s going on in man is moving forward at a very fast pace. At the other extreme, our ability to understand how we can generate new brain cells and how these new brain cells might help improve circuit functions, say after a stroke or in patients with dementia, is going to be an area which will, I’m sure in the next decade, move forward very fast.

When you combine these two – being able to potentially put specific receptors that will improve brain function into a human brain and being able to follow them, using new scanning techniques to see how they work within the normal circuits of the brain – this should create a huge difference in the way we are able to start to treat disease and help people who have got degenerative and other conditions of the brain.

An ethical question

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Everything that we do needs very careful ethical assessment because, obviously, we are our brains. Our brains are a repository of all of our experiences and everything that has happened to us. From this, we synthesise who we are and what we’re doing, and obviously, we need to be really careful that we don’t do anything that is going to change that. We know that there are certain drugs that can make susceptible people manic and make them do things which would be unacceptable, so we have to be very careful at every single stage and make sure that society has oversight of everything that neuroscientists are doing in these areas, particularly in anything which might alter behaviour.

However, I think we are going to be moving fairly slowly in these areas because, for instance, putting stem cells into the brain is potentially putting something in that could become a tumor. These are areas that need to be controlled. They need to fit in with what society is happy with. There’s a huge area for human ethics to be tied in with what neuroscientists can do and, obviously, this cannot be done in isolation. As the treatment for many other diseases is getting better, the problems of neurodegeneration are becoming a major problem of human life and of how we’ll deal with humans who are living much longer lifespans.

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Human brain patterns

Russell, G. M., Durant, C., Ataya, A., et al. (2014). Subcutaneous pulsatile glucocorticoid replacement therapy. Clinical Endocrinology (Oxf), 81(2), 289–293.

Lightman, S. L., Birnie, M. T., & Conway-Campbell, B. L. (2020). Dynamics of ACTH and Cortisol Secretion and Implications for Disease. Endocrine Reviews, 41(3), 470–490.

Stubbs, F. E., Conway-Campbell, B. L., & Lightman, S. (2019). Thirty years of neuroendocrinology: Technological advances pave the way for molecular discovery. Journal of Neuroendocrinology, 31(3).

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