Primate neuroscience from lab to clinic part 1 - mental health

Last year I partnered with leading neuroscientists to review three very different fields of research where studies in primates are transforming the treatments that can be provided to human patients. This research is ongoing, and creating new, cutting edge treatments, that are making a real difference in people’s lives. This article summarises just one of them.

The full paper is available at https://doi.org/10.1016/j.crneur.2022.100049

We use animals to advance scientific understanding or as models to study human diseases when the research cannot be done any other way. To work with research animals in the UK and in Europe, investigators must provide clear justifications explaining why their line of research is needed, the expected benefits that will come from a particular study and why this work is so important that it justifies the use of animals. Choosing the right species for the research is key to this explanation and must be fully justified in planning the research.

This is even more the case when our close relatives, non-human-primates, are studied. When monkeys are used in research they are considered ‘specially protected’ and extra ethical requirements, checks and justifications must be met to ensure that they are not used unnecessarily and that the research will deliver clear benefits to humankind. If other species could deliver similar knowledge or understanding, then primates cannot be used in the study. The use of great apes such as chimpanzees, gorillas or bonobos in research is banned in both the UK and the EU.

All primates, including humans, have complex brains which connect to complex nervous systems. These contain structures that only primates have and are associated with things that only primates can do. The brains of our primate cousins vary, and each species is different. None of them are identical to people, so the marked differences need to be kept in mind, but when it comes to studying neuroscience and which part of the brain does what, the similarities over, say, a rat, are enormous. Some parts of the brain only exist in primates and some neurological conditions can only occur in primates, although aspects of them are, of course studied using other methods and models. We can tell when we have it right, because the scientific findings from primate research reveal new lines of thinking and new treatments that can be used effectively in human patients. This research is ongoing, and creating new, cutting edge treatments, that are making a real difference in people’s lives.

Emotional rollercoasters: the prefrontal cortex and mental health

The prefrontal cortex is located in the frontal lobes of the brain, and while other mammals typically used in research, such as rats and mice are also considered to have a prefrontal cortex, at some point in our evolutionary history the primate brain became dominated by ‘higher functions’. It is thought that primate brains developed specialised areas for dealing with abstract tasks, and ‘neo-cortical’ regions such as the prefrontal cortex grew bigger and more complex. Many key areas of the prefrontal cortex do not have equivalents in other mammals and their connections to other brain areas create distinct networks. The prefrontal cortex is so complex and interconnected to other parts of the brain that it is impossible to study isolated cells, or even groups of them in a way that is meaningful.

The key reason to study the prefrontal cortex is that in people it is thought to regulate emotions, and to be important for our mental health. Illnesses like depression, anxiety, schizophrenia and even drug abuse all involve changes in the prefrontal cortex, which are thought to be responsible for the emotional symptoms experienced, but relatively little is known about a normally-functioning prefrontal cortex, how it differs in psychiatric disorders and how it changes to cause people to experience emotions so differently. Without better understanding of how this part of the brain works it is difficult to design new treatments, or to understand why treatments that work in one person are unsuccessful in another. The failure rate in treating mental health disorders is high, and many sufferers urgently need better and more effective treatments.

In uncovering the role of the prefrontal-cortex, non-animal approaches such as computational models and organoids are unlikely to succeed in the near future, as this part of the brain is so highly structured that they cannot mirror its complexity. Studies carried out in other animals, and in humans are also limited, as they are unable to link cause and effect, and often raise further questions that can only be answered by deliberately causing a change and observing the impact it has: something that cannot be done ethically in people. Often, monkeys such as marmosets are used to help interpret data that came from non-invasive studies in humans. In monkeys it is possible, for example, to deliberately alter how a neurotransmitter such as dopamine or serotonin affects a particular group of cells or pathway by directly applying a drug into the brain. The effects of changing the messages sent between particular groups of neurons can be observed in the behaviour of the monkeys as they move around their colonies interacting with others. Importantly, the monkeys can also use touchscreens, and can carry out tasks and tests, which are very similar to the assessments used to diagnose human patients in psychiatric clinics.

Studies in marmosets have revealed that there are distinct types of a condition known as cognitive inflexibility, which is common to many psychiatric disorders and can make recovery more difficult. At least two forms of inflexibility, one associated with the neurotransmitter dopamine and another with serotonin, are regulated by different circuits in the prefrontal-cortex, and understanding these differences is now leading to new approaches in treating patients.

Other studies have helped show how the prefrontal cortex influences which emotional stimuli we (and our primate cousins) respond and pay attention to, allowing a better understanding of depression and anxiety in humans. Marmosets, with changed activity in circuits of neurons within specific regions of the prefrontal cortex appear to be more anxious, a finding that has helped to identify different, and biologically distinct forms of anxiety. Understanding that there are different forms of anxiety, and how they relate to different changes in the brain allows treatments whether they are drugs or behavioural therapies to be better tailored to individuals, so that the right treatment is given to the right patient. Research in this field has also shown that the effectiveness of antidepressants is altered when they are given to marmosets that carry different forms of a gene. This gene is known to control the development of their prefrontal cortex and understanding how the genetic make-up of the prefrontal cortex leads to different structures and circuits in the marmoset brain, is helping to show why human patients respond to antidepressants so differently.

Non-human primate studies are allowing us to think differently about mental health, and how changes in our emotional circuitry, likely brought about by stress, can cause profound changes in how we experience the world around us. While much of this understanding comes from human patients, in this area of neuroscience monkeys have been vital for providing insight into fundamental biological differences which might change diagnostic criteria or helping to understand why some approaches work well in some patients but fail in others.

The accompanying paper to this article https://doi.org/10.10.16/j.crneur.2022.100049 provides further examples of this enormously important area of research, and the wealth of research that underpins it provides more detail still. The outcomes and changes to treatment protocols that result from studies like these have profound effects on people’s lives, and understanding how the primate brain regulates emotion, and how that might go wrong, is crucial not only to knowing ourselves better, but to being able to provide help where it is greatly needed.

Monkeys are intelligent, social and experience a huge range of emotions, just as people do. Their use in research is rightly limited, with checks and safeguards on their use. But this must be balanced with the enormous social benefit of this research, as we develop better understanding of the primate brain.?