Circuits in the brain that are crucially involved in implementing decisions by directing between perseverance, exploration and disengagement have been identified by a UCL-led research team, in a new study in mice.
The neural circuits found in the brainstem may help to further understand a number of neuropsychiatric conditions including obsessive-compulsive disorder (OCD), autism and major depressive disorder.
The research, published in Nature, outlines how scientists at the Sainsbury Wellcome Centre at UCL studied a midbrain area called the median raphe nucleus (MRN), found near the top of the brainstem (which connects the brain to the spinal cord).
The researchers tested the function of neural circuits in the MRN under different conditions and revealed how animals switch between states and strategies.
The study's first author, Dr Mehran Ahmadlou, Senior Research Fellow in the Hofer Lab at the Sainsbury Wellcome Centre at UCL, said: "For all living beings, survival depends on the ability to adapt their goals. Animals must constantly decide whether to persevere in their current goal, explore alternative options, or disengage altogether.
"We wanted to understand the neural circuits that drive these behavioural strategies and enable animals to maintain or switch between them. The need to maintain the correct balance between these strategies is common across the animal kingdom, so the underlying neural circuits are likely to be evolutionarily conserved and subcortical."
To explore how the brain controls behavioural strategies, the researchers used both instinctive, naturalistic tasks, where the animals did not need any previous knowledge, as well as learned tasks in which animals acted on prior knowledge of where to expect a food reward. Using optogenetic manipulations (using light to direct activity of brain cells), calcium imaging, and neural circuit tracing, the researchers revealed three cell types in the MRN with complementary function.
Professor Sonja Hofer, Group Leader at the Sainsbury Wellcome Centre at UCL and corresponding author of the study, said: "Manipulating the neural activity of specific cell types in the median raphe strongly biased the animals' behaviour in similar ways in both instinctive and learned behavioural paradigms. Three types of neurons in the median raphe could between them drive decisions on whether to stick to what you are doing, try something else, or give up all together."
Explaining how specific types of brain cells helped to determine if an animal persevered, tried something new, or gave up, Dr Ahmadlou said: "We found that suppression of GABAergic neurons causes perseverance in a current or familiar goal; activation of glutamatergic neurons drives exploration of alternative options; and suppression of serotonergic neurons in the median raphe nucleus causes the animal to disengage."
Professor Hofer added: "We were really surprised to find that the three main cell types in this small brain structure had three fundamentally different but complementary functions with such strong control over the animals' behaviour."
The researchers also uncovered that the median raphe receives information about whether an experience is positive or negative from two further brain regions, the lateral hypothalamus and the lateral habenula, and these signals in turn can drive perseverance in a goal or disengagement from it.
Together these findings establish the MRN as a central behavioural switchboard for decision-making, uniquely positioned to flexibly control behavioural strategies.
The neural circuits revealed in this study may help to further understand a number of neuropsychiatric conditions. For instance, an overly high drive to persist in familiar actions and repetitive behaviours can be observed in OCD and autism, while pathological disengagement and lack of motivation is one symptom of major depressive disorder. Changes in the firing rate of specific median raphe cell types could therefore contribute to certain aspects of these conditions.
Professor Hofer concluded: "It is possible that in some mental disorders specific median raphe neurons could have pathological firing rates. For example, very low activity of serotonergic neurons specifically in the median raphe nucleus could contribute to a depressive phenotype. This is interesting as most of the more effective treatments for depressive disorders are indeed centered around the neurotransmitter serotonin. But these drugs are unspecific, slow and do not work for everybody.
"A better understanding of the brain mechanisms underlying healthy and pathological behavioural phenotypes can hopefully provide a basis for the development of new, more specific treatments."
This research was funded by the Sainsbury Wellcome Centre Core Grant from the Gatsby Charity Foundation and Wellcome and a European Research Council Starting Grant.
