Understanding how psychedelic drugs affect brain and behaviour in rodents

The profound perception-, emotion- and cognition-altering properties of psychedelic drugs have been hailed as a "breakthrough therapy" for pervasive, difficult-to-treat neuropsychiatric conditions such as major depressive disorder. As such, drugs such as psilocybin have unique potential to treat the causes of psychiatric illness and enable recovery (1). However, the mechanisms by which psychedelics impact brain function remain poorly understood.

In human diseases such as major depression the communication between brain regions appears to become too rigid. This results in patients being 'stuck in a rut', unable to 'break out' of repetitive negative thoughts and feelings as well as expressing high anxiety, poor self-esteem and self-blaming. These thought patterns may arise from the abnormal dominance of certain brain states, often due to hyperactive 'top down' focus on negative thoughts. Psychedelics may act to reverse this state by increasing the variety of brain states through temporarily reorganizing how brain regions interact, thereby, enabling the formation of new, long-range communication patterns (1, 2). This, in turn, may lead to more flexible cognition and emotional breakthroughs in patients (3). Such an effect may 're-program' maladaptive thinking patterns by enhancing bottom-up information transmission, allowing the emergence of a new, potentially brighter, cognitive perspective (4). However, it is difficult to investigate this hypothesis purely via human brain scanning, as this is an indirect measure of brain activity; thus, invasive approaches to record the activity of neurons directly are required and this can only be accomplished using rodents.

To reveal the neural and synaptic effects of psychedelics the student on this project will record from multiple regions of the rodent brain during psychedelic drug challenge. Recordings will target brain regions including the prefrontal and parietal cortices, hippocampus and amygdala, as well as early stages of sensory systems. Recordings in freely moving animals will allow us to correlate drug effects in the brain with changes in motor, sensory and cognitive functions (such as fear and anxiety). The student will also learn how to explore these large datasets using powerful analytical techniques (such as information theory (5)) to reveal whether psychedelics do indeed increase the number, strength and direction of links between brain regions. The positive effects of psychedelics in patients persist long after drug treatment, suggesting that they produce equally long-term brain changes. The student will explore this through protein and epigenetic changes in our targeted brain regions at various delays after drug challenge. Finally, it will be important to translate the project's findings to the clinical setting, so the student will also carry out non-invasive imaging of brain activity in rodents under psychedelic challenge (e.g., fMRI and magnetic resonance spectroscopy). This will correlate their earlier invasive, direct measures of brain activity with indirect but clinically relevant measures of global brain function and neurochemistry.