Dose-dependent changes in global brain activity and functional connectivity following exposure to psilocybin: a BOLD MRI study in awake rats

Evan Fuini¹Arnold Chang¹Richard Joaquin Ortiz²Md Taufiq Nasseef³Josh Edwards¹Marc Latta¹Elias Gonzalez¹Taylor Joel Woodward⁴Heather Bradshaw⁴Bryce Axe¹Ashwath Maheswari¹Heather Bradshaw¹Praveen Kulkarni¹Craig Ferris^1*

• ¹Northeastern University, Boston, United States
• ²Northern Illinois University, DeKalb, Illinois, United States
• ³Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
• ⁴Indiana University, Bloomington, Indiana, United States

Psilocybin is a hallucinogen with complex neurobiological and behavioral effects. This is the first study to use MRI to follow functional changes in brain activity in response to different doses of psilocybin in fully awake, drug naive rats. We hypothesized that psilocybin would show a dose-dependent increase in activity in the prefrontal cortex and thalamus, while decreasing hippocampal activity. Female and male rats were given IP injections of vehicle or psilocybin in doses of 0.03 mg/kg, 0.3 mg/kg, and 3.0 mg/kg while fully awake during the imaging session. These levels were validated by measuring psilocybin and its metabolite, psilocin. Changes in BOLD signal were recorded over a 20 min window. Data for resting state functional connectivity were collected approximately 35 min post injection. All data were registered to rat 3D MRI atlas with 169 brain areas providing site-specific changes in global brain activity and changes in functional connectivity. Treatment with psilocybin resulted in a significant dosedependent increase in positive BOLD signal. The areas most affected by the acute presentation of psilocybin were the somatosensory cortex, basal ganglia and thalamus.Males and females showed different sensitivity to psilocybin dose, with females exhibiting greater activation than males at 0.3 mg/kg, especially in thalamic and basal ganglia regions. There was a significant dose-dependent global increase in functional connectivity, highlighted by hyperconnectivity to the cerebellum. Brain areas hypothesized to be involved in loss of sensory filtering and organization of sensory motor stimuli, such as the cortico-striato-thalamo-cortical circuit and the claustrum, showed increased activation at higher doses of psilocybin. Indeed, the general neuroanatomical circuitry associated with the psychedelic experience was affected but the direction of the BOLD signal and pattern of activity between neural networks was inconsistent with the human literature.