The role of cerebellar CB1 receptors in general anxiety

Abstract

Recently, the cerebellum has gained increased attention for its role in the regulation of emotional responses, like anxiety. In addition, the endocannabinoid system is known to be an important regulator of anxiety phenotypes. However, little is known about cerebellar endocannabinoids and their role in anxiety. The present project aims to close that gap by
studying the effects of blocking endocannabinoid signalling in the cerebellar vermis and measuring the behavioural response of the animals in anxiety tests. In order to test this, I implanted a cannula into the cerebellar vermis of both male and female Sprague-Dawley rats. My data show that blocking CB1 signalling in the cerebellar vermis (lobules V/VI) decreases the time spent in the open arms of the elevated plus maze. Because of this, complementary
electrophysiological recordings were performed in another cohort of animals treated with the same CB1 antagonistsystemically. In this new cohort I found that there is an increase in power in the lower range of frequency oscillations (4 - 12 Hz) in the medial prefrontal cortex immediately after the animals enter the open arms of the elevated plus maze that is abolishedwhen the animals are treated with the CB1 antagonist. Finally, in collaboration with the University of Pavia, I performed extracellular recordings in sagittal cerebellar slices treated
with the CB1 agonist ACEA. These results showed an impairment in the induction of synaptic plasticity responses in mossy fibre synaptic inputs to granular cells that recovered with higher frequencies of stimulation. Collectively, these results provide novel evidence that cerebellar CB1 receptors contribute specifically to anxiety-related behaviors, particularly those involving approach-avoidance conflicts. This work expands our understanding of the cerebellum's role
beyond motor control into emotional regulation and highlights the endocannabinoid system as a key molecular pathway through which the cerebellum influences anxiety states.

Date of Award	17 Jun 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Richard Apps (Supervisor), Charlotte Lawrenson (Supervisor) & Jasmine Pickford (Supervisor)