Existing anti-anxiety medications are not always effective for all patients and frequently cause unwanted side effects. Understanding the brain networks and mechanisms that underpin fear and anxiety may provide a new approach to developing better anxiety treatments. Bristol’s School of Physiology, Pharmacology, and Neuroscience researchers wanted to know how the cerebellum, which is linked to many brain regions associated with survival networks, influences activity in another area of the brain called the periaqueductal grey (PAG).

This PAG area is at the center of central networks that coordinate survival mechanisms such as fear-evoked coping responses like “freezing.”To investigate this, researchers implanted electrodes in animal models to record activity in the PAG region of the brain and used a conditioning task in which an auditory tone is paired with a small foot shock, eliciting the formation of a “fear memory” and freezing, a behavioral index of fear.

The researchers discovered that within the PAG area of the brain, a subset of brain cells increased their responsiveness to the conditioned tone, which is consistent with the encoding of fear memory. When cerebellar output was altered during conditioning, the subsequent timing of fear-related neuronal activity in the PAG became less precise, and the duration of fear-related freezing behavior increased, confirming that cerebellar-periaqueductal grey interactions contribute to fear conditioning processes.

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The researchers discovered that disrupting a direct cerebellar-PAG pathway impaired fear-conditioned freezing and ultrasonic vocalizations. Dr. Charlotte Lawrenson and Dr. Elena Paci, the study’s lead authors, explain: “Until now, little was known about how the cerebellum influences neuronal activity in other brain regions, particularly those associated with fear and anxiety.

Importantly, our findings show that the cerebellum is a component of the brain’s survival network, which regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network underpin fear-related disorders and comorbidities.

“The findings of the study provide new insights into how the PAG encodes fear memory, as well as evidence that the cerebellum is an additional key structure in the list of brain regions that contribute to the fear/anxiety network and offer a novel target for treating psychological conditions such as post-traumatic stress disorder. The study, titled “Cerebellar modulation of fear behavior and memory encoding in the PAG,” will be published in eLife.

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