University of Bristol scientists say they have identified a new target in the brain which underpins the eliciting of anxiety and fear behaviors such as “freezing.” The neuro-researchers believe their study, “Cerebellar modulation of memory encoding in the periaqueductal grey and fear behavior” on the discovery of a key pathway in the brain, published in eLife, offers a potential new drug target for treating anxiety and psychological disorders, which affect an estimated 264-million people worldwide.

Existing anxiety-reducing drugs are not always effective for all patients and often have unwanted side effects. Understanding the brain networks and mechanisms which underlie fear and anxiety may offer a new approach to developing better treatments for anxiety disorders.

Neuroscientists from Bristol’s School of Physiology, Pharmacology, and Neuroscience, sought to investigate how the brain’s cerebellum, which is connected to many brain regions associated with survival networks, influences activity in another area of the brain called the periaqueductal grey (PAG). This PAG area lies at the hub of central networks that coordinate survival mechanisms including fear-evoked coping responses such as “freezing.”

To investigate this, researchers fitted animal models with electrodes to record activity within the brain’s PAG region and applied a conditioning task, whereby 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 team showed that within the brain’s PAG area, a subset of brain cells increased their responsiveness to the conditioned tone, consistent with encoding a fear memory.

However, 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 was increased confirming that cerebellar-periaqueductal grey interactions contribute to fear conditioning processes. The team showed that the manipulation of a direct cerebellar-PAG pathway also caused impairments in fear-conditioned freezing and ultrasonic vocalizations.

“The pivotal role of the PAG in fear learning is reinforced by the identification of neurons in male rat ventrolateral PAG (vlPAG) that encode fear memory through signaling the onset and offset of an auditory-conditioned stimulus during presentation of the unreinforced conditioned tone (CS+) during retrieval,” the investigators wrote.

“Some units only display CS+ onset or offset responses, and the two signals differ in extinction sensitivity, suggesting that they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to (a) disruption of the temporal precision of vlPAG offset, but not onset responses to CS+, and (b) an increase in duration of freezing behavior.

“And (ii) chemogenetic manipulation of the MCN-vlPAG projection during fear acquisition (a) reduces the occurrence of fear-related ultrasonic vocalizations, and (b) during subsequent retrieval, slows the extinction rate of fear-related freezing.

“These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities.”

According to the study’s lead authors, Charlotte Lawrenson, PhD, senior research associate and Elena Paci, PhD, teaching associate, “Until now, little was understood about how the cerebellum modulates neuronal activity in other brain regions, especially those related to fear and anxiety. Importantly, our results show that the cerebellum is part of the brain’s survival network that regulates fear memory processes at multiple timescales and in multiple ways; raising the possibility that dysfunctional interactions in the brain’s cerebellar-survival network may underlie fear-related disorders and comorbidities.”

The study’s findings reportedly provide new insights into the way the PAG encodes fear memory and also provides evidence that the cerebellum is an additional key structure in the list of brain regions that contribute to the fear/anxiety network and offers a novel target for treating psychological conditions including post-traumatic stress disorder.