Fear in Mind: Coping Mechanism Identified in New Brain Region

A study conducted at Texas A&M University has identified a new area in the brain involved in inhibiting fear, a discovery that holds potential for clinical interventions in patients with psychiatric diseases such as post-traumatic stress disorder (PTSD).

Studies in rats by Stephen Maren, Ph.D., and colleagues have found that a small region of the thalamus known as the nucleus reuniens (RE) plays a key role in suppressing fear responses. Previous work had indicated that this part of the brain acts as a conduit for sensory information traveling from the periphery of the brain to the cortex.

“It’s interesting because we know that the prefrontal cortex plays an emotion regulation role, and so there has been a lot of interest in how it accomplishes that,” comments Dr. Maren, who is University Distinguished Professor of psychological and brain sciences and Claude H. Everett, Jr. ’47 chair of liberal arts at Texas A&M University. “So this basic research, identifying this particular projection from the prefrontal cortex to the nucleus reuniens in the thalamus, points us to parts of the brain that are important for the inhibitory function of fear, which could be an avenue to new drugs, therapies, and interventions for psychiatric disorders.”

The researchers report their findings in Nature Communications, in a paper titled, “Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction.”

Animals, whether humans or rats, learn how to detect danger and set in motion appropriate defensive behaviors or actions as an essential survival mechanism, the authors write. However, in humans this fast response to perceived danger can backfire. “… Aversive learning can become maladaptive and lead to pathological conditions such as panic disorder, anxiety, and post-traumatic stress disorder …”

Through evolution we have been programmed to readily acquire and keep hold of fear memories, and apply them in both familiar and novel situations. Letting go of these memories isn’t so easy, and in animals, applying processes such as exposure therapy to reduce fear and anxiety tends to work only slowly, is short-lived and dependent on context.

Emotional memory is studied in the laboratory using processes such as Pavlovian fear conditioning and extinction procedures, the authors explain.  During fear conditioning animals quickly learn that a harmless conditioned stimulus (CS) can also predict an aversive unconditioned stimulus (US). They will then display conditioned fear responses (CR), such as freezing, even when they are only presented with the harmless CS. Desensitization involves repeatedly presenting the animals with the same CS, to gradually dampen their conditioned fear responses (a process known as extinction training). However, while the process of extinction training involves new learning, it doesn’t erase the original fear memory, and fear to an extinguished CS may commonly be re-established if that CS is encountered in unfamiliar contexts.

In humans, extinction learning is also at the heart of clinical practices such as exposure therapy that are designed to treat conditions such as PTSD or stress-related disorders, but while such treatments can be effective, many patients will be prone to relapse.

Research over many years has implicated the hippocampus (HPC), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) in the processes of how we store and express extinction memories. More recent work in humans indicates that suppressing the retrieval of fear memories may involve connections between the prefrontal cortex to the hippocampus. As the researchers note, “anatomically, the mPFC does not project directly to the HPC, but it can influence the HPC through indirect projections.”

The RE is one area of the brain that represents a potential a candidate for mediating how the mPFC influences hippocampal function. The latest studies in rats by the Texas A&M University team showed that chemically inactivating the RE in animals undergoing fear conditioning, extinction, and retrieval testing impaired the process of fear extinction learning. Although animals with chemically inhibited RE acquired similar levels of conditioned fear as did the control animals, the chemically treated rats didn’t demonstrate the same level of fear extinction as control rats. Follow-on tests indicated that RE inactivation also inhibited extinction retrieval, although not fear renewal.

“These results indicate that the RE is required for the inhibition of conditioned fear to an extinguished CS,” the team writes. “… RE inactivation causes a deficit in the retrieval of extinction memories … Pharmacological inactivation of the RE during extinction learning or retrieval increases freezing to an extinguished conditioned stimulus (CS); renewal of fear outside the extinction context was unaffected.”

Rats undergoing fear conditioning, extinction, and retrieval testing were similarly unable to suppress fear when the researchers harnessed a pharmacogenetic technique using inhibitory DREADDs (designer receptors exclusively activated by designer drugs) to specifically block prefrontal cortex neurons that project into the RE. This set of experiments confirmed that it was the connections bewteen mPFC to RE that were involved, and not any connections between the mPFC and other areas of the brain. “The role for the RE in suppressing extinguished fear requires the mPFC, insofar as pharmacogenetically silencing mPFC to RE projections impairs the expression of extinction memory,” the authors write.

The researchers say their studies are the first to demonstrate that the nucleus reuniens of the midline thalamus is needed for both encoding and retrieving extinction memories. “Extinction training or retrieval testing increased the activity of RE neurons and inactivation of the RE or its projections from the mPFC produced deficits in extinction memory … Taken together, these data reveal a novel role for the prefrontal-reuniens circuit in the inhibition of fear after extinction. This circuit may function to oppose fear expression after threat has passed.”