The ability to remember is crucial for our daily lives, yet the mechanisms behind it are still largely unknown despite their significance. Engram theory, memory traces, is a theoretical concept in neuroscience believed to be the principle by which the brain forms memories. Engrams are defined as small clusters of neuron ensembles that are activated upon experience and undergo offline, persistent chemical and/or physical changes (long-term plasticity). Reactivation of the engram cells induces successful memory recall.

This concept has been broadly investigated in various brain regions mainly composed of excitatory cells, such as the hippocampus and the neocortex. However, there is a lack of understanding of the role of inhibitory neurons in the engram theory. This gap in knowledge makes it difficult to reveal how fear memories are regulated and how the brain reacts to them, such as maintaining an excitatory-inhibitory balance during memory formation and recall.

In this study, the researchers focused on the central lateral amygdala (CeL), a brain region that contains mostly inhibitory neurons. They first identified fear learning triggers inhibitory synaptic long-term plasticity in CeL neurons. Next, using genetically modified mice, researchers marked these nerve cells activated by fear experiences (inhibitory engram). These tagged cells mainly expressed the neuropeptide somatostatin. Silencing this CeL inhibitory engram disinhibits the activity of targeted extra-amygdaloid areas, thereby selectively increasing the expression of fear. These findings define the behavioral function of an engram formed exclusively by GABAergic inhibitory neurons in the mammalian brain.

The first author, assistant professor Wen-Hsien Hou, explains; “These cells act like brakes, preventing excessive behavior reactions in response to fear. When these specific nerve cells were inhibited, the mice froze longer when they anticipated an upcoming electric shock”.

Humans and rodents both exhibit fear responses or, more precisely, defensive behaviors, which can generally be divided into active and passive behavioral patterns. Active behaviors include fleeing (escaping from harmful stimuli) or fighting (confronting harmful stimuli, commonly known as "fight or flight"). Passive defensive behaviors include freezing or feigning death. In this study, the fear memory being investigated primarily involves mice exhibiting passive freezing behavior when recalling a fear event.

This study focuses on fear memories formed through conditioned responses. In this scenario, mice associate a previously harmless cue (such as a specific sound frequency) with a harmful stimulus (like a mild foot shock). After several pairings of the sound with the shock, the mice develop a fear memory linking the two. The next time the mice hear the same sound, they recall the previous experience, anticipate an impending harmful stimulus, and respond with a conditioned freezing reaction.

In human cases, if someone experiences a car accident while running a yellow light, this traumatic event might form a strong fear memory. Later, the person may feel fear or anxiety when encountering yellow lights and may break early to avoid potential harm (injury). This phenomenon's underlying mechanism can be studied through mice's freezing responses to a shock-associated sound, as both share similar neural mechanisms and behavioral patterns.

The brain regions activated during fear memory formation in mice (such as the amygdala and hippocampus) are similar to those in human fear memory processing. The brain regions responsible for fear behaviors in mice closely resemble those in humans. Understanding how these regions influence fear behavior in mice can help us infer the neural basis of human fear memory.

From a behavioral perspective, the fear responses observed in mice and the methods used by scientists to train mice to overcome fear have already been partially applied in clinical treatments. For example, exposure therapy involves repeatedly exposing mice (or PTSD patients) to fear-inducing situations without any harmful stimuli, which helps to extinguish the fear memory.

Link to publication: https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00797-6#secsectitle0020

Important notes:

1. This study has limitations. Although the brain structures of mice and humans are similar, there are differences in their neural circuits and connections. Further research is needed to determine if the central amygdala neurons regulate fear memories and responses in PTSD patients. Additionally, using advanced techniques like gene editing and chemogenetics in humans poses significant challenges for clinical development.

2. This paper is dedicated to the memory of Prof. Marco Capogna, who passed away on December 2, 2022, at the age of 64. We remember him as an enthusiastic scientist, a cherished colleague, and a dear friend. Prof. Marco Capogna from Aarhus University in Denmark led this study in collaboration with Prof. Cheng-Chang Lien from the College of Life Sciences at National Yang-Ming Chiao Tung University in Taiwan and Prof. Francesco Ferraguti from the Medical University of Innsbruck in Austria.