News From The Field

Scientists Discover Brain Cells That Compete To Sustain or Suppress Traumatic Memories

Two clusters of brain cells compete to promote either the persistence or disappearance of traumatic memories, according to a new study conducted in mice. The findings could provide important insights into human conditions— such as posttraumatic stress disorder (PTSD), anxiety disorders, and associated problems such as alcohol use disorder (AUD)—that can arise from the persistence of traumatic memories. The new research, led by Andrew Holmes, Ph.D., chief of the Laboratory of Behavioral and Genomic Neuroscience at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and other colleagues in the United States, Switzerland, and Germany, is reported in the journal Nature.

For some individuals who experience trauma, fearful responses that are provoked by traumatic memories may continue long-term and affect their ability to engage in everyday activities. These fearful responses may continue even though a person may repeatedly encounter cues associated with the traumatic experience without any harm. The current study sheds light on specific neural circuits that may underlie the persistence and the extinction of fearful memories associated with trauma. The scientists examined clusters of neurons, known as intercalated cells (ITCs), that are packed tightly around the mouse amygdala. The amygdala is found deep within the temporal lobes of mammals’ brains and is a hub for processing emotions. It may also play a role in the brain systems that underlie the formation of fearful memories that are associated with certain cues in an individual’s environment and the successful extinction of those memories when the same cues later predict no harm.

In a series of behavioral, brain imaging, and neurophysiology studies, the scientists assessed the potential roles of ITCs as mice learned to associate a cue (e.g., a sound) with a foot shock (a fear-inducing event), and then extinguished the association by no longer pairing the cue with a foot shock.

The scientists identified two distinct ITC clusters that promote either a fear response or extinction of the cue/foot shock association. The study further revealed that the clusters effectively compete with one another, through a process known as mutual synaptic inhibition, to determine the relative strength of each memory and, hence, the level of defensive behavior shown by the animal. The study also showed that the ITC clusters have long-range connections to known fear-regulating regions in the midbrain and prefrontal cortex.

These findings identify a neural circuit within the amygdala that orchestrates activity across a broad brain network to exert a powerful influence over the ability to switch between high and low fear states. This result raises interesting questions about whether dysfunction of this brain system could contribute to individual differences in risk for trauma-related psychiatric disorders.

Hagihara, K.M.; Bukalo, O.; Zeller, M.; Aksoy-Aksel, A.; Karalis, N.; Limoges, A.; Rigg, T.; Campbell, T.; Mendez, A.; Weinholtz, C.; Mahn, M.; Zweifel, L.S.; Palmiter, R.D.; Ehrlich, I.; Luthi, A.; and Holmes, A. Intercalated amygdala clusters orchestrate a switch in fear state. Nature 594(7863):403–407, 2021. PMID: 34040259