Fear generalization is when conditioned fear responses spread and are displayed with other environmental cues, usually innocuous stimuli. These responses are defining features of anxiety disorders and posttraumatic stress disorders (PTSD), which are known to severely impair someone’s quality of life. While looking for more information, I came across an article titled “Scientists discover ‘switch’ that may turn off PTSD fear response,” and it talked about the published work of neurobiologists at the University of California San Diego.
In their article, “Generalized fear after acute stress is caused by change in neuronal cotransmitter identity” (Li et al. 2024), they used a mouse model to study contextual fear and the mechanism of fear generalization. They produced fear generalization by increasing the intensity of the foot shocks (unconditioned stimuli) in different contexts. After establishing fear generalization, they performed immunostaining to measure the neurons that coexpressed 5-HT, VGLUT3, and GAD67. This was done because the activity of neurons in the lateral wings had been linked to panic-like fear responses in previous studies. They found a strong shock triggered a switch in neurotransmitter co-expression from glutamate to GABA in serotonergic neurons. To support their findings, they looked for evidence of neuron death and found none. Subsequently, they went on to selectively tag the glutamatergic neurons with genetic markers to track the neurotransmitter changes. They saw an increase in neurons expressing GABA but not glutamate. These results matched the samples from postmortem brains of individuals with PTSD. They concluded that the increase in GAD67-expressing neurons is needed to produce generalized fear.
Building on these findings, further research might help identify any potential molecular markers that target the switching transmitters. Li et al. (2024) study found that blocking the switch before exposing the mice to the unconditioned stimulus was enough to prevent generalized fear, and with this in mind, they believe the Tet-on/Tet-off system could be used to reverse the transmitter switch after fear is established. If molecular markers are identified, could they allow us to reverse the switch and terminate generalized fear?
In the study, “Artificially enhancing and suppressing hippocampus-mediated memories,” conducted by Dr. Grella, they also used a context-dependent fear generalization model, similar to the one used in the previous study, but with an emphasis on hippocampal cells. Using a Tet-on or Tet-off system, they targeted cells involved in a specific fear memory. By performing both acute reactivation and chronic reactivation using optogenetics, they found that the dorsal and ventral hippocampal cells played different roles in memory formation, retrieval, and overall fear responses.
Similarly, Zaki et al. (2022) investigated fear relapse and reinstatement in their study, “Hippocampus and amygdala fear memory engrams re-emerge after contextual fear relapse,” where they performed optogenetic stimulation and inactivation of cells active during fear conditioning to see if it was enough to disrupt fear responses after relapse. They found that the cells active during fear conditioning could be reactivated once the fear was reinstated in the mice.
Together, these studies look at different aspects of fear and the many mechanisms that underlie the brain’s neuronal circuits. I wonder if the study regarding the co-expressed neurotransmitters will be replicated while looking at fear relapse. Or if they will continue to look at other regions involved in fear, like those involved in the freezing response, to find out if other neurons also undergo transmitter switching further downstream. The implications of these studies are promising and could improve the lives of those who suffer from PTSD or other stress-related disorders.
References:
Adarlo, S. (2024, February 16). Scientists discover "switch" that may turn off PTSD fear response. Futurism. https://futurism.com/neoscope/brain-fear
Hui-quan Li et al., Generalized fear after acute stress is caused by change in neuronal cotransmitter identity.Science383,1252-1259(2024).DOI:10.1126/science.adj5996
Zaki, Y., Mau, W., Cincotta, C. et al. Hippocampus and amygdala fear memory engrams re-emerge after contextual fear relapse. Neuropsychopharmacol. 47, 1992–2001 (2022). https://doi.org/10.1038/s41386-022-01407-0
Chen, Briana K et al. “Artificially Enhancing and Suppressing Hippocampus-Mediated Memories.” Current biology: CB vol. 29,11 (2019): 1885-1894.e4. doi:10.1016/j.cub.2019.04.065
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