Studies in mice reveal neural mechanism of fear conditioning

The capacity to sense the feelings of others is not unique to humans, and the biological mechanisms are shared with other mammals

Updated - February 25, 2023 11:44 pm IST

Published - February 25, 2023 08:20 pm IST

The capacity to sense the feelings of others is not unique to humans, and its biological mechanisms are shared with other mammals, including rodents. File

The capacity to sense the feelings of others is not unique to humans, and its biological mechanisms are shared with other mammals, including rodents. File | Photo Credit: The Hindu

Researchers have, for the first time, demonstrated in mice the underlying neural mechanism that allows mice to feel empathy. In mice, observational fear, a form of emotional contagion, provokes an emotional response in the form of empathy.

The findings about empathy in mice may turn out to be true in the case of humans too, but further studies are needed in humans to conclusively prove this.

The capacity to sense the feelings of others is not unique to humans, and its biological mechanisms are shared with other mammals, including rodents. Observational fear, which is a rodent model for emotional contagion, is the basic form of affective empathy. 

During the observational fear experiment, a demonstrator mouse is given an electric shock, while an observer mouse watches from behind a transparent screen. When witnessing another animal receiving a shock, the observer mouse displays an immediate fear response, as demonstrated by its freezing behaviour. The observer mouse is also known to be able to recall the experience at a later time. Thus, observational fear is considered as a basic form of affective empathy. 

Brain-imaging studies in humans have shown that the neuronal activities of the anterior cingulate cortex (ACC) and the amygdala change during observation of others experiencing fear or others’ fearful facial expressions. It was also known that another region of the brain — basolateral amygdala (BLA) — is essential for observational fear. 

“ACC is considered an important region of the brain for the convergence of sensory and emotional information,” says Dr. Gireesh Gangadharan, DBT-Ramalingaswami Fellow at the Department of Cell and Molecular Biology at Manipal School of Life Sciences, Mahe and a co-author of a paper published in Neuron.  

So, a team led by Dr. Shin Hee-Sup at the Institute for Basic Science (IBS) in Daejeon, South Korea, began to study the neural circuits involving the ACC and basolateral amygdala (BLA) in both the right and left hemispheres of the brain to understand the neural mechanism underlying observational fear. 

Lab studies

The researchers turned to optogenetic experiments to prove that reciprocal connection between ACC and BLA regions of the brain is essential for observational fear learning. Light sensitive protein was injected into the anterior cingulate cortex (ACC) in the right hemisphere and the BLA was bilaterally illuminated with a yellow laser.

The experiment was repeated by injecting the light sensitive protein into ACC in the left brain and BLA was bilaterally illuminated with a yellow laser.

“When we optogenetically inhibited the ACC-BLA circuits only in the right brain, mice showed reduced observational freezing. On the other hand, the mice were unaffected when only the left side was inhibited,” says Dr. Gangadharan.

Next, the researchers inserted electrodes into the ACC and BLA to measure brain oscillation or brain activity in mice as they observe demonstrator mice receiving electrical shock. They recorded electroencephalogram (EEG) in the ACC and BLA.

“We found the brain rhythms with the range of 5-7 Hz selectively increased in the observer mice experiencing observational fear but only in the right brain,” he says. The enhanced 5-7 Hz oscillations in the right ACC and BLA ended immediately as observational freezing was terminated.

“This provided further support for the strong temporal correlation between these oscillations and observational fear,” Dr. Gangadharan says. “The specific increase in 5-7 Hz oscillations in the right ACC and BLA during observational fear suggests a pivotal role for these oscillations in the expression of empathic responses.”

Causal link

To test whether brain activity is causally linked to observational fear, the researchers undertook a closed-loop disruption of theta waves in the right ACC. “Whenever theta waves were seen in the right anterior cingulate cortex (ACC), we disrupted the oscillation (brain activity) and observed a reduction in freezing in the observation mice. This proved the causal link,” he says.

The next step was to confirm the source of the theta oscillation. The researchers hypothesised that hippocampal theta waves may tune the synchronised theta oscillations in the ACC and BLA in the right brain during observational fear. To test this hypothesis, the theta oscillations in the entire hippocampal complex were first stimulated and later inhibited and its effect on the ACC and BLA in the right brain and the empathic response was studied. 

“Following the changes in hippocampal theta oscillations power, 5-7 Hz rhythm in the ACC-BLA circuits and empathic responses were bi-directionally modulated. This conclusively showed that the theta oscillation is hippocampal-dependent,” he says. 

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