Understanding Critical Components of the Brain’s Stress Circuitry

Study identifies how the PVT interacts with other brain areas during stress

July 9, 2018 • Science Update

Everyone feels stressed from time to time. While people often learn to deal with stress in a healthy, adaptive way, sometimes people respond to stress in a maladaptive way, which can put them at greater risk for developing mental illnesses. Now, a new studyconducted by researchers at the National Institute of Mental Health (NIMH) has revealed more about the organization and function of a brain structure that may serve a key role in linking stress detection to the development of adaptive behaviors. The study, published online June 18, 2018, appears in Nature Neuroscience.

The paraventricular nucleus of the thalamus (PVT) is a brain structure that has been identified as a player in emotional processing, learning, and in adaptive responses to stress. Although knowledge of the role of this brain structure in stress responses is growing, researchers are still working to understand how this structure is organized and how it connects with other parts of the brain.

The PVT has a unique place in the brain, receiving inputs from brain areas that make it sensitive to both environmental cues as well as to internal bodily signals. The dual nature of these inputs has led some to hypothesize that the PVT may serve as a critical link in the brain, helping integrate information about environmental stressors and internal physiological states to guide behavior. In this study, NIMH IRP researchers investigated the cellular and circuit mechanisms by which stressors impact PVT function. To do this, the researchers examined the contribution of different neurotransmitter systems in the PVT. They found that, during stress, dopamine (a major modulator of brain function) triggered a reduction in inhibition of the PVT. Notably, the disinhibition produced by dopamine made the PVT more sensitive to aversive outcomes.

“A stressful event typically leads to an increase in our sensitivity to new stressors, which suggests that a ‘stress memory’ center exists in the brain,” said study author Mario Penzo, Ph.D., chief of the Unit on the Neurobiology of Affective Memory at the NIMH. “Previously, scientists speculated that the PVT may be such a center. We now have evidence that indicates this is indeed the case. Our results suggest that stress-induced changes of the PVT circuit may promote susceptibility to future stressors.”

A surprising observation made by the researchers was that the stress-induced disinhibition of the PVT by dopamine was brought about through input from the locus coeruleus (LC). The LC is a small structure of the mammalian brainstem that is involved in physiological responses to stress and panic, but that it is primarily thought to do so via the release of the neurotransmitter norepinephrine. According to lead study author B. Sofia Beas, Ph.D., a postdoctoral fellow in the NIMH Unit on the Neurobiology of Affective Memory, the uncovering of dopaminergic modulation of the midline thalamus by the LC was unexpected and remarkable.

“Our finding that the LC, which is primarily known as a hub for norepinephrine, is the main source of dopamine to the midline thalamus is outstanding, given that this region is normally thought of as a norepinephrine center and not as a dopaminergic one,” said Beas. “This finding also emphasizes the intricacies of the neurotransmitter systems and challenges how they are defined in the nervous system”

While the researchers know that the PVT plays a role in stress processing, they are currently working to better understand how modulation there impacts downstream structures that are also involved in emotional processing and adaptive responding.

The findings help clarify the structural and functional roles of an important piece of the brain’s stress circuity and provide a platform for future research into how the brain responds to, and is impacted by, stress.

An overlay image of the PVT showing the terminals from the locus coeruleus (red) and the neurons that project to the nucleus accumbens (green). Image credit: B. Sofia Beas, Mario A. Penzo, and Nature Neuroscience.

Reference

Beas, B. S., Wright, B. J., Skirzewski, M., Leng, Y., Ho Hyun, J., Koita, O., … Penzo, M. A. (2018). The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism. Nature Neuroscience, 21, 963–973.

Grants:
NIMH Intramural Research Program
NIMH Grant MH107460
NICHD Intramural Research Program