Designer drugs bring new hope for PTSD and anxiety patients

Stanford University researchers have successfully “flipped a switch” inside the mouse brain to change fearful responses to bold, assertive ones. The findings—published in Nature—hold promise into identifying and potentially altering how humans with PTSD, anxiety, or a variety of other conditions respond to real or perceived threats.

In this study, which was partially funded by the National Institutes of Health (NIH) Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the research team identified a new circuit involved in fine-tuning the brain’s decision either to hide from or confront threats.

The team was led by Andrew Huberman, PhD, professor of neurobiology and of ophthalmology at Stanford University, Stanford, CA. They investigated the role of the ventral midline thalamus (vMT) to determine how animals respond to visual threats.

“This study may help explain why acts of courage, such as standing up for yourself or for a cause, or a physical challenge can feel empowering,” Dr. Huberman said. “Experiencing that good feeling can also make it more likely [that you will] respond to future threats in a similar way. Although our study was done in mice, learning more about the vMT may provide some insight into conditions such as generalized anxiety disorder and post-traumatic stress disorder and we are now pursuing study of the human vMT for that reason.”

The thalamus acts as a relay station that takes sensory information and sorts out where in the brain to send that information.

“Being able to manipulate specific circuits can uncover surprising relationships between brain areas and provide great insight into how the sensory, emotional, and behavioral centers work together to drive reactions,” said Jim Gnadt, PhD, program director,NIH’s National Institute of Neurological Disorders and Stroke (NINDS), and a team lead for the BRAIN Initiative. “The tools and technologies developed through the BRAIN Initiative have made studies such as this one possible.”

Drs. Huberman and Gnadt and colleagues used a “looming threat” model, which involved displaying a growing black circle above the mouse’s head that simulated an approaching aerial threat.

They observed that the vMT was activated when mice were confronted with a threat—the mice spent most of the time freezing or hiding and very little time rattling their tails– typically an aggressive or assertive response to a threat.

To further investigate the vMT, the team then used state-of-the-art tools, including a designer drug that allowed specific circuits to be turned on and off. Results showed that inactivating the vMT had no effect on freezing and hiding, but it did eliminate the tail rattling response.

Conversely, turning on the vMT increased the number of tail rattling responses and decreased the amount time the mice hid or froze.

Dr. Huberman’s group also discovered that the vMT sends information primarily to two brain areas: the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC). These circuits are critical for determining how the mice reacted to a visual threat.

Turning on the circuit that projected to the BLA caused more freezing responses, while activating the mPFC circuit increased tail shaking responses. Activation of the vMT caused an increase in the state of heightened alertness. Interestingly, the mice preferred spending more time in a location where they received vMT activation, suggesting that turning on that brain circuit made them feel good.

Although there may have been a difference in response to the visual threat (ie, tail rattling or freezing), the authors state that the underlying positive feeling was the same for both types of reactions.

Future research is needed to increase understanding of ways in which the vMT circuit affects behavior and how to develop treatments that can target specific parts of this system.  

This study was supported by the NINDS.