Neuron: New Research on Acute Stress and the Prefrontal Cortex

Acute stressors affect how we perceive the world, allocate our mental energy, and make decisions. Although the prefrontal cortex is known to be an essential brain region involved in adaptive behaviors related to stress, our understanding of the individual cell types and synaptic plasticity mechanisms in the prefrontal cortex is limited. 

In a recent study published in Neuron, a team of investigators including co-corresponding and first author, Max Joffe, PhD (Assistant Professor of Psychiatry), used a combination of transgenic, optogenetic, and pharmacologic tools to interrogate interneuron synaptic plasticity and circuit function in the prefrontal cortex of mice. “We took advantage of several transgenic and viral tools to identify, tag, and manipulate several types of prefrontal cortex neurons. We then recorded the electrical synaptic activity of many prefrontal cortex cell types and systematically evaluated how each was altered following an acute stress experience,” said Dr. Joffe.

The research showed that stress enhances excitatory drive onto a specific type of interneuron that expresses the neuropeptide somatostatin. These somatostatin-expressing interneurons have been previously linked with suppressing excitatory inputs onto other cells. Consistent with this literature, the team found that stress enhanced signals onto these interneurons from the amygdala, an emotional center, and attenuated signals from other regions. Finally, this research identified the mGlu5 subtype of metabotropic glutamate receptors as a key regulator of synaptic plasticity onto somatostatin-expressing interneurons and determined that this signaling pathway is necessary for stress-induced changes to prefrontal cortex function. 

“These studies add to the growing literature that somatostatin neurons are key cells involved in the cognitive responses to stress and provide new insight into related molecular and circuit-level mechanisms. In addition, compounds that inhibit mGlu5 receptors (and other glutamate receptors, indirectly) have been investigated as potential antidepressants, but these drugs have had limited clinical success due to dose-limiting side effects. Now that we appreciate this separate signaling pathway involved in the stress response, it may be possible to develop more specific mGlu5 antidepressants with minimal side effects,” said Dr. Joffe.

Acute restraint stress redirects prefrontal cortex circuit function through mGlu5 receptor plasticity on somatostatin-expressing interneurons
Joffe ME, Maksymetz J, Luschinger JR, Dogra S, Ferranti AS, Luessen DJ, Gallinger IM, Xiang Z, Branthwaite H, Melugin PR, Williford KM, Centanni SW, Shields BC, Lindsley CW, Calipari ES, Siciliano CA, Niswender CM, Tadross MR, Winder DG, Conn PJ

Neuron (2022).