As a tenure-track investigator recruited to NIEHS in 2009, Jensen holds a secondary appointment in the Reproductive and Developmental Biology Laboratory. (Photo courtesy of Steve McCaw)

A subset of brain cells that release a fight-or-flight chemical called norepinephrine unexpectedly reduces anxiety and stress in mice, according to new findings by NIEHS researchers. The study, published Sept. 13 in the journal Molecular Psychiatry, could explain why antidepressants that nonspecifically affect these so-called noradrenergic neurons have inconsistent effects among patients.

“We identified a subpopulation of noradrenergic neurons whose function in the stress response is opposite from the well-documented functions of the noradrenergic system,” said senior study author Patricia Jensen, Ph.D., head of the NIEHS Developmental Neurobiology Group.

“Knowing that noradrenergic neurons are diverse and contain subpopulations with very different functions may help us understand why targeting the system as a whole can have such unpredictable results,” she explained. “This understanding may inform the search for drugs that have more specific activity.”

Noradrenergic neurons regulate diverse functions such as attention, emotion, appetite, memory, and response to stress. Particular groups of these neurons are especially susceptible to disease and certain environmental toxins.

Because of this variability, the Developmental Neurobiology Group at NIEHS aims to uncover developmental and genetic factors that characterize unique subtypes of noradrenergic neurons (see sidebar).

Decreasing anxiety

Norepinephrine has long been regarded as a stress chemical that triggers anxiety. In a previous study in mice, the Jensen lab discovered two subpopulations of noradrenergic neurons that reach into stress-related brain regions. During embryonic development, neurons in one of these groups express a gene called Hoxb1.

Chen worked at NIEHS from 2015 to May 2018, following two years as a visiting fellow at the National Institute on Drug Abuse. (Photo courtesy of Steve McCaw)

“It has been thought that noradrenergic neurons are largely unified in actions that drive the stress response, including anxiety,” said first author Yu-Wei Chen, Ph.D., who was a postdoctoral fellow in Jensen’s group. “But our new study revealed that Hoxb1-noradrenergic neurons seem to have the opposite action in response to short-term stress — decreasing anxiety-like behavior and promoting an active coping strategy.”

Using well-established paradigms, the researchers observed behavior of mice under short-term stress. The researchers recorded the time the mice spent immobile, which is considered a measure of stress or despair.

Genetically modified mice with hyperactive Hoxb1-noradrenergic neurons spent less time immobile — indicating less stress — compared with mice that had unmodified Hoxb1-noradrenergic neurons.

Moreover, activation of Hoxb1-noradrenergic neurons increased the time mice chose to spend in the illuminated portion of a box and in open arms of a maze. These are stressful environments mice would normally avoid.

Brain imaging provides more evidence

In another part of the study, functional magnetic resonance imaging revealed that stimulating Hoxb1-noradrenergic neurons in mice led to decreased activity in stress-related regions of the brain.

“Taken together, the findings suggest that activating these neurons mimics the effect of antidepressants, by promoting an active coping response to stress and by decreasing anxiety-like behavior,” said study co-author Nicholas Plummer, Ph.D., a staff scientist in the Developmental Neurobiology Group.

“These observations contrast with the general belief that norepinephrine signaling promotes the stress response,” he added. “They clearly demonstrate that the noradrenergic system consists of multiple subpopulations with distinct functions.”

Citation: Chen YW, Das M, Oyarzabal EA, Cheng Q, Plummer NW, Smith KG, Jones GK, Malawsky D, Yakel JL, Shih YI, Jensen P. 2018. Genetic identification of a population of noradrenergic neurons implicated in attenuation of stress-related responses. Mol Psychiatry; doi: 10.1038/s41380-018-0245-8 [Online 13 Sept 2018].

Robertson SD, Plummer NW, de Marchena J, Jensen P. 2013. Developmental origins of central norepinephrine neuron diversity. Nat Neurosci 16:1016–1023.

(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)