How Norepinephrine Helps Us Adapt to Uncertainty

In volatile times, research suggests that norepinephrine promotes adaptability.

Posted Nov 15, 2020

ESB Professional/Shutterstock
Source: ESB Professional/Shutterstock

Norepinephrine (NE) and noradrenaline (NA) are two different terms used to describe the same thing. In the United Kingdom, "noradrenaline" is the British-approved name for this neurotransmitter and hormone, whereas "norepinephrine" is the recommended non-proprietary name used internationally and in the United States.

As a neurotransmitter, this catecholamine is primarily synthesized in the pons region of the brainstem and activates different adrenergic receptors associated with the sympathetic ("fight-or-flight") nervous system. The secretion of NE/NA increases arousal, focuses attention, makes us more alert, helps to promote vigilance, and can enhance memory formation and retrieval. A "noradrenaline rush" can increase anxiety and is associated with panic attacks when specific adrenergic pathways are "hijacked."

Centrally acting beta-adrenergic antagonists (i.e., beta-blockers), such as propranolol (which was first patented in 1962), can effectively lower blood pressure, reduce anxiety, and are used to treat migraine headaches. Beta-blockers have also been shown to inhibit the consolidation of traumatic memories associated with PTSD. Before public speaking engagements, some people use propranolol off-label to curtail their performance anxiety and stage fright.

In the early 1990s, a study (Faigel, 1991) found that administering 40mg of propranolol one hour before taking standardized SAT exams improved performance among adolescents prone to stress-induced cognitive dysfunction due to test anxiety. In 2017, U.S. pharmacists reported filling almost 18 million propranolol prescriptions.

 Vaccinationist - PubChem/CC BY-SA 4.0
Ball-and-stick model of norepinephrine (also known as noradrenaline)—a hormone and a neurotransmitter
Source: Vaccinationist - PubChem/CC BY-SA 4.0

New Research Puts Norepinephrine/Noradrenaline in the Spotlight

Recently, norepinephrine-producing neurons, distinct noradrenergic pathways, noradrenaline's role in volatility-linked learning, and some previously unrecognized side effects of propranolol have been making international science news headlines.

Earlier this month, researchers (Bari et al., 2020) from MIT in Cambridge, Massachusetts, reported that specific norepinephrine-producing neurons in the locus coeruleus improve focus and curb impulses via two distinct pathways. These findings were published on Nov. 2 in Proceedings of the National Academy of Sciences

This week, researchers from the University of Cambridge and University College London in the UK report that noradrenaline appears to help the human brain adapt to learning in uncertain situations and that propranolol reduces volatility-linked learning. These findings (Lawson et al., 2020) were published on Nov. 13 in the journal Current Biology.

For this study, first author Rebecca Lawson and her UK-based colleagues created a relatively simple model for assessing how the human brain responds to learning under conditions of uncertainty in a laboratory environment.

The goal of their double-blind, placebo-controlled study was to test the "effects of attenuating noradrenergic neurotransmission on learning" during times of uncertainty. To investigate the role that noradrenaline might play in human learning in uncertain circumstances, the researchers probed the effects of propranolol (40mg) vs. placebo while study participants performed a probabilistic associative learning task. 

The task used for this experiment involved learning to associate various tones with being shown either an image of a house or a face. The association between particular sounds and images were randomly changed at unpredictable intervals; this increased uncertainty and required study participants to quickly adapt by learning to make new associations.

"The ability to represent and respond to uncertainty is fundamental to human cognition and decision-making," the authors explain. "Noradrenaline is hypothesized to play a key role in coordinating the sensory learning and physiological states necessary to adapt to a changing world, but direct evidence for this is lacking in humans. Here we assessed the effects of propranolol, a common anxiolytic medication and β-adrenergic receptor antagonist, on sensory probabilistic associative learning." 

Notably, the researchers found that when previously learned associations became less predictable as the experiment progressed, those who'd been given the placebo adapted more quickly to uncertainty. On the flip side, those who received 40mg of propranolol (which blocks noradrenaline) tended to rely more heavily on their previous expectations. Subsequently, study participants who had taken this beta-blocker adapted less swiftly to uncertainty and were slower to learn new associations.

"Adapting to uncertain situations helps us to survive. When something unexpected happens, we have to decide whether it's a one-off and ignore it, or whether it's going to keep happening—in which case we might benefit by doing things differently," Lawson said in a news release. "In the face of uncertainty, people taking the anti-anxiety drug propranolol showed an increased reliance on past experience to inform their behavior—they were less influenced by changes in their environment that contradicted that experience."

Having the cognitive flexibility to adapt one's expectations in the face of uncertainty is especially important in a topsy-turvy world. "Relying more on prior expectations, by updating less in response to unexpected stimuli, is optimal in a stable environment. In a volatile environment, one ought to update their beliefs readily to learn quickly about the changing state of the world," the authors write in the paper's Discussion.  

This latest "learning during times of uncertainty" research suggests that noradrenaline plays a pivotal role in humans' ability to let go of previously held expectations and adapt more quickly to volatility. "Our findings underscore the relationship between the cognitive and autonomic effects of anxiety and offer computational insights into the possible mechanisms underlying therapeutic effects of beta-blockers," Lawson et al. conclude.


Rebecca P. Lawson, James Bisby, Camilla L. Nord, Neil Burgess, Geraint Rees. "The Computational, Pharmacological, and Physiological Determinants of Sensory Learning under Uncertainty." Current Biology (First published: November 13, 2020) DOI: 10.1016/j.cub.2020.10.043

Andrea Bari, Sangyu Xu, Michele Pignatelli, Daigo Takeuchi, Jiesi Feng, Yulong Li, Susumu Tonegawa. "Differential Attentional Control Mechanisms by Two Distinct Noradrenergic Coeruleo-Frontal Cortical Pathways." PNAS (First published: November 02, 2020) DOI: 10.1073/pnas.2015635117