New brain findings open pathways for understanding behavioral and neurological disorders

When danger lurks, instinct keeps us safe. It compels us to run from a burning building or wrestle a knife-wielding attacker to the ground. It also adjusts our body physiology to support these behaviors.

Survival helps explain why. But the mechanisms that link the brain and the body – the "switch" between rest and action – have long been shrouded in mystery.

A research team at Rutgers University-New Brunswick thinks they may have identified a key mechanism, and the findings may hold important clues to how diverse neurological conditions, such as alcohol use disorder and Parkinson's, could be diagnosed and treated.

In a paper published in the journal Science Advances, Rafiq Huda, an assistant professor in the Department of Cell Biology and Neuroscience within the Rutgers School of Arts and Sciences, together with lead author Nithik Chintalacheruvu, an undergraduate in the lab at the time of the research, report on a series of mouse studies that modeled the human brain's response to autonomic arousal – the sympathetic nervous system's involuntary response to neutral, stressful, threatening or emotional stimuli.

"What we've discovered is the region in the brain that can control the gain of these autonomic responses for movement and environmental stimuli," Huda said. "It acts as a dial to mediate how strongly our heart rate and other measures of sympathetic tone, like the pupil diameter, respond in these situations."

Cardiovascular and metabolic demands at rest are vastly different than during action. To assess the mechanisms that trigger and regulate autonomic responses, Huda and his team looked at how two brain regions – the locus coeruleus, a brainstem nucleus that releases the neurotransmitter norepinephrine, and the anterior cingulate cortex, a frontal brain region responsible for cognitive control – respond during movement and sensory stimulation.

Previous studies have identified the locus coeruleus as a trigger for autonomic arousal. Less clear is the role of the anterior cingulate cortex in this process.

Huda and his team speculated the anterior cingulate cortex might control the intensity of autonomic responses. For instance, if our heart races or palms start to sweat when we hear a sudden noise, perhaps the anterior cingulate cortex is the reason.

Testing the theory required a multistep experiment. First, Huda and colleagues injected the mice with a virus. Then, they implanted tiny fiber optics into the animals' brains. In some experiments, when the fiber optics were activated, they delivered pulses of light to a target protein that could turn brain activity on or off in real time. In others, the fiber optics allowed recording of brain activity associated with autonomic changes.

Next, the researchers set up a video camera with custom machine vision software to record changes in the mouse's pupils as a measure of sympathetic tone. As with humans, minute changes in pupil size occur in mice before a movement happens, and they continue to dilate as the activity intensifies.

With the camera trained on the eyes, the researchers then switched on their fiber optics and waited.

What they found was strong evidence that these two brain areas work together to trigger and regulate an arousal event, Huda said. When activity in the anterior cingulate cortex was turned off, the arousal event was suppressed. When activity in this region accelerated, pupil dilation "dramatically increased," Huda said. Mice were even triggered to start moving.

Connecting the results to movement and stress-induced behavioral conditions will take more research, Huda said, but the evidence points in this direction.

Consider Parkinson's disease.

"One of the major symptoms of the disease is an inability to start moving," Huda said. "If there is a dysfunction in processes that connect your intention to move to preparing your body to enact those movements, it might help explain the disease's most debilitating symptoms."

Future research will test whether changes in autonomic regulation by the anterior cingulate cortex could be what drives the mobility challenges in Parkinson's.

The findings also could have implications for alcohol use disorder, Huda said, something he and his team are exploring with a National Institutes of Health grant. Because alcohol use is often linked to stress and a high baseline sympathetic tone, Huda is looking to see if the response dial – the anterior cingulate cortex – could be tuned to control cravings or reduce dependence.

These are early days for this research, but the implications for modulating negative physiological responses to external stressors are profound, said Huda.

"We believe our findings will be transformative, not only for researchers working on arousal and the prefrontal cortex but broadly for scientists interested in cortical information processing and cortical-subcortical interactions in both health and disease," he said.