Harvard researchers identify the specific cells in the brain that process perceived threats
Walking down a dark alley, you might quicken your pace or even break out into a run – even if there is nothing there to harm you. Your instinct to flee is based on an ambiguous threat in your environment. But what part of your brain controls that response? How are those nebulous feelings relayed to your brain, and what compels you to run, or approach with caution?
New research from Harvard sheds some light on that dark-alley response. Published in Nature Neuroscience, the study reveals a specific population of neurons in mice that regulate behavior in situations the animals have learned to associate with unpleasantness. It also identifies some surprising fight-or-flight circuitry between the hippocampus and deeper structures in the brain, beyond the ‘thinking’ structure of the cortex.
The findings point to a population of brain cells that could be a promising targets for the treatment of post-traumatic stress disorder.
Fight or flight
If you find yourself passing by a dark, neglected space, whether you stroll, walk quickly, or run past it depends on whether your brain associates that environment with an unpleasant experience. Inside your brain, your hippocampus computes that association and relays it to regions of the brain that are beyond the reaches of the cerebral cortex, where conscious thought is processed. Those sub-cortical regions, like the amygdala and hypothalamus, ultimately mediate your behavioral response, signalling to walk or run.
“What we really want to understand is how the brain guides behavior,” explains Amar Sahay, Ph.D., who led the study. “We know that the hippocampus encodes the details of episodic memories – our environmental context. It ‘gates’ the activation of brain regions involved in flight or fear, and instructs these regions when they should come online. So when the hippocampus loses control of flight/fight/fear circuits, people experience dysregulation of fear and anxiety—as seen in many anxiety disorders and post-traumatic stress disorder.”
What the researchers did
In this study, the team set out to identify exactly how the hippocampus gates basic decisions about fight or flight when animals are confronted with ambiguous threats in their environment. Specifically, they wanted to pinpoint how information about threats is relayed from the hippocampus to subcortical regions of the brain.
Quite sensibly, they started by creating a map.
Antoine Besnard, Ph.D., who is a postdoctoral fellow in Sahay’s lab, set up a series of tasks for his laboratory mice. The goal was for them to learn the difference between
- a dark-colored box where they actually got a mildly unpleasant foot shock, and
- just a dark-colored box (no foot shock).
Besnard looked at all the brain regions that were activated during the task. He input that information to a tried-and-true computational model, which generated a map of activated neural pathways between the hippocampus and subcortical circuits.
What they found
One circuit stood out from the rest: in fear-related responses, the hippocampus was communicating directly with a brain region called the dorsolateral septum (DLS), bypassing the cerebral cortex. This was unexpected, so they investigated further.
Using miniaturized, single-photon microscopes implanted above the DLS in mice, the researchers observed a population of neurons that act essentially like ‘threat sensors’.
These neurons express somatostatin (a neuropeptide) in the DLS, and have long-range projections that enable them to directly relay complex computations from the hippocampus to subcortical circuits. This allows them to modulate defensive behaviors such as halting or moving.
“These neurons calibrate motion, which has generally been considered to be the domain of ‘higher brain’ computations – not of subcortical regions,” said Sahay. “They calibrate aspects of defensive behavior, like movement. That is really important – just consider how much we move in response to our changing context, pretty much all the time.”
Importantly, the researchers were also able to track and decode the activity of these threat sensors to predict the behavior of the mice.
Why it matters
“These threat sensors could be targets for rectifying pathological responses to perceived threats in the environment. That could help people with post-traumatic stress disorder, who suffer from overgeneralization of fear,” explained Sahay, who is an associate professor of psychiatry at Massachusetts General Hospital and Harvard Medical School.
Threat sensors are just one subpopulation of a larger family of neurons that express somatostatin in the DLS. The next step for the team is to investigate other subpopulations of these cells, which may be responsible for mediating a diverse range of motivational and defensive behavioral responses. This will illuminate the circuitry involved in relaying inputs from the hippocampus and cerebral cortex to structures deep within the brain.
Contributing authors and organizations
This paper was the result of a collaboration led by Amar Sahay at the Massachusetts General Hospital (MGH) Center for Regenerative Medicine. Co-authors included Michael TaeWoo Kim, Hannah Twarkowski, Alexander Keith Reed, Tomer Langberg, and Wendy Feng of the MGH Center for Regenerative Medicine; Yuan Gao and Ian Davison of Boston University; Larry Zweifel of the University of Washington; Xiangmin Xu of the University of California, Irvine; Dieter Saur of the Technical University of Munich; and Antoine Besnard of Sahay’s laboratory in the Psychiatric & Neurodevelopmental Genetics Unit at Massachusetts General Hospital.
Besnard A, Gao Y, TaeWoo Kim M, et al. (2019) Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses. Nat Neurosci 22:436-446. Published online 4 February; doi: 10.1038/s41593-018-0330-y
A press release about this study, written by Terri Ogan Janos, was published on 11 February 2019 on the Massachusetts General Hospital news site.
Support for the study includes a NARSAD Independent Investigator and Young Investigator Awards from the Brain & Behavior Research Foundation, National Institutes of Health (NIH) Biobehavioral Research Awards for Innovative New Scientists (BRAINS) grant R01 MH104175, and NIH grants R01 AG048908 and 1R01 MH111729.
This work also received support from the Alzheimer’s Association, the Bettencourt Schueller Foundation, the Blue Guitar Fund, the Ellison Family, the Ellison Medical Foundation, the Harvard NeuroDiscovery Center, the Harvard Stem Cell Institute, the Massachusetts Alzheimer’s Disease Research Center, Massachusetts General Hospital, the Philippe Foundation, and the Whitehall Foundation.