Scientists have uncovered a new layer of regulation in the brain that helps to control activity in the hippocampus, the center of memory and learning. The regulation allows the hippocampus to become sensitive, enabling animals to distinguish between new and familiar as well as harmful versus neutral circumstances. The work has implications not only for understanding learning and memory in healthy individuals but may also help shed light on post-traumatic stress disorder (PTSD) and other anxiety disorders.

The hippocampus is well known for its role in memory storage. It is intimately connected with the cerebral cortex, the area of the brain that is responsible for thought and cognition. In particular a neighboring cortical area- the entorhinal cortex - conveys information about the outside world to the hippocampus. Neurons reach between the two structures, providing signals that convert experiences into long-term memories.

At the most basic level, neurons in the brain perform two different roles: they can be “excitatory,” mainly activating other cells in their area, or “inhibitory,” acting to tamp down the signals sent by nearby cells. Researchers have known for some time that signals from excitatory neurons in the cortex are crucial for memory formation in the hippocampus. But the cortex also sends inhibitory neurons into the hippocampus. Their function remained largely unclear.

Now, researchers from Columbia University have found that these so-called “long range inhibitory projections” (LRIPs) play a crucial role in memory storage. The research team was led by Jayeeta Basu, Ph.D., a 2010 NARSAD Young Investigator grantee, and Steven Siegelbaum, Ph..D.; it also included Attila Losonczy, M.D., Ph.D., a 2012 NARSAD Young Investigator grantee.

In work published online in Science on January 8, 2016, the researchers describe how LRIPs from the cortex interfere with local inhibitory neurons in the hippocampus, producing an effect that is akin to releasing the brakes on a car.

Loss of inputs from these cortical neurons has a dramatic effect on the behavior of animals. When researchers inhibited LRIPs arriving from the cortex to the hippocampus of mice, the mice had difficulty distinguishing familiar objects from new ones. Furthermore, mice found it hard to tell apart environmental cues associated with harmful experiences versus safe experiences. Typically mice freeze only in environments where they receive a small shock; but without the cortical LRIP inputs they show an inappropriate freezing response in all environments, even those that are neutral or safe. This type of learning deficiency may play a role in diseases like PTSD, where fear memories become overgeneralized and disrupt routine activities. Results like these inform researchers as they work to develop therapies to treat PTSD and other anxiety disorders.