Learning and memory are among the brain’s most fundamental tools for survival. Accurate encoding of ‘contextual’ memories, which are associated with particular experiences, enables the person to exhibit the appropriate fear responses and, importantly, avoid dangerous situations. Of equal importance is the brain’s ability to discriminate between an environment that it has previously learned to be dangerous and one that is safe.
Earlier research demonstrated that contextual memories are formed and stored in two interconnected brain regions, namely the hippocampus and the entorhinal cortex, which are involved in memory and navigation respectively. These two regions are linked via a complex network of neurons. However, although scientists have been able to determine how most of this network operates, one connection has remained elusive. Now, a study from researchers at Columbia University has identified the cellular circuit which helps the mouse brain to remember which environments are safe, and which are harmful. The team state that their findings also reveal what can happen when that circuitry is disrupted, and may offer new insight into the treatment of conditions such as post-traumatic stress, panic and anxiety disorders. The study is published in the journal Science.
Previous studies show that neurons in the entorhinal cortex wind their way into the hippocampus via two distinct routes, or pathways. It is thought that contextual memories are formed when these two pathways became activated as part of a carefully timed sequence. However, a few years ago a third pathway that linked the two regions was identified, whose purpose is still unknown. About 80% of neurons in the brain are excitatory, meaning that they carry communications long distances across brain regions, while the other 20% are inhibitory. These inhibitory neurons act locally to slow or halt the excitatory activity, much like tapping the brake pedal after a period of acceleration. What was so unusual about the neurons in this recently discovered third pathway was that they acted across a relatively long distance, and were also inhibitory. So researchers called them long-range inhibitory projections, or LRIPs. The current study investigated the role these LRIPs play in learning and memory.
The current study temporarily silenced LRIPs in the mouse brains, after which the mice were placed in a room where they were given a brief and aversive footshock. Results show that when returned to the same room 24 hours later, the mice remembered the shock and exhibited a fear response, indicating that LRIPs were not required for the formation of fearful memories. In contrast, data findings show that when placed in a completely different room, these mice again exhibited fear, suggesting they were generalizing their initial fear in a different context.
The lab state that this is in stark contrast to what was observed in normal mice, which only exhibited a fear response in the room where they had been shocked, revealing their ability to distinguish between dangerous and neutral environments. Additional imaging experiments and electrical recordings from normal, healthy mouse brains also revealed the precise role of LRIPs in astounding detail.
The group explain that normally a stimulus, such as a sound, light or small footshock, activates the LRIPs, which send an inhibitory signal from the entorhinal cortex into the hippocampus. They go on to add that upon arrival, the LRIP signal actually inhibits another set of inhibitory neurons in the hippocampus; this then frees up neurons in the hippocampus to switch on and, ultimately, generate a memory. Results show that these series of signal relays are actually part of a sophisticated gating mechanism, as evidenced by a short, 20-millisecond delay between when the LRIPs are initially activated, and when their inhibitory signals arrive in the hippocampus.
Data findings show that this brief delay enables the electrical signals to flow into the hippocampus in an elegant, precisely timed sequence, which is ultimately what allows the memory to form and be stored with the appropriate specificity so that it can be recalled accurately. The researchers conclude that without this delay, fearful memories lack specificity and accuracy, preventing the brain from appropriately distinguishing danger from safety.
The team surmise that their findings identify the input which enables precisely-timed information transfer within the cortico-hippocampal circuit and in this way, long-range inhibitory projections play an important role in providing specificity of fear conditioning to help prevent overgeneralization. For the future, the researchers state that their study suggests that any alterations in these pathways activity, particularly a disruption of the timed delay, may contribute to pathological forms of fear response, such as posttraumatic stress, anxiety, or panic disorders.