When I was young, my family lived in an old farmhouse. It was cozy and had a lot of character but, at over 150 years old, it showed its age. My bedroom was unique since it had been updated with blue shag carpet sometime in the 1970’s. It was also unique because there was a tiny nail that poked up through the floorboards a few inches past the doorway, hidden from view by the shag. I knew exactly where that nail was though; I had stepped on it late one night and woke the house with my cries of pain! I quickly learned to always step just a little bit farther into my room to avoid the hidden nail. What I later found surprising was that I always took larger steps into my room but never any other room in the house. How was my brain able to tell the difference between similar rooms in the house and only warn me of the hidden tack when I entered my bedroom? The ability to distinguish between memories learned in similar contexts (i.e. similar rooms) is a called pattern separation and is thought to be a major function of the dentate gyrus region of the hippocampus. For many years, the neurobiology of how the dentate gyrus and the hippocampus worked together to separate similar memories was relatively unknown. However, research in past decade has revealed some of this mystery.
For decades, neuroscientists believed that the human brain was unable to generate new neurons after birth. However, a research article published in 1998 by Fred Gage Ph.D. in the journal Nature challenged this dogma and demonstrated that the dentate gyrus region of the hippocampus actually generates new neurons throughout adult life! The dentate gyrus is a specialized region of the hippocampal formation; a brain region critical for forming and storing spatial memories. It is one of two regions in the brain where neural progenitor cells continuously generate new neurons, which then integrate into the neural network and form new synapses with other neurons (Figure 1). Once integrated, these neurons survive for the rest of a person’s life! Interestingly, various environmental factors such as exercise and exposure to new environments can increase the rate of new neuron formation while other stress is known to reduce it.
Although the neurobiology of how these neurons develop is fairly well understood, less is known about what their function is in the brain and how they contribute to learning and memory. One current theory is that newly generated neurons in the dentate gyrus are critical for memory pattern separation. Essentially, pattern separation is a scientific term for describing how the brain separates two distinct memories that were formed in similar contexts. In the case of the hidden nail in my bedroom, my brain formed a memory of my room’s blue carpet and associated that memory with the painful toe prick. However, when I entered a different room in the house, my brain realized that there was no hidden nail, so I did not need to step further into the room.
In 2012 a research article by Nobel Prize-winning professor Susumo Tonegawa Ph.D. demonstrated that newly generated neurons were necessary for behavioral pattern separation. Dr. Tonegawa’s lab used a behavioral test called contextual fear conditioning to look at pattern separation in mice (Figure 2). At the beginning of the experiment, each mouse was placed in a box (Context A) that had specific sensory cues (i.e. smell, sound and color) and given a foot shock! Just like the nail in the floor of my room, the mice learned to associate Context A with the foot shock. Next the mouse was placed in a different box (Context B) that was slightly different from Context A and were not given a foot shock. This sequence was repeated several times, and each time the researchers assessed the level of fear the mouse showed in each context. Mice with normal dentate gyrus neurogenesis, were able to learn quickly that Context A was associated with a foot shock and that Context B was safe. However, mice that were genetically engineered to lack neurogenesis were unable to distinguish between the two boxes and exhibited fear behavior in both contexts (Figure 2)! This discovery showed was that newly generated neurons in the dentate gyrus play an important role in helping the brain distinguish between similar environments and apply the appropriate memories to them. If the dentate gyrus is unable to produce new neurons, memories formed in similar contexts become fuzzy and can overlap with each other.
The brain is amazingly good at forming memories of people, places, events and ideas. Some psychologists estimate that our brains are capable of storing up to 2.5 petabites (~2500 1 Tb hard drives!) of information, in fact. But we would all be lost if it did not have a way of separating and organizing those memories the same way that books are organized on a library bookshelf. Adult neurogenesis plays a critical role in this and keeps the pages of our lives neatly organized!
Written by Ryan Jones.
Eriksson P.S., Perfilieva E., Björk-Eriksson T., Alborn A.M., Nordborg C., Peterson D.A. & Gage F.H. (1998). Neurogenesis in the adult human hippocampus, Nature Medicine, 4 (11) 1313-1317. DOI: 10.1038/3305
Nakashiba T., Cushman J., Pelkey K., Renaudineau S., Buhl D., McHugh T., Barrera V., Chittajallu R., Iwamoto K. & McBain C. (2012). Young Dentate Granule Cells Mediate Pattern Separation, whereas Old Granule Cells Facilitate Pattern Completion, Cell, 149 (1) 188-201. DOI: 10.1016/j.cell.2012.01.046
Images made by Ryan Jones and from Zhao C., Teng E.M., Summers R.G., Ming G.L. & Gage F.H. (2006). Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus., The Journal of neuroscience : the official journal of the Society for Neuroscience, PMID: 16399667