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New role for immature brain neurons in the dentate gyrus identified

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BIRMINGHAM, Ala. – University of Alabama at Birmingham researchers have proposed a model that resolves a seeming paradox in one of the most intriguing areas of the brain — the dentate gyrus.

This region helps form memories such as where you parked your car, and it also is one of only two areas of the brain that continuously produces new nerve cells throughout life.

"So the big question," said Linda Overstreet-Wadiche, Ph.D., associate professor in the UAB Department of Neurobiology, "is why does this happen in this brain region? Entirely new neurons are being made. What is their role?"

In a paper published in Nature Communications on April 20, Overstreet-Wadiche and colleagues at UAB; the University of Perugia, Italy; Sandia National Laboratories, Albuquerque, New Mexico; and Duke University School of Medicine; present data and a simple statistical network model that describe an unanticipated property of newly formed, immature neurons in the dentate gyrus.

These immature granule cell neurons are thought to increase pattern discrimination, even though they are a small proportion of the granule cells in the dentate gyrus. But it is not clear how they contribute.

This work is one small step — along with other steps taken in a multitude of labs worldwide — towards cracking the neural code, one of the great biological challenges in research. As Eric Kandel and co-authors write in Principles of Neural Science, "The ultimate goal of neural science is to understand how the flow of electrical signals through neural circuits gives rise to the mind — to how we perceive, act, think, learn and remember."

Newly formed granule cells can take six-to-eight weeks to mature in adult mice. Researchers wondered if the immature cells had properties that made them different. More than 10 years ago, researchers found one difference — the cells showed high excitability, meaning that even small electrical pulses made the immature cells fire their own electrical spikes. Thus they were seen as "highly excitable young neurons," as described by Alejandro Schinder and others in the field.

But this created a paradox. Under the neural coding hypothesis, high excitability should degrade the ability of the dentate gyrus — an important processing center in the brain — to perceive the small differences in input patterns that are crucial in memory, to know your spatial location or the location of your car.

"The dentate gyrus is very sensitive to pattern differences," Overstreet-Wadiche said. "It takes an input and accentuates the differences. This is called pattern separation."

The dentate gyrus receives input from the entorhinal cortex, a part of the brain that processes sensory and spatial input from other regions of the brain. The dentate gyrus then sends output to the hippocampus, which helps form short- and long-term memories and helps you navigate your environment.

In their mouse brain slice experiments, Overstreet-Wadiche and colleagues did not directly stimulate the immature granule cells. They instead stimulated neurons of the entorhinal cortex.

"We tried to mimic a more physiological situation by stimulating the upstream neurons far away from the granule cells," she said.

Use of this weaker and more diffuse stimulation revealed a new, previously underappreciated role for the immature dentate gyrus granule cells. Since these cells have fewer synaptic connections with the entorhinal cortex cells, as compared with mature granule cells, this lower connectivity meant that a lower signaling drive reached the immature granule cells when stimulation was applied at the entorhinal cortex.

The experiments by Overstreet-Wadiche and colleagues show that this low excitatory drive make the immature granule cells less — not more — likely to fire than mature granule cells. Less firing is known in computational neuroscience as sparse coding, which allows finer discrimination among many different patterns.

"This is potentially a way that immature granule cells can enhance pattern separation," Overstreet-Wadiche said. "Because the immature cells have fewer synapses, they can be more selective."

Seven years ago, paper coauthor James Aimone, Ph.D., of Sandia National Laboratories, had developed a realistic network model for the immature granule cells, a model that incorporated their high intrinsic excitability. When he ran that model, the immature cells degraded, rather than improved, overall dentate gyrus pattern separation. For the current Overstreet-Wadiche paper, Aimone revised a simpler model incorporating the new findings of his colleagues. This time, the statistical network model showed a more complex result — immature granule cells with high excitability and low connectivity were able to broaden the range of input levels from the entorhinal cortex that could still create well-separated output representations.

In other words, the balance between low synaptic connectivity and high intrinsic excitability could enhance the capabilities of the network even with very few immature cells.

"The main idea is that as the cells develop, they have a different function," Overstreet-Wadiche said. "It's almost like they are a different neuron for a little while that is more excitable but also potentially more selective."

The proposed role of the immature granule cells by Overstreet-Wadiche and colleagues meshes with prior experiments by other researchers who found that precise removal of immature granule cells of a rodent, using genetic manipulations, creates difficulty in distinguishing small differences in contexts of sensory cues. Thus, removal of this small number of cells degrades pattern separation.

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The first author of the paper, "Low excitatory innervation balances high intrinsic excitability of immature dentate neurons," Cristina Dieni, Ph.D., was a postdoctoral fellow at UAB and now has an independent position at University of Perugia, Italy. Coauthors include Jacques I. Wadiche, UAB Department of Neurobiology and Evelyn McKnight Brain Institute; Roberto Panichi, University of Perugia, Italy; James B. Aimone, Sandia National Laboratories, Albuquerque, New Mexico; and Chay T. Kuo, Duke University School of Medicine. Corresponding author is Overstreet-Wadiche.

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