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A brain clock keeps our memories ticking

Just as members of an orchestra need a conductor to stay on tempo, neurons in the brain need well-timed waves of synapse activity to organize memories across time.

In the hippocampus, the brain's memory center, a temporal order of neural events  — the chronological sequence of events according to time — is important to building a mental map of where you've been, where you are, and where you are going.

Published in Nature Neuroscience, researchers from the RIKEN Brain Science Institute in Japan, used mice to pinpoint how neurons not only represent space, but stay arranged according to time.

As a mouse navigates in its environment, the central hippocampal area — CA1 — relies on rhythmic waves coming from nearby brain regions to map the space occupied by the mouse.

When researchers turned off input from the CA3 hippocampal area, brain maps became jumbled.

Mice still performed simple navigation tasks, and signals coming from single neurons appeared to represent space accurately, but 'orchestration' was out of synch and full of errors.

"The neural music didn't change, but by silencing CA3 input to CA1 in the hippocampus, we got rid
of the conductor."

Thomas McHugh PhD, Circuit
and Behavioral Physiology Team
Leader, Riken Institute, and senior

Schematic of the hippocampus.
Image Source: Yang et al., 2008

McHugh and co-author Steven Middleton were able to accomplish silencing CA3 by genetically engineering the mice to express a nerve toxin in CA3. The toxin shut down the synaptic junctions between CA3 and other brain areas. Overall neural activity was preserved, but synaptic communication was muted. Then researchers measured the affect a muted CA3 hypocampus had on the space map created in area CA1.

While mice ran up and down a track, researchers recorded individual neurons as well as the sum of all electric currents coming from a larger group of mouse brain neurons. The data collected allowed researchers to monitor the output from each region by their theta cycle. The hippocampus used theta cycles to create a neural map of the space being occupied by the mouse.

Comparing activity in individuals, as well as in populations of normal and transgenic mice, researchers observed a paradox. As the transgenic mice moved around their enclosure, individual neurons could be seen to update their activity at regular intervals of 8 Hz, known as theta-cycle phase precession. However, the organization of information by theta-cycles, was still missing in the larger population of neurons.

"Without input from CA3, there was no global organization of neural signals across theta cycles to define where the mouse came from or where it went."

Thomas McHugh PhD

In 2014, the Nobel Prize in Physiology or Medicine was awarded for the discovery of the mental map of space found recorded in the hippocampus. The circuitry connecting the ensemble of place cells is also used for memory processing, but how neural ensembles update in realtime wasn't identified.

Without input from the CA3 hypocampal region, accurate prediction of spatial location received from this ensemble of neural coding regions, was haphazard. The mouse still knew where it was in space, but there were small errors in the representation of that space coming from individual neurons. The number of errors became compounded without CA3's direction.

"If neurons don't activate [synapses] in sequence, you can't organize memories across time. Whether in mice or humans, you need temporal organization to get from here to there, to make decisions and reach goals."

Thomas McHugh PhD

If shutting down CA3 were possible in humans, McHugh suggests, memories would become useless jumbles. Earlier work has also pointed to CA3 neurons as organizers of information during our sleep, sleep being a known process required for long-term memory storage.

Disruptions in brain oscillations have been identified in diseases ranging from schizophrenia to Alzheimer's.

With a deeper understanding of how brain rhythms organize information, we might be able to determine the circuit mechanisms underlying these disorders.

In addition to the place-cell rate code, hippocampal area CA1 employs a temporal code, both on the single-cell and ensemble level, to accurately represent space. Although there is clear evidence that this precise spike timing is organized by theta and gamma oscillations that are present in hippocampus, the circuit mechanisms underlying these temporal codes remain poorly understood. We found that the loss of CA3 input abolished temporal coding at the ensemble level in CA1 despite the persistence of both rate and temporal coding in individual neurons. Moreover, low gamma oscillations were present in CA1 despite the absence of CA3 input, but spikes associated with these periods carried significantly reduced spatial information. Our findings dissociate temporal coding at the single-cell (phase precession) and population (theta sequences) levels and suggest that CA3 input is crucial for temporal coordination of the CA1 ensemble code for space.

Middleton SJ, McHugh TJ (2016) Silencing CA3 disrupts temporal coding in the CA1 ensemble. Nat Neurosci. DOI: 10.1038/nn.4311
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Jun 7, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

The human brain, showing the location of the hippocampus,
the frontal lobes, and the medial septum.
Image Credit: Aaron M. White, PhD, Department of Psychiatry, Duke University



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