Memory, Alzheimer’s Dynamic Mechanisms Revealed in New Study

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by Charles Moore |

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A study newly published in the journal Nature Neuroscience reveals that activity within the memory-oriented brain region of the hippocampus is in fact bidirectional, a key observation that could fuel new advancements into Alzheimer’s research.

williamssThe study, entitled Reversal of theta rhythm flow through intact hippocampal circuits,” (Nature Neuroscience (2014) doi:10.1038/nn.3803) is coauthored by Dr. Sylvain Williams, PhD, and his research team; Jesse Jackson, Bénédicte Amilhon, Frédéric Manseau, andChristian Kortleven at the Research Centre of the Douglas Mental Health University Institute and McGill University, at Montreal, Canada; Romain Goutagny ad Jean-Bastien Bott of Université de Strasbourg-CNRS, Strasbourg, France; and Steven L Bresslerof the Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, Florida; may lead to an increased understanding of how neural circuitry works within the brain, impacting dynamic mechanisms that control memory and the role that the subiculum, a major component of the hippocampus, plays in brain health and cognition.

In 2009, the researchers developed an in vitro preparation of a hippocampal formation. Now, Dr. Williams’s research team has been successful in further demonstrating via a mouse model that memory activity within the hippocampus region of the brain does not flow unidirectionally, a revelation that reverses nearly one hundred years of established science.

In the Nature Neuroscience paper, the coauthors note that activity flow through the hippocampus is thought to arise exclusively from unidirectional excitatory synaptic signaling from CA3 to CA1 to the subiculum, and that Theta rhythms are important for hippocampal synchronization during episodic memory processing; thus, it is assumed that theta rhythms follow these excitatory feedforward circuits.

However, to the contrary, the research team found that theta rhythms generated in the rat subiculum flowed backward to actively modulate spike timing and local network rhythms in CA1 and CA3. They observed that this reversed signaling involved GABAergic mechanisms. However, when hippocampal circuits were physically limited to a lamellar slab, CA3 outputs synchronized CA1 and the subiculum using excitatory mechanisms, as predicted by classic hippocampal models.

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Finally, their analysis of in vivo recordings revealed that this reversed theta flow was most prominent during REM sleep — these data demonstrating that communication between CA3, CA1 and the subiculum is not exclusively unidirectional or excitatory and that reversed inhibitory theta signaling also contributes to intrahippocampal synchrony.

memory flowPerspectives on the Flow of Memory

“Memories form the very core of our identity,” notes a Douglas Mental Health University Institute release, but despite this, creation and retrieval of memories are phenomena that are not yet well understood. The neural circuitry underlying learning and memory are studied primarily because of their fundamental role in memory and diseases affecting it, such as Alzheimer’s.

The work of Dr. Williams and his team in the last few years has been concerned with understanding the dynamics of this circuitry, and while it’s established that processes of memory encoding and retrieval require the activation of hundreds of thousands of neurons in the hippocampus working together synchronously, we still know very little about the circuits or “routes” underlying these processes.

Consequently, greater understanding how neurons of the hippocampus behave will provide powerful insights into anomalies in neural circuitry involved in Alzheimer’s disease and schizophrenia and will lead to more targeted interventions.

“It is only by identifying these circuits as well as their dynamic within the hippocampus that we will understand the mechanisms responsible for memory,” says Dr. Williams. “Moreover, a better comprehension of the intricate dynamics of these circuits could be used to identify very early changes indicating the development, or future development, of Alzheimer’s disease. Indeed, we have recent results that show that, in mouse models of Alzheimer’s, these small alterations can appear long before memory loss.”

This recent research was able to be undertaken thanks to optogenetics, a revolutionary technique which offers the unique capability to manipulate specific groups of neurons with light to better understand their role in neural circuits and brain rhythms.

Dr. Williams and his team are pursuing several complementary lines of study aimed towards discovering the neural circuits underlying learning and memory. For example, they have developed a unique approach using a complete hippocampus formation preparation in vitro in combination with electrophysiology, immunohistochemistry and molecular biology, to reveal which neurons can generate brain oscillations.

Moreover, they have also developed optogenetics, which offers the unique capability to manipulate specific groups of neurons with light to better understand their role in neural circuits and brain rhythms. They also developed a special interest in determining the role of identified neurons in freely behaving animal during learning and memory.

Together, these research approaches promise to shed light on how memory processes can become disrupted ultimately giving rise to the development of Alzheimer Disease.

The Douglas Institute

The Douglas Mental Health University Institute is a world-class facility affiliated with McGill University and the World Health Organization. It treats people suffering from mental illness and offers them both hope and healing. Its teams of specialists and researchers are constantly increasing scientific knowledge, integrating this knowledge into patient care, and sharing it with the community in order to educate the public and eliminate prejudices surrounding mental health.

Douglas Institute researchers are particularly interested in the identification and prevention of dementia the elderly. The topics they are exploring are listed here:

Douglas Mental Health University Institute
Nature Neuroscience

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Douglas Mental Health University Institute