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The machinery of memory

Understanding how memories are made, retrieved, and eventually fade over a lifetime is the stuff of poems and song. To medical research, solving the mysteries of memory is even more elusive.


Researchers believe that when making a new memory or storing an old memory — each process involves creating new proteins at the point of synapse, or where one neuron meets another. But forming a new memory or storing an old one, also requires new gene expression (function) in a neuron cell nucleus. The nucleus of a cell is where DNA is stored and genes are "read" establishing a newly changed function on a part of a gene.

Now, researchers at the Perelman School of Medicine (University of Pennsylvania) have identified a key metabolic enzyme working directly within a neuron's nucleus that turns genes on or off as new memories are made. Their findings are published online this week in Nature.

"This enzyme, called acetyl-CoA synthetase 2, or ACSS2, 'fuels' a whole machinery of gene expression in the nucleus of nerve cells to turn on key memory genes after learning.

"We found both direct gene-association of ACSS2 and a role for it in neurons, regulating learning and memory - two completely unanticipated novel discoveries."


Shelley L. Berger PhD, the Daniel S. Och University Professor in the departments of Cell and Developmental Biology and Biology, and Director, the Pennsylvania Epigenetics Program.

"This study provides a new target for neuropsychiatric disorders, such as anxiety and depression, where neuro-epigenetic mechanisms are known to be key," says first author Philipp Mews PhD, a former graduate student in the Berger lab and now a postdoctoral fellow at the Friedman Brain Institute of the Icahn School of Medicine at Mount Sinai in New York City. Mews continues: "We suspect that ACSS2 might [also] play a role in memory impairment in neurodegenerative disorders."

Forming memories involves restructuring the synapse, which involves coordinating expression of a group of memory genes. This involves adding a chemical group in a process called acetylation, where specific spots located on neurons, histone groups, actually open up tightly-wound DNA to make memory genes accessiable or "readable" to encode proteins and secure "memories."

Epigenetic mechanisms in neurobiology — the addition or subtraction of chemical groups which influence how genes are expressed or function — are becoming better understood as scientists discover these regulators of neural functions. In this study using mice, the Penn team has found that ACSS2 binds to memory genes in neurons to directly regulate their acetylation, ultimately controlling the spatial memory of mice.

Researchers found that ACSS2 increases in the nuclei of differentiating neurons, gathering near gene sites with elevated histone acetylation.

At the same time, decreases in ACSS2 lowers acetyl-CoA and acetylation in the nucleus, therefore lowering expression or function of memory genes.


Working in mice, the team found that if the animals' ACSS2 expression (function) was blocked, long-term memory of where objects were placed during a study exercise — was impaired. Low ACSS2 level mice did not investigate a moved object on the second day of a two day trial, while a control group of mice did investigate any moved object. "This is because, without ACSS2, the mice had no molecular path to engage memory genes to lock in where the objects were placed," Mews explains.
The decrease of ACSS2 in specific brain regions impaired the read-out of key genes that function to form new memories or to update old ones.


In the future, Mews and Berger hope to alter this newfound memory pathway to see if they can prevent retention of traumatic memories — or perhaps even erase them. They hope by blocking ACSS2 in the hippocampus, a brain region that processes long-term memory, people who suffer from post-traumatic stress disorder may find relief.

Abstract
Metabolic production of acetyl coenzyme A (acetyl-CoA) is linked to histone acetylation and gene regulation, but the precise mechanisms of this process are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) directly regulates histone acetylation in neurons and spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in the nuclei of differentiating neurons and localizes to upregulated neuronal genes near sites of elevated histone acetylation. A decrease in ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long-term spatial memory, a cognitive process that relies on histone acetylation. A decrease in ACSS2 in the hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a connection between cellular metabolism, gene regulation, and neural plasticity and establish a link between acetyl-CoA generation ‘on-site’ at chromatin for histone acetylation and the transcription of key neuronal genes.

This work was supported by the National Institutes of Health. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.


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Jun 2, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Primary neurons in mouse embryo hippocampus

Primary neurons from hippocampus of a mouse embryo. Axons are GREEN,
nuclei BLUE and ACSS2 is RED, overlaps are pink-purple.
Image Credit: Phillip Mews PhD, Perelman School of Medicine,
University of Pennsylvania.

 


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