Research finds key molecules involved in forming long-term memories
How does one's experience of an event get translated into a memory that can be accessed months, even years later? A team led by University of Pennsylvania scientists has come closer to answering that question, identifying key molecules that help convert short-term memories into long-term ones. These proteins may offer a target for drugs that can enhance memory, alleviating some of the cognitive symptoms that characterize conditions including schizophrenia, depression and Parkinson's and Alzheimer's diseases.
Joshua Hawk, now a postdoctoral research fellow at Yale University, led the study, which was conducted as part of his Ph.D. work in the Neuroscience Graduate Group at Penn. He worked with Ted Abel, Penn's Brush Family Professor of Biology. Additional Penn team members were Shane Poplawski, Morgan Bridi, Allison Rao, Michael Sulewski and Brian Kroener. The Penn researchers collaborated with Angie Bookout and David Manglesdorf of the Howard Hughes Medical Institute and the University of Texas Southwestern Medical Center.
"There are many drugs available to treat some of the symptoms of diseases like schizophrenia," Abel said, "but they don't treat the cognitive deficits that patients have, which can include difficulties with memory. This study looks for more specific targets to treat deficits in cognition."
Published in the Journal of Clinical Investigation, the study focused on a group of proteins called nuclear receptors, which have been implicated in the regulation of a variety of biological functions, including memory formation.
Nuclear receptors are a kind of transcription factor, proteins that can bind to DNA and regulate the activity of other genes. Their regulatory role may be significant in memory formation, as gene transcription is required to turn short-term memories into long-lasting ones by strengthening neuronal synapses in the brain.
To identify how this class of transcription factors figures in memory formation, the research team trained mice using a common method to create memories of a place and event, in which animals learn to associate a particular context or a certain tone with a specific experience. Associations with a place or context are believed to be encoded in the hippocampus, while memories associated with a cue such as a tone are believed to be encoded in the amygdala.
In the 24 hours after exposing mice to the initial training, the researchers examined expression patterns of all 49 nuclear receptor genes. They found 13 that increased in expression in the hippocampus in the first two hours after training. Included in this group were all three members of a class of nuclear receptors called Nr4a. Nr4a genes had previously been found to increase in expression upon use of a memory-enhancing class of drugs called histone deacetlylase inhibitors, or HDAC inhibitors.
The scientists next created a transgenic mouse in which they could selectively block the activity of the three Nr4a genes.
"Having the transgenic mouse is very useful," Hawk said. "We can manipulate it so that the Nr4a genes will only function in certain brain regions and then see how the mouse's memory-forming ability is affected."
When the researchers exposed the mice to the training context a second time, they found that the transgenic mice had reduced memory of the location where the training took place—memories that are located in the hippocampus—compared to normal mice. In contrast, the mutant mice's amygdala-associated memories of a cue—the tone played during training—remained intact.
"The mice had impairment for contextual memory, which means something in the hippocampus is affected," Abel said. "That is the type of memory that goes away in Alzheimer's and schizophrenia."
The research team also showed that the mutant mice's short-term memory was not impaired. When trained in short-term memory tasks, their performance ranked similarly to their normal siblings.
In addition, the scientists confirmed that Nr4a genes play a role in long-term memory storage by injecting the Nr4a-deficient mice with HDAC inhibitors, which have been shown to enhance memory in normal mice. The treatment did not enhance the memory-forming ability of the mutant mice, suggesting that the drug acts upon the Nr4a genes to boost long-term-memory storage.
Finally, the researchers screened mice for molecules that act "downstream" of Nr4a and could be part of the signaling cascade by which those nuclear receptors help create long-term memories. They found two genes, Fosl2 and Bdnf1, that appeared to be downstream targets of Nr4a genes and also increased in expression following treatment with an HDAC inhibitor.
"Finding these targets is promising in terms of new drug development," Abel said. "Most drugs for schizophrenia, depression and some other neurological disorders now target neurotransmitter systems and can have affects on many systems. In this case, we would change gene expression much more specifically."
"The more selective we can get for the pathway that's enhancing memory," Hawk said, "the more likely we can find effective drugs."
Journal reference: Journal of Clinical Investigation
Provided by University of Pennsylvania
- Scientists ID gene key to Alzheimer's-like reversal May 06, 2009 | not rated yet | 0
- Cancer drug enhances long-term memory Jun 05, 2007 | not rated yet | 0
- Mutation improves memory, may lead to memory-enhancing pill Apr 05, 2007 | not rated yet | 0
- Neuroscientists pinpoint brain site for rapid learning Oct 23, 2006 | not rated yet | 0
- Cancer drug may improve memory in Alzheimer's patients Sep 07, 2009 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
- More from Physics Forums - Medical Sciences
More news stories
Trends in Helicobacter pylori (H. pylori) and smoking explain a significant proportion of the decline of intestinal-type noncardia gastric adenocarcinoma (NCGA) incidence in US men between 1978 and 2008, and are estimated ...
Medical research 14 hours ago | not rated yet | 0
Widely available in pharmacies and health stores, phosphatidylserine is a natural food supplement produced from beef, oysters, and soy. Proven to improve cognition and slow memory loss, it's a popular treatment for older ...
Medical research 18 hours ago | 5 / 5 (3) | 0 |
Researchers at Emory University have identified a protein that stimulates a pair of "orphan receptors" found in the brain, solving a long-standing biological puzzle and possibly leading to future treatments for neurological ...
Medical research 19 hours ago | 5 / 5 (1) | 0 |
Australian scientists have charted the path of insulin action in cells in precise detail like never before. This provides a comprehensive blueprint for understanding what goes wrong in diabetes.
Medical research 19 hours ago | 4.6 / 5 (7) | 0 |
Researchers at the University of Illinois at Chicago College of Medicine will study gender differences in how the heart uses and stores fat—its main energy source—and how changes in fat metabolism play ...
Medical research 22 hours ago | not rated yet | 0
(AP)—The mayor of Portland, Ore., has conceded defeat in an effort to add fluoride to the city's drinking water.
24 minutes ago | not rated yet | 0
(AP)—Alabama health officials say a mysterious respiratory illness has left five people hospitalized and two dead in the southeastern part of the state.
4 minutes ago | not rated yet | 0
Is it permissible to harm one to save many? Those who tend to say "yes" when faced with this classic dilemma are likely to be deficient in a specific kind of empathy, according to a report published in the scientific journal ...
2 hours ago | not rated yet | 0 |
Phthalates: Study links chemicals widely found in plastics, processed food to elevated blood pressure in children, teens
Plastic additives known as phthalates (pronounced THAL-ates) are odorless, colorless and just about everywhere: They turn up in flooring, plastic cups, beach balls, plastic wrap, intravenous tubing and—according to the ...
3 hours ago | not rated yet | 1 |
(Medical Xpress)—Native peoples in regions where cameras are uncommon sometimes react with caution when their picture is taken. The fear that something must have been stolen from them to create the photo ...
19 hours ago | 4.2 / 5 (5) | 0 |