Research finds key molecules involved in forming long-term memories
September 10, 2012 in Medical research
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
-
Why is zone 1 in liver more prone to ischemic injury?
3 hours ago
-
How can there be villous adenoma in colon, if there are no villi there
23 hours ago
-
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013
-
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013
-
If you became brain-dead, would you want them to pull the plug?
May 17, 2013
-
MRI bill question
May 15, 2013
- More from Physics Forums - Medical Sciences
More news stories
Baby's life saved with groundbreaking 3-D printed device that restored his breathing
Every day, their baby stopped breathing, his collapsed bronchus blocking the crucial flow of air to his lungs. April and Bryan Gionfriddo watched helplessly, just praying that somehow the dire predictions ...
Medical research
13 hours ago |
5 / 5 (2) |
0
Research shows how immune system peacefully co-exists with 'good' bacteria
The human gut is loaded with commensal bacteria – "good" microbes that, among other functions, help the body digest food. The gastrointestinal tract contains literally trillions of such cells, and yet the ...
Medical research
17 hours ago |
5 / 5 (3) |
0
|
Slowing the aging process—only with antibiotics
Swiss scientists reveal the mechanism responsible for aging hidden deep within mitochondria—and dramatically slow it down in worms by administering antibiotics to the young.
Medical research
17 hours ago |
4.9 / 5 (9) |
1
|
How healthy are you for your age?
On May 22, JoVE will publish details of a technique to measure the health of human genetic material in relation to a patient's age. The method is demonstrated by the laboratory of Dr. Gil Atzmon at New York's Albert Einste ...
Medical research
21 hours ago |
not rated yet |
0
A molecular explanation for age-related fertility decline in women
(Medical Xpress)—Scientists supported by the National Institutes of Health have a new theory as to why a woman's fertility declines after her mid-30s. They also suggest an approach that might help slow ...
Medical research
22 hours ago |
not rated yet |
0
|
US teen birth rate drops to record low
US teen births have dropped to a record low, but the country still has one of the highest rates among developed nations, the US Centers for Disease Control and Prevention said Thursday.
Researchers complete largest genetic sequencing study of human disease
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
Brain can be trained in compassion, study shows
Until now, little was scientifically known about the human potential to cultivate compassion—the emotional state of caring for people who are suffering in a way that motivates altruistic behavior.
Rate of bicycle-related fatalities significantly lower in states with helmet laws
Existing research shows that bicyclists who wear helmets have an 88 percent lower risk of brain injury, but researchers at Boston Children's Hospital found that simply having bicycle helmet laws in place showed a 20 percent ...
Having both migraines, depression may mean smaller brain
(HealthDay)—Migraines and depression can each cause a great deal of suffering, but new research indicates the combination of the two may be linked to something else entirely—a smaller brain.
Novel approach for influenza vaccination shows promise in early animal testing
A new approach for immunizing against influenza elicited a more potent immune response and broader protection than the currently licensed seasonal influenza vaccines when tested in mice and ferrets. The vaccine ...
Sep 10, 2012
Rank: 5 / 5 (1)
Sep 11, 2012
Rank: not rated yet
That would be beautiful, wouldn't it? I look forward to such a day, when this becomes a reality.
Sep 11, 2012
Rank: 1 / 5 (1)