Losing our memories

Memory loss that accompanies normal aging is primarily a deficit in working memory, due to changes in the prefrontal cortex. It includes absent-mindedness, a shortened attention span, and a decreased ability to hold a thought. This slower, less-precise working memory is a nuisance, but by itself it does not signal the beginning of a degenerative disease, and it is not inevitable. Although memory generally declines with age, some octogenarians retain better working memories than people in their twenties.

Pathological amnesias, on the other hand, differ from regular, age- related memory loss. They occur in either of two main forms: retrograde and anterograde. Retrograde amnesia is the loss of memories of the past. A person who experiences physical trauma to the brain or an electroconvulsive shock may forget his past while retaining the ability to create new memories.

Most of us and Hollywood associate the term amnesia with this form, although its occurrence is rare. When it does happen, memories of the recent past are more likely to be lost than older ones. The extent of the loss varies from events that happened just some seconds back to those that occurred several years ago, depending on the strength of the learning and the severity of the disruption.

Anterograde amnesia is the inability to create new memories. The patient is trapped in an ever-present "now"--whether meeting with the same people or experiencing a recurrent event, he regards them as being new and novel, over and over again. He still has memories from before onset of the amnesia, but he cannot add to them. Common causes of this kind of memory loss include trauma, stroke, viral encephalitis, and Alzheimer's disease. All of them damage the hippocampus, which lies deep on both sides of the brain. Thiamine deficiency experienced by some chronic alcoholics also produces anterograde amnesia, by creating lesions in parts of the brain known as the mammillary bodies and the medial thalamus.

Every time we perceive something, a unique set of brain cells is activated in a specific sequence. If not pursued, the perception fades and the cells return to their original state. If the thought is entertained, the relationship between these cells is strengthened. The transmission of signals through synapses becomes easier between these cells than between cells that do not have this relationship. The set of cells with facilitated synapses is now the anatomical correlate of the memory and is called a memory engram. Once the engram is formed, anything that activates it will revive the original perception as a memory. If allowed to lie dormant for too long, this relationship dissolves and so does the memory.

Synapses between neurons that produce the neurotransmitter dopamine in the prefrontal cortex are responsible for working memory. The hippocampus of the temporal lobes is responsible for consolidating or solidifying the memory. Every time the memory engram is activated, the hippocampus facilitates the synapses and strengthens the relationship between neurons in the circuit.

Memory consolidation can occur consciously, by repetition, but it usually occurs unconsciously, by the action of the hippocampus. The latter is more likely to happen when the experience is novel, has emotional significance, or relates to something we already know. The more the engram is activated, the stronger the memory. This facilitation involves electrical, biochemical, and anatomical changes.

Most long-term memories are physically consolidated (recorded) somewhere in the 100 billion nerve cells of the brain. Initial facilitation is based on changes in the long-term electrical potentials of cells and modification of preexisting proteins. Important neurotransmitters responsible for these changes include glutamate and nitric oxide.

Stronger facilitation requires the expression (turning on) of certain genes and the synthesis of new proteins. These events produce anatomical changes in cells, including the sprouting of new branches and the creation of new synapses.

Among the substances important for this growth is a peptide called BDNF (brain-derived neurotrophic factor). New research has shown that the brain also grows new cells in response to learning. In other words, our experiences can restructure our brains.

Brain regeneration, memory genes, smart pills

Brain cell growth.For decades it has been considered a fundamental truth that adult brains never grow new cells. But one of the most exciting recent discoveries in memory research is that neurons do multiply. Recent work with monkeys has shown that new cells are constantly being made in the hippocampus, the part of the brain that consolidates long-term memories. Experts believe that this is true for human brains as well.

If we can discover how to control this intrinsic ability of the brain, we would be able to create new cells to replace dead or degenerating ones. This knowledge could lead to new treatments for stroke, trauma, or degenerative brain diseases such as Parkinson's and Alzheimer's.

Memory genes. In the 1970s, Seymour Benzer found that a particular genetic mutation in a fruit fly caused it to become a "dunce." Several years ago, Tim Tully and Jerry Yin at Cold Spring Harbor Laboratory (on Long Island in New York) developed a "smart" fruit fly by stimulating the same gene (CREB) that was mutated in Benzer's fly. CREB functions as a master switch that unlocks dozens of other genes important for the consolidation of memory. It is like a general contractor, who controls the work crews that actually do the remodeling of the synapses to create memories. Based on past experience, the CREB gene probably occurs in humans, too. But there are at least 23 other genes known to affect memory, and researchers have yet to find ways to turn on these genes selectively in the brain.