New research shows that cocaine, defeat stress, the rapid-acting antidepressant ketamine, and learning and memory can change the size, shape, or number of spines on the dendrites of neurons. Dendrites conduct electrical impulses into the cell body from neighboring neurons.
Several researchers, including Peter Kalivas at the Medical University of South Carolina, have reported that cocaine increases the size of the spines on the dendrites of a certain kind of neurons (GABAergic medium spiny neurons) in the nucleus accumbens (the reward center in the brain). This occurs through a dopamine D1 selective mechanism. N-acetylcysteine, a drug that can be found in health food stores, decreases cocaine intake in animals and humans, and also normalizes the size of dendritic spines.
Depression in animals and humans is associated with decreases in Rac1, a protein in the dendritic spines on GABA neurons in the nucleus accumbens. Rac1 regulates actin and other molecules that alter the shape of the spines.
In an animal model of depression called defeat stress, rodents are stressed by repeatedly being placed in a larger animal’s territory. Their subsequent behavior mimics clinical depression. This kind of social defeat stress decreases Rac1 and causes spines to become thin and lose some function. Replacing Rac1 returns the spines to a more mature mushroom shape and reverses the depressive behavior of these socially defeated animals. Researcher Scott Russo has also found Rac1 deficits in the nucleus accumbens of depressed patients who committed suicide. Russo suggests that decreases in Rac1 are responsible for the manifestation of social avoidance and other depressive behaviors in the defeat stress animal model, and that finding ways to increase Rac1 in humans would be an important new target for antidepressant drug development.
Another animal model of depression called chronic intermittent stress (in which the animals are exposed to a series of unexpected stressors like sounds or mild shocks) also induces depression-like behavior and makes the dendritic spines thin and stubby. The drug ketamine, which can bring about antidepressant effects in humans in as short a time as 2 hours, rapidly reverses the depressive behavior in animals and converts the spines back to the larger, more mature mushroom-shape they typically have.
Learning and Extinction of Fear
Researcher Wenbiao Gan has reported that fear conditioning can change the number of dendritic spines. When animals hear a tone paired with an electrical shock, they begin to exhibit a fear response to the tone. In layer 5 of the prefrontal cortex, spines are eliminated when conditioned fear develops, and are reformed (near where the eliminated spines were) during extinction training, when animals hear the tones without receiving the shock and learn not to fear the tone. However, in the primary auditory cortex the changes are opposite: new spines are formed with learning, and spines are eliminated with extinction.
Editor’s Note: It appears that we have arrived at a new milestone in psychiatry. In the field of neurology, changes seen in the brains of patients with strokes or Alzheimer’s dementia have been considered “real” because cells were obviously lost or dead. Psychiatry, in comparison, has been considered a soft science because neuronal changes have been more difficult to see and illnesses were and still are called “mental.” Now that new technologies have made a deeper level of precision, observation, and analysis possible, we know that the brain’s 12 billion neurons and 4 times as many glial cells are exquisitely plastic–capable of biochemical and structural changes that can be reversed using appropriate therapeutic maneuvers.
The changes associated with abnormal behaviors, addictions, and even normal processes of learning and memory now have clearly been shown to correspond with the size, shape, and biochemistry of dendritic spines. These subtle, reproducible changes in the brain and body are amenable to therapeutic intervention, and are now even more demanding of sophisticated medical attention.
As young mice transition into adolescence, they experience a “sensitive” period in which their context-based fear memories are temporarily suppressed. In a recent study, young animals learned to avoid an environment associated with a mild shock. Later, when they entered adolescence, this learning was temporarily forgotten or suppressed. However, when the same mice aged into adulthood, they reacquired this learned fear memory and began to again avoid the environment associated with the earlier shock. This temporary loss of fear memory differs in mice depending on their genes.
At the 2012 meeting of the Society of Biological Psychiatry, researcher Francis S. Lee reported that mice with a certain genetic variation display an impairment of this fear memory process. There are several common variants of the gene responsible for the production of brain-derived neurotrophic factor (BDNF), which protects neurons and is necessary for long-term memory. Mice with the poorer functioning variant known as Val66Met (as opposed to the better functioning Val66Val) fail to recall the earlier fear-related events not only in adolescence, but also in adulthood when the fear memory is usually retrievable again.
Editor’s Note: In mice and humans, Val66Val is the most frequently occurring allele in the population, but Val66Met is also a fairly common variation of the BDNF gene. It is this Val66Met allele that is associated with not retaining earlier learned experience about a “dangerous” environment that should be avoided.
These data suggest an intriguing explanation for some of the “wild” behavior and poor judgment to which even the smartest adolescents are prone. This kind of behavior may be based in part on the temporary forgetting in adolescence of earlier learning about which situations or environments are safe versus which ones are dangerous. Read more
Opening The Reconsolidation Window to Extinguish Fear Memories: A New Conceptual Approach to Psychotherapeutics
Memory processes occur in several phases. Short-term memory is converted to long-term memory by a process of consolidation that requires the synthesis of new proteins. Transcription factors in the nuclei of hundreds of millions of nerve cells are activated so that specific synapses can be modified for the long term. If protein synthesis is inhibited during a period within a few hours after new learning has occurred, what was learned never gets consolidated and is essentially forgotten. It is thought that this phase of consolidation happens when a memory trace moves from short-term storage in the hippocampus to long-term storage in the cerebral cortex.
Recently a later phase of memory storage called reconsolidation has been identified. When an old memory is recalled, the reconsolidation window opens, and the memory trace becomes temporarily amenable to change. The reconsolidation window (the period during which the trace can be revised) is thought to begin five minutes after a memory is recalled and last for an hour or possibly two. New learning that takes place during the reconsolidation window can be more profound than learning that occurs without recall of the related memory or after the reconsolidation window has closed.
Consider the example of a fearful memory created when a person is attacked in a dark alley. If the person repeatedly visits the same alley without being attacked, they can eventually become less afraid of dark places. Repeated viewing of pictures of dark places can also extinguish the fear. These are typical ways in which a fear memory is extinguished. However, the original fear is subject to spontaneous recovery (the fear of dark places returns without provocation) or to reactivation (if another dangerous situation is encountered, the person may regain their fear of dark alleys).
The new findings suggest that if the extinction process (the repeated exposures to the pictures of the dark alley) takes place during the reconsolidation window after the fear memory of being attacked is recalled, the old fear can be permanently reversed (wiped clean, or re-edited such that it appears forgotten) so that it is no longer subject to spontaneous recovery or reactivation.
Editor’s Note: To accomplish extinction training within the reconsolidation window, first a person must actively recall the old memory, opening the reconsolidation window. Then, after a 5-minute delay, extinction training (e.g. new learning that the old feared place is now safe) should take place within the next hour. This process has been demonstrated in animal studies and is thought to be clinically relevant for humans in the case of phobic anxiety and post-traumatic stress disorder (PTSD). The psychotherapeutic implications of using the reconsolidation window to better ameliorate PTSD fears, avoidance, and flashbacks are enormous.
Observing the Amygdala’s Role in the Extinction of Fear Memory Traces
The amygdala is a crucial part of the learned or conditioned fear pathway. It is activated during fear conditioning and during the recall of cues associated with the fear experience. If the amygdala is removed, conditioning fear does not occur.
A new study published in Science this year by Agren et al. indicates that in humans, the amygdala-based response to conditioned fear can be completely abolished using extinction training within the memory reconsolidation window. Training that took place 10 minutes after the fear memory was activated was successful, while training that took place 6 hours later was not. Read more