When a memory is formed in the brain, connections are strengthened between neurons requiring transcription of genes that are dependent upon CREB, a transcription factor that binds to DNA and regulates gene expression. However, this gene expression need not occur in every neuron involved in the memory but only in a subset of the neurons. How is a neuron selected to participate in a memory trace? Jin-Hee Han and colleagues from the University of Toronto, Canada demonstrate in a recent Science article that neuronal selection during memory formation is not a random process but depends upon the neuron's relative CREB activity at the time of learning, such that a neuron with relatively high CREB activity would be selected over a neighboring neuron with low CREB activity. These data indicate that neuronal competition plays an important role not only in development but in the adult brain as well.
Mice deficient in CREB have difficulty learning to fear a tone that was previously associated with a foot shock. To find out how many neurons need CREB in order to form a memory, the team took CREB-deficient mice and micro-injected a viral vector expressing CREB into the lateral amygdala, a brain area essential for learning this task. This `viral' CREB is capable of initiating gene transcription in infected neurons.
In order to visually track which neurons were infected with the viral vector, the team fused CREB to a green fluorescent protein (CREB–GFP). They found that the mice could form a memory associating the tone with a foot shock even though only ∼18% of neurons glowed, showing that they were infected by CREB–GFP. This clearly shows that CREB is only required in∼ 18% of neurons of the lateral amygdala to form this memory.
In order to show that those neurons infected with CREB–GFP were the same neurons that were recruited to the fear memory trace, the authors looked for neurons that were positive for RNA of the activity-dependent gene, Arc, which is transcribed when neurons fire. Arc RNA found in the nucleus acts as a molecular marker, showing that a neuron was active in the preceding 5–15 min. The authors demonstrated that neurons containing Arc RNA were also positive for CREB–GFP. Thus, the neurons that had increased CREB function were the ones that were activated and recruited to form the fear memory trace.
What happens if you decrease CREB function in ∼18% of neurons in a mouse that has normal CREB levels to begin with? Nothing; there were no memory impairments in this scenario because the remaining neurons with intact CREB function were able to out-compete the CREB-deficient neurons for inclusion in the memory trace. The authors propose that, during learning, neurons are selected to participate in a memory trace as a function of their relative CREB activity at that time. These findings could offer an explanation of why emotionally arousing stimuli result in such strong memories for associated cues. Stress activates the noradrenergic system, and the stress hormone norepinephrine activates CREB, meaning that emotionally arousing stimuli may cause CREB activity to increase in more neurons and prime them for memory selection.
- © The Company of Biologists Limited 2007