Title : Addition associated engram cells as therapeutic targets of addiction
Abstract:
Norman M. White employed the theory of learning and memory to explain the mechanism of drug addiction. Base on his theory, we can understand addiction as a kind of memory that associates a feeling of euphoria with the use of a substance or a certain behavior. Memory engram cells are a group of intermediate neurons that associate with different events and represent a percept, memory, or concept in brains. Memory engram technology can label and manipulate the specific memory engram cells. Cocaine addiction associated engram cells have been found in the mice brains. When these engram cells were abolished or suppressed, the addictive behavior was significantly relieved. Thus, selectively eliminating the memory engram associated with addiction, i.e. eliminating the association between euphoric sensation and drug use, may be an effective treatment of addiction.
Synaptic pruning plays an important role to remove unnecessary neuronal connection from the developing and mature brains. The process of synaptic pruning implicates activation of pro-apoptotic caspases, the proteasome-ubiquitin pathway, repulsive guidance cue signaling, and growth-promoting signaling, etc. Elimination of addiction associated memory may be achieved by activating the synaptic pruning process in the addiction associated engram cells. Hereon, a gene therapy framework is proposed to achieve this goal.
Step 1. The design of the gene transfer system: firstly, this system should be able to identify the engram cells under a “turn on” situation. Secondly, the system can initiate synaptic pruning process in the target engram cells. Temporal specificity of labeling is achieved by the exogenously controlled gene regulation systems (turn on), such as tetracycline, rapamycin, RU486. Memory engram technology which is based on the experimental fusion of immediate early gene, such as c-foc, arc, that can be used to identify the engram cells. The transcription factor CREB and ΔFosB are also related to addiction associated memory, they could be used to identify the engram cells, too.
Step 2. Location of the gene delivery sites: It has been reported that the hippocampus mediates contextual control of drug self-administration, the dorsal striatum mediates stimulus–response habitual responding for drug reinforcement, and the amygdala mediates conditioned drug seeking. Regarding to different situations of addictive patients, it is necessary to determine the appropriate sites of brain for gene therapy.
Step 3. Identification of the special mental state: to identify the engram cells associated with addiction, the subjects must be in a particular mental state, such as the onset of drug addiction or a euphoric state after drug use. In this particular mental state, the targeted immediate early gene shall be expressed in the engram cells that is associated with addiction. Meanwhile, the exogenously controlled gene regulation system is turned on, so that these engram cells are recognized and future pruning mechanism is activated to erase the addiction associated memory.
In summary, this proposal suggests that the addition associated engram cells could be used as therapeutic targets for addiction, and the gene therapy techniques that combines memory engram technology and synaptic pruning will be used to erase the addiction associated memory.
