The Neural Basis of a Circadian Oscillator Underlying Time Memory

Mice anticipate the time of day that important conditions or events are likely to occur based on their previous experiences with those conditions. They can learn to expect positive (rewarding) or negative (aversive) events. The ability to predict the coming of specific events in its environment (time memory) is crucial for its survival. Current evidence has led to three hypotheses: 1) The clock(s) underlying time memory are located in the dopamine target regions, 2) The hippocampus is a site of cells that register the time of day, and 3) Subpopulations of hippocampal cells that are activated during spatial learning are also responsible for time of day learning. If the same cells that are involved in the formation of spatial memories are also oscillators, then the cells most closely involved in context learning should be the ones most readily phase shifted by a learning experience. Therefore we should be able to distinguish cells linked to specific memories by recording the phase of their circadian rhythms. Using qRT-PCR and ISH, I found that several tissues as a whole do not exhibit shifts of their clocks, particularly, the hippocampus. Instead, behavioral conditioning induced a phase shift in the circadian clock protein PERIOD 2 expression, specifically in the shell region of the nucleus accumbens (NAS) and the dorsal striatum (DS). Next, using the Tetracycline Transactivator Controlled Genetic Tagging of Active Neural Circuits (TetTag) system and ICC, my data suggests that only a few cells in the hippocampus participated in the conditioning. The hippocampal cells whose rhythms were set at the time of conditioning may be critical to the expression of craving. In human health, this research will provide a new perspective on the regulation of craving and as such, will contribute to the development of treatments for drug/substance abuse.Ph.D