Neuromodulatory and astrocyte influences on hippocampal place cell plasticity

Project Summary/Abstract The role of astrocytes in circuit function, particularly with respect to neural plasticity, has been explored but is debated. One excellent brain area to study neural plasticity is the hippocampus, since it has neurons that represent cognitively relevant dimensions of the world that change in a behaviorally relevant manner. The hippocampus contains place cells that represent locations in the environment, and show reorganized restructuring relevant to behavior, for example at a reward location. This occurs during goal-oriented learning (GOL) tasks in mice. Dopamine (DA) is a good candidate neuromodulator to influence reward-related remapping, since it is known to affect the stability of place cells. The source of DA in the hippocampus was recently shown to be the locus coeruleus (LC), which also releases norepinephrine (NE). The role of the LC during GOL is unknown. NE and DA released from the LC during learning could act directly on neurons, but it could also influence astrocytes. Astrocytes in cortex respond to NE with large changes in calcium levels, but this has not been examined in the hippocampus. These calcium responses may cause alterations in neural network function. This proposal will examine 1) the activity of LC projections to the hippocampus and astrocyte calcium during GOL 2) the relationship between LC axon activity and astrocyte calcium, 3) the LC?s effect on reward-related place cell remapping, 4) and whether the LC?s effect on place cells requires intact astrocyte calcium. I hypothesize that LC activity causes place cell shifts toward the reward zone via its effects on astrocyte calcium levels. I will examine these questions using two-photon calcium imaging in awake, behaving mice. A better understanding of the relationship between neuromodulation, astrocyte function, and neural plasticity will generate new theories about circuit function and pathology.