Brain circuits can be structurally rearranged with experience, and synaptic connections can grow and be eliminated, even in adults. We have shown that activity at specific inputs can lead to the production of new proteins, promoting either long lasting growth of single spines, or cooperation and competition between multiple synapses following potentiation. The balance between such interactions during structural plasticity can be the basis for plasticity at the circuit level, which allows for the rewiring of inputs within a dendritic domain. However, in order to be able to achieve such reorganization, mechanisms for strengthening co-active inputs as well as those that would achieve weakening and elimination of inputs would be required. The synthesis of new proteins is crucial for the long term storage of information, long lasting synaptic potentiation and structural plasticity. Of interest, this is also necessary for long lasting forms of synaptic depression, while much less is understood about the bidirectional regulation of structural plasticity. In addition to these Hebbian plasticity processes, additional forms of plasticity, such as homeostatic modulation, impact the plasticity capacity of dendritic branches. Homeostatic plasticity can scale synaptic currents, as well as spine structures, and can interact with Hebbian plasticity to elicit plasticity at non active neighbors. In addition, neurons receive diverse patterns of activity at their inputs, and it is unknown how these effect structural plasticity, or whether they are more or less likely to be subject to complex integration between co-active inputs. Therefore, using two-photon imaging and glutamate uncaging to stimulate and monitor plasticity at single spines or defined groups of spines, we will investigate the relationship between different forms of plasticity and spine structural changes. Specifically, we will determine whether synaptic depression can be induced at single inputs, what are the structural outputs of this form of plasticity, and whether protein synthesis dependent depression at multiple inputs can undergo competition. Further, we will investigate the structural plasticity rules of interactions between different forms of activity, such as Hebbian and homeostatic plasticity, when they coincide within a dendritic domain at multiple inputs. Beyond these forms of plasticity, we will also investigate non-regular patterns of activity, that follow instead a Poisson distribution, in order to build an understanding of how individual inputs process a diversity of activity, how they integrate this with events at co-active neighbors, and what are the structural correlates of these forms of plasticity. These experiments will allow us to investigate with unprecedented precision at the molecular, subcellular and circuit level the dynamics of synaptic interactions, and how they contribute to the building and refinement of neural circuits necessary for cognitive function.
Information is believed to be encoded at the cellular level through alterations in synaptic weights, and changes in connections between neurons are correlated with structural modifications of spines, such as growth or elimination. Additional forms of plasticity also impinge on these structures, such as homeostatic modulation of synaptic strength. In this proposal, we will use two-photon imaging and glutamate uncaging to test a variety of plasticity mechanisms at individual spines and between groups of spines, to understand with high precision how information is physically stored in the brain.
