Role of dopamine in hippocampal plasticity and hippocampus-dependent memory

How the brain stores memories is one of the great mysteries in neuroscience. How can we recollect what happened in the past? Scientists believe that memories are stored in the connections between neurons in the brain. These connections are called synapses, and a change in the strength of these connections is known as synaptic plasticity. Whereas synaptic plasticity can account for the immediate storage of information, it is less well understood how different memories are bound together. We have recently discovered a mechanism of synaptic plasticity that can account for such associations over time, with a time scale of many minutes. We have found that activity at a synapse leaves a trace which can be turned into synaptic changes later by activity of the receiver neuron of the synapse if a specific signalling molecule, dopamine, is present. Dopamine is released when we receive an unexpected reward. This mechanism could link together the actions we took prior to the reward with their rewarding outcome, thus making it more likely that we will take the same actions to be rewarded again in the future. Now we want to understand how naturally released dopamine influences synaptic plasticity, whether such release is necessary for new memories to form, and whether dopamine can link memories together. The experiments will be done in a structure in the mouse brain that is known to be important for memory, namely the hippocampus. We will test the hypothesis that release of dopamine is both necessary and sufficient for neuronal activity to convert an initial memory trace into long-term memory. The results of these experiments will be important for our understanding of how memories are linked together. The experiments will give us new insights into memory and could potentially open new avenues for improving our capacity for memory and for treating memory disorder.

The overall aim of this project is to investigate the role of dopamine neurons in hippocampal synaptic plasticity and hippocampus-dependent memory in mice. To this end, we will use a combination of optogenetics and patch-clamp recording in mouse hippocampal slices, and optogenetics, extracellular recording and calcium imaging in freely-moving mice. Briefly, to investigate the conversion of a synaptic eligibility trace into long-term potentiation (LTP) of synaptic transmission in hippocampal slices, we will use a standard Hebbian timing-dependent long-term depression protocol for priming of synapses, followed by postsynaptic action potential bursting activity to induce LTP in individual CA1 pyramidal neurons in the presence of dopamine. Dopamine will be bath applied or released by photolysis of caged dopamine, or by optogenetic release from dopaminergic fibres originating in either the ventral tegmental area (VTA) or the locus coeruleus (LC). To investigate the role of dopamine in hippocampus-dependent memory, we would train the mice in a simple reward-based spatial navigation task (3-arm maze). In one set of experiments, to test for sufficiently, we would replace the reward with optogenetic activation of dopaminergic input fibres from either the VTA or LC. In another set of experiments, to test for necessity, we would use optogenetics to inhibit dopaminergic neurons in the VTA or LC and to prevent the release from dopaminergic input fibres locally in the hippocampus. In a final set of experiments, to test for the requirement of reactivation for learning this task, we would silence hippocampal neurons at the reward location. The results of this study would identify the timing requirement of dopamine release for burst-induced LTP and demonstrate the role of dopaminergic neurons in hippocampus-dependent reward-based spatial learning and to establish whether local release of dopamine in the hippocampus is necessary and sufficient to induce a place preference.