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Neuromodulation of hippocampal spike timing-dependent plasticity

Supervisors: Ole Paulsen, Tanja Fuchsberger

Spike timing-dependent plasticity (STDP) is a physiologically relevant form of Hebbian learning, in which near coincident pre- and postsynaptic firing induces synaptic plasticity: Long term potentiation (LTP) is induced when the presynaptic spike precedes postsynaptic firing, and long term depression (LTD) when postsynaptic firing precedes the presynaptic spike [1]. However, these plasticity rules are profoundly influenced by neuromodulators [2]. Reward, novelty or surprise are correlated with neuromodulatory signals, such as dopamine, acetylcholine or noradrenaline, which modulate memories and behavioural outcome. They regulate STDP through various mechanisms, as they can control the biophysical properties of dendrites, including the dynamics of spike backpropagation, and can influence the state of kinases and phosphatases implicated in synaptic plasticity (Seol et al., 2007). In our laboratory we recently demonstrated a retroactive effect of dopamine on STDP, which converts LTD into LTP [3].

Typically, in acute brain slices action potentials for STDP induction are evoked by electrical stimulation, which does not allow for controlled release of neuromodulators. In this project we will use optogenetic tools, which provide additional possibilities in the investigation of synaptic plasticity by selective photostimulation of specific neurons. Opsin genes can be expressed in specific brain areas in transgenic animals or can be introduced into specific neuronal populations by viral injection. Targeted and selective light activation of these neurons will then be used to induce plasticity. It has not yet been shown whether optogenetic stimulation alone (without addition of neuromodulators) is sufficient to induce STDP. In the first part of this project STDP protocols will be established that use selective light activation of hippocampal neurons to induce synaptic potentiation or depression. The second part of the project will address specific mechanisms of how neuromodulators influence these plasticity rules, and the third part will explore the roles of these neuromodulators for behavioural learning and memory.

 

Relevant references

Bi GQ and Poo MM (1998) Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. The Journal of Neuroscience 18: 10464–10472.

Seol GH, Ziburkus J, Huang S, Song L, Kim IT, Takamiya K, Huganir RL, Lee HK and Kirkwood A (2007) Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity. Neuron 55: 919–929.

Brzosko Z, Schultz W and Paulsen O (2015) Retroactive modulation of spike timing-dependent plasticity by dopamine. eLife 4: e09685.