Regulation of hippocampal spike-timing dependent plasticity by endogenous sources of dopamine and BDNF: synergy or distinct mechanisms?

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Unimpaired learning and memory processes are important for a normal behavior of an individual. Neuroscientists are therefore interested in understanding memory related brain functions. To understand how the brain works, scientist focus on cellular processes involved in learning and memory. Cellular engrams of memory are thought to be formed by long-term changes in synaptic efficacy of neurons, which are called either long-term potentiation (LTP) in case of a long-lasting increase of synaptic transmission or long-term depression (LTD) resulting from decreased synaptic transmission between neurons. In order to prevent a general over-excitation or over-depression of the brain, additional compensatory homeostatic plasticity mechanisms are engaged to keep the brain in a beneficial mode of activity. The hippocampus (HIP) and especially the CA1 region are central brain regions or areas involved in learning and memory processes. In our grant application, we will study the role of physiologically highly relevant spike timing-dependent plasticity (STDP) protocols in synaptic plasticity in the HIP. We focus on STDP paradigms which have been shown to occur in in vivo situations and will pinpoint how neuromodulators like brain-derived neurotrophic factor (BDNF) or dopamine (DA) influence this type of hippocampal synaptic plasticity. Our experiments will determine whether different stimulation patterns engage distinct signaling cascades and subsequent expression mechanisms. To this aim we will apply pharmacological and optogenetic approaches and read out the resulting effects on synaptic plasticity with electrophysiological recordings. Furthermore our project is focused on the time constrains of neuromodulatory actions and we ask whether neuromodulators act at certain, specific time points during LTP or LTD. Parallel experiments will address the role of compensatory homeostatic plasticity mechanisms. Since it is known that different sub-regions of the HIP are involved in different memory functions, we will study regional differences in efficacy of STDP and neuromodulation. The experiments will be rounded up by solving the still open question how DA is delivered to the HIP and whether the ventral tegmental area is the actual source of hippocampal DA. In the last part of our experiments we will confirm key findings on the DA and BDNF-dependent regulation of STDP also in paired recordings of unitarily connected CA3-CA1 pyramidal neurons.With the help of the proposed experiments we will collect information about neuromodulatory functions and possible regional differences in in vivo like synaptic plasticity in the HIP. With these data we should be able to better understand how different signaling cascades act either independent or in concert to form memory traces. Additionally, our results will provide insights into the multitude of ways for activity-dependent potentiation and depression phenomena contributing to learning and memory processes.