Hippocampal Plasticity, Representation and Memory during Stress

Hippocampal Plasticity, Representation and Memory during Stress

The capability to store and consciously recall past experiences is crucial for survival and establishing a coherent sense of reality. This ability in mammals is dependent on the hippocampal formation, which encodes experience through coordinated neuronal activity enabling memory acquisition and recall. Our group is interested in the cellular mechanisms underlying the hippocampal ability to encode experience and memory. Furthermore, we are interested in how stress response impairs such an ability leading to temporary and permanent memory impairment.

We use intravital optical imaging as the main tool to study neuronal plasticity and experience representation in the hippocampus of mice performing hippocampal-dependent tasks. We also take advantage of molecular and genetic tools to investigate defined synapses and neuronal subpopulations and manipulate the activity of defined neuronal populations. Together, these tools enable us to investigate the interplay between cellular events and learning in the hippocampal formation going from molecular mechanisms to network-level computation.

How does synaptic plasticity of CA1 pyramidal neurons enable learning and memory in vivo and how does stress influence this process?

It is widely assumed that synapses are a basic substrate of memory. While two-photon imaging is casting light on the relationship between learning and synaptic turnover in the neocortex, such a relationship is still obscure in the hippocampus. Our lab aims at establishing a direct link between synaptic plasticity and learning in vivo in the hippocampal CA1, and to examine how stress influences this function through some of its established molecular mediators. To this aim, we use optical imaging of dendritic spines in the basal aspect of hippocampal CA1 (Fig. 1) to in vivo investigate long-term synaptic turnover (Fig. 2) learning to perform a memory task that requires the hippocampus.

Long-term tracking of the same synapses or cells in behaving mice permits for longitudinal studies of the same individuals in different conditions, e.g., prior and after stress or prior and after downregulation/overexpression of specific molecular effectors. This greatly increases statistical power and, importantly, allows direct correlations between molecular, cellular and behavioral phenotypes in the same animal.

How does hippocampal plasticity affect the neural codes underlying representation of experience in CA1?

CA1 representations of the same environment are not stable but turn over with time. We are interested in cellular mechanisms of such turnover and in particular on the influence of regions presynaptic to CA1 on such turnover. To investigate how activity of upstream hippocampal regions affects stability of CA1 representation we probe turnover of CA1 representations repeatedly over long periods of time by in vivo chronic optical imaging by two complementary means: in vivo Immediate Early Gene (IEG) imaging (Fig. 3) or Ca2+ imaging (Ghosh et al., 2011; Ziv et al., 2013) (Movie). We combine long-term imaging of CA1 representations with optogenetic control of CA3 and EC neurons to probe the influence of these presynaptic regions on CA1 representations.

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