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Abstract

Chronic stress is associated with impairments in learning and memory, as well as changes in dendritic structure and synaptic connections of the hippocampus, a brain region key for spatial and episodic learning and memory. However, the cellular- and circuit- level mechanisms by which stress-induced structural synaptic changes impair learning and memory are not yet clear. Structural changes have historically been studied mostly by ex vivo preparations, due to the necessity to sacrifice the subjects to quantify structural changes. This approach however, is limited in its temporal resolution and lacks the ability to study the dynamic response to stress within the same subjects. This is important because responses to stress and learning and memory are intrinsically dynamic processes and individuals may differ in their baseline dynamics based on a host of uncontrollable factors.
In order to overcome these drawbacks, I employed deep brain 2-photon in vivo time lapse optical imaging to longitudinally study the dorsal hippocampal CA1 region in live mice. I used a transgenic mouse model where a green fluorescent protein targeted to the cytoplasm sparsely labels a subset of excitatory neurons (Thy1-GFPm line). This enabled me to visualize the structure and the spines ? protrusions on the dendrites where most of the excitatory synapses of excitatory neurons occur ? of CA1 pyramidal neuron?s basal dendrites, further allowing me to track structural synaptic changes upon multi-modal stress (MMS). MMS involves exposure of mice to multiple simultaneous stressors.
In this work, I tracked synaptic dynamics over two weeks during baseline and acute and repeated MMS by deep brain 2-photon in vivo time lapse optical imaging of groups of Thy1-GFPm mice. This enabled me to investigate ? for the first time in vivo ? stress-induced changes in CA1 synaptic dynamics.
With this approach I was able to determine that MMS results in disruption of homeostatic structural plasticity. In addition I found that MMS strongly alters dynamics of immature synapses by decreasing their survival. Conversely, recovery increased the survival of spines born after stress, demonstrating higher survival rates in comparison to internally controlled baseline survival.
In addition, I observed that stress increased the distance between newly formed spines and decreased the distance between lost spines, supporting spatially modulated alterations.
Finally, I investigated the extent to which acute MMS and recovery and repeated MMS impair CA1 dependent learning and recall by using the Morris Water Maze (MWM) spatial learning paradigm and observed an impairment in learning in both stress groups.
Understanding how stress impacts the dynamics of synapses is important to elucidate the basic mechanisms by which stress impairs learning and memory and it will be important for the development of therapeutic interventions both in terms of time scales and targets.