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High-speed mesoscale cortical imaging in mouse reveals altered functional connectivity and activity dynamics in mouse models of chronic stress

University of British Columbia

Stress is a relevant etiological contributor to major mental health conditions, including, but not limited to, major depression. Stress changes brain networks with diverse consequences on arousal, valence systems, cognition, social processes such that the individual’s representation of themselves and the world is altered. Here, I characterize functional networks and changes to activity dynamics that accompany the pathological effects of stress in mouse. I do so using spontaneous activity to align with data collection from human resting state imaging. I capture a wide expanse of dorsal neocortex with millisecond timescale resolution using 1) an acute surgical preparation together with voltage sensitive dye (VSD) incubated over the entire dorsal neocortex and 2) transgenic animals expressing fluorescent sensors (iGluSnFR and GCaMP6s) of neural activity together with chronic cranial windows. I first characterize functional connectivity as measured by zero-lag interregional correlation together with longitudinal real time in vivo sampling of extracellular glutamate signals in conjunction with the chronic social defeat model of stress. This reveals stress susceptibility of a midline network, the murine default mode network, and hyperconnectivity after stress that is selectively restored by the rapid acting antidepressant, ketamine. I then examine how spontaneous cortical dynamics impact faithful representation of external stimuli by isolating a specific set of activity stereotypies resembling sensory experience and processing. Focusing on events resembling limb and whisker sensory experience in spontaneous activity, I show that the occurrence of these motifs has a lasting impact on the magnitude of sensory evoked responses. I further show using multiple models of chronic stress and manipulation of circuitry implicated in negative affect, that these motifs are susceptible to stress and that a dominant motif is upregulated after stress in proportion with emotional behavior. The upregulation of sensory motifs in stressed animals accordingly results in decreased sensory reliability. My data confirms the utility and importance of murine modelling of stress and the potential to identify common and divergent effects of specific stressors, as well as identify putative biomarkers with potential treatment relevance in humans.

Text

2019-01-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/68294

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/