Local field potentials identify features of cortico-hippocampal communication impacted by stroke and environmental enrichment therapy

Abstract

Objective. Cognitive and memory impairments are common sequelae after stroke, yet how middle cerebral artery (MCA) stroke chronically affects the neural activity of the hippocampus, a brain region critical for memory but remote from the stroke epicenter, is poorly understood. Environmental enrichment (EE) improves cognition following stroke; however, the electrophysiology that underlies this behavioral intervention is still elusive. Approach. We recorded extracellular local field potentials simultaneously from sensorimotor cortex and hippocampus in rats during urethane anesthesia following MCA occlusion and subsequent EE treatment. Main results. We found that MCA stroke significantly impacted the electrophysiology in the hippocampus, in particular it disrupted characteristics of sharp-wave associated ripples (SPW-Rs) altered brain state, and disrupted phase amplitude coupling (PAC) within the hippocampus and between the cortex and hippocampus. Importantly, we show that EE mitigates stroke-induced changes to SPW-R characteristics but does not restore hippocampal brain state or PAC. Significance. These results begin to uncover the complex interaction between cognitive deficit following stroke and EE treatment, providing a testbed to assess different strategies for therapeutics following stroke.

Pathological changes of brain oscillations following ischemic stroke

“…Contrary to its known benefit on synaptic plasticity and cognition, EE unexpectedly lowers the levels of h-c coupling in the hippocampus. 49 Via mechanisms that are currently unknown, these results suggest there is a reduction of information flow between the corticohippocampal networks for both stroke and EE groups. Our results begin to uncover the complex interaction between stroke and EE, albeit further studies in awake animals are warranted to validate these findings and determine the underlying mechanisms.…”

“…During SPW-R firing, current through the CA1 field of the hippocampus as measured by current source density analysis, revealed pairs of dipoles with the apparent source centered in the pyramidal layer and the sink in the radiatum. Following dMCAO, the strength of the current dipole increases above baseline at two weeks and then decreases below at one month 49 (Figure 5). Thus, it appears there is a compensatory hyperactivity as a result of stroke that peaks at two weeks after stroke, followed by frequency-specific normalization or restoration to pre stroke level around one month post stroke.…”

“…47 Disturbance of physiological ripple oscillation has been reported after experimental stroke during acute and chronic phases. 48,49 Apart from ischemic stroke, changes in SPW-Rs are also observed in murine neurodegenerative disease models. For example, diminished ripple occurrence rates were found in aged mice with human Apolipoprotein E4 knocked in, 50 which led to the loss of hilar GABAergic interneurons, 51 while rTg4510 transgenic mice, a model of tauopathy and dementia, had reduced inhibitory control of the hippocampal network and smaller amplitude-SPW-R. 52 Therefore, a well-orchestrated action between excitation and inhibition is required for the normal physiological function of SPW-R since synchronous activation of excitatory pyramidal cells and certain classes of inhibitory GABAergic interneurons are necessary for SPW-R generation.…”

“…EE mitigated the stroke induced increase to SPW-Rs signal power and decreased its duration, suggesting that EE counterbalanced the excitatory and inhibitory networks disrupted by stroke. 49 Although prolonging SPW-R via optogenetic stimulation of the CA1 neurons reportedly also improved the memory performance, 54 further studies are needed to understand the optimal SPW-R duration for memory function to differentiate the effects of stroke and EE on the increased duration of SPW-R.…”

“…An increased current difference was detected at 2 weeks after dMCAO (2 WS) and dissipated at 1 month after stroke (1MS). Modified from Ip Z et al, figure 4 49.…”