Contribution of hippocampal diaschisis to the memory deficits associated with focal cerebral ischemia in the rat: converging behavioral, electrophysiological and functional evidencedécembre 2015 Directeur(s) de thèse : Bruno BONTEMPI Résumé de thèse
The cognitive consequences and the underlying mechanisms leading to cognitive impairments after cerebrovascular occlusive diseases are still unclear. In addition to the infarct zone that suffer the deadly consequence of ischemic stroke, the penumbra surrounding the lesion site and some brain regions more remote to the ischemic areas can be functionally affected by the insult. This phenomenon is referred to as diaschisis. In light of the importance of interactions between hippocampus and cortex during memory processing, we hypothesized that the cognitive impairments observed following focal ischemia could occur in the absence of direct hippocampal insult, possibly via impaired connectivity within cortico-hippocampal networks leading to diaschisis-induced hypofunctioning in specific hippocampal subregions. To examine this possibility, we used the distal middle cerebral artery occlusion (dMCAO) ischemic model in rats which induces restricted cortical infarct in the somatosensory (SS) cortex in the absence of direct hippocampal injury. dMCAO rats exhibited reduced expression of the activity-dependent gene c-fos in the hippocampus when exploring a novel environment, indicating neuronal hypoactivation. Ischemic rats also showed impaired associative olfactory and spatial memory when tested in the social transmission of food preference (STFP) task and the Barnes maze test, respectively. To confirm that the ischemic-induced hippocampal hypofunctioning resulted from reduced afferent inputs (i.e. deactivation) originating in the damaged cortex, we performed region-specific pharmacological inactivation of SS and/or HPC using lidocaine or CNQX. Fos imaging revealed that these treatments induced hippocampal hypoactivation and impaired memory performance as measured in the STFP task. We additionally performed electrophysiological recordings of hippocampal activity in anesthetized rats during acute stroke and two weeks later or after SS cortex inactivation. We found an alteration in the occurrence of sharp-wave ripples associated with instability of theta frequency during reperfusion after stroke and SS cortex inactivation, suggesting an alteration in the dynamics of hippocampal-cortical interactions. Taken collectively, these findings identify hippocampal diaschisis as a crucial mechanism for mediating stroke-induced hippocampal hypofunction and associated memory deficits.
Key words: spatial memory, associative memory, ischemic stroke, hippocampal oscillations, c-fos, rat