Retrograde and anterograde trans-synaptic viral tracing of neuronal connections reveals local and distant effects of ischemic stroke on dendritic spines

Focal stroke leads to complex neurological disturbances with variable recovery. One explanation for this variability is that stroke disrupts local and remote neural circuits via the connectome, termed 'diaschisis'. Past studies have yielded mixed effects of stroke on dendritic structure in distant regions. However, a previous limitation was the lack of sampling specifically from neurons directly connected to those within the infarct. To overcome this, we used retrograde and anterograde trans-synaptic AAVs to examine dendritic spine density in neurons that provide inputs to, or receive outputs (pre- and post-synaptic) from primary forelimb somatosensory cortex at 1 or 6 weeks after stroke. For both pre- and post-synaptic neurons, spine density was generally lower in superficial and deep neurons in peri-infarct and motor cortex at 1 week, which recovered by 6 weeks. By contrast, no changes in spine density were observed in ipsilateral secondary somatosensory (S2) or contralateral primary somatosensory cortex at 1 week, although there was an increase in spines in select S2 neurons at 6 weeks. Our data show that some cortical connections are more disrupted by stroke than others, particularly those in peri-infarct and motor cortex which could serve as an important substrate for stroke recovery and future therapies.