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Huitinga, I.

Publications and source records attributed to Huitinga, I..

2 recordsLinked to original sources

Common micro- and macroscale principles of connectivity in the human brain

The brain requires efficient information transfer between neurons and between large-scale brain regions. Brain connectivity follows predictable organizational principles: at the cellular level, larger supragranular pyramidal neurons have larger dendritic trees, more synapses, more complex branching and perform more complex neuronal computations; at the macro-scale, region-to-region connections are suggested to display a diverse architecture with highly connected hub-areas facilitating complex information integration and computation. Here, we explore the hypothesis that the branching structure of large-scale region-to-region connectivity follows similar organizational principles as known for the neuronal scale. We examine microscale connectivity of basal dendritic trees of supragranular pyramidal neurons (300+) across ten cortical areas in five human donor brains (1M/4F). Dendritic complexity was quantified as the number of branch points, tree length, spine count, spine density and overall branching complexity. High-resolution diffusion-weighted MRI was used to construct white matter trees of cortico-cortical wiring. Examining the complexity of the resulting white matter trees using the same measures as for dendritic trees shows multimodal association areas to have larger, more complexly branched white matter trees than primary areas (all p<0.0001) and regional macroscale complexity to run in parallel with microscale measures, in terms of number of inputs (r=0.677, p=0.032), branch points (r=0.790, p=0.006), total tree length (r=0.664, p=0.036) and branching complexity (r=0.724, p=0.018). Our findings support the integrative theory that brain connectivity is structured following similar principles of connectivity at the neuronal and macroscale level, and provide a framework to study connectivity changes in brain conditions at multiple levels of brain organization.

neuroscience

Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory

The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer, and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we further found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by a reduced spike output. Ultimately, we show that these electrophysiological changes were associated with an impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS.

neuroscience