ABSTRACT
Myelination increases the conduction velocity in long-range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement-related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike-time arrivals through long-range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.
Subject(s)
Action Potentials/physiology , Learning/physiology , Motor Cortex/metabolism , Nerve Fibers, Myelinated/metabolism , Neurons/metabolism , Psychomotor Performance/physiology , Animals , Male , Mice , Mice, Transgenic , Motor Cortex/chemistry , Myelin Sheath/metabolism , Nerve Fibers, Myelinated/chemistry , Neurons/chemistry , Optogenetics/methodsABSTRACT
Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.
Subject(s)
Blood-Brain Barrier/metabolism , Cerebrovascular Circulation/immunology , Endothelial Cells/metabolism , Lupus Erythematosus, Systemic/immunology , Microglia/immunology , Animals , Astrocytes/immunology , Astrocytes/metabolism , Blood-Brain Barrier/diagnostic imaging , Blood-Brain Barrier/immunology , Claudin-5/immunology , Claudin-5/metabolism , Disease Models, Animal , Endothelial Cells/immunology , Humans , Intravital Microscopy , Male , Mice , Microglia/metabolism , Permeability , Phagocytosis/immunology , Receptors, CCR5/immunology , Receptors, CCR5/metabolism , Stereotaxic Techniques , Tight Junctions/immunology , Tight Junctions/metabolismABSTRACT
Microglia are highly motile immunoreactive cells that play integral roles in the response to brain infection and damage, and in the progression of various neurological diseases. During development, microglia also help sculpt neural circuits, via both promoting synapse formation and by targeting specific synapses for elimination and phagocytosis. Microglia are also active surveyors of neural circuits in the mature, healthy brain, although the functional consequences of such microglia-neuron contacts under these conditions is unclear. Using in vivo imaging of neurons and microglia in awake mice, we report here the functional consequences of microglia-synapse contacts. Direct contact between a microglial process and a single synapse results in a specific increase in the activity of that contacted synapse, and a corresponding increase in back-propagating action potentials along the parent dendrite. This increase in activity is not seen for microglia-synapse contacts when microglia are activated by chronic lipopolysaccharide (LPS) treatment. To probe how this microglia-synapse contact affects neural circuits, we imaged across larger populations of motor cortical neurons. When microglia were again activated by LPS (or partially ablated), there was a decrease in the extent to which neuronal activity was synchronized. Together, our results demonstrate that interactions between physiological or resting microglia and synapses in the mature, healthy brain leads to an increase in neuronal activity and thereby helps to synchronize local populations of neurons. Our novel findings provide a plausible physical basis for understanding how alterations in immune status may impact on neural circuit plasticity and on cognitive behaviors such as learning.
