Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.

Motor Learning Promotes Remyelination via New and Surviving Oligodendrocytes

“…These data show a clear link between cortical myelin content, neuronal function, and motor behavior. Future work characterizing the cell-type specific changes in neuronal excitability 64 and plasticity 65 , along with circuit-level alterations in excitatory and inhibitory balance within motor cortex 66 will provide insights into the cellular and circuit origins of demyelinationinduced hyperexcitability.…”

Navigating the translational roadblock: Towards highly specific and effective all-optical interrogations of neural circuits

“…In our recent studies, we already applied a rigorous analysis routine to 2-P imaging data. And indeed, this provided an improved platform for testing the efficacy of drug treatments [14,15]. Here, we extend this greatly conservative approach to all-optical physiology.…”

“…Utmost specificity is of crucial importance for applications of all-optical approaches in the context of preclinical research in animal models of neurological disorders. For instance, across different neurological disorders [13][14][15] an early shift of microcircuit activity towards a hyperactive cortical network phenotype has been observed in pre-or asymptomatic phases, and over time these hyperactive network dysregulations itself may lead to neurodegeneration [15]. Although these dysregulations are subtle and include complex changes in the activity of single neurons [16,17], they represent a promising target for preventive, network-based therapy approaches [18,19].…”

“…In this case, using all-optical approaches is not farfetched as the combination of 2-P calcium imaging and 2-P optogenetic stimulation would (a.) allow to detect individual hyperactive neurons [13][14][15] and would (b.) allow to modulate their activity in a highly specific manner, e.g.…”

Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

“…However, such cytokines might well have complex effects, as for example TNF can potentiate existing synaptic connections, and hence contribute to transient hyperactivity of cortical circuits, e.g. during the recovery phase of subcortical neuroinflammation (Ellwardt et al, 2018;Yang et al, 2013). Thus, other 10 confounders, such as age (Confavreux and Vukusic, 2006;Scalfari et al, 2011) or threshold effects of accumulating subtle damage that exhaust repair or compensation capacities (Friese et al, 2014) might contribute to the lasting cortical deficits observed in progressive MS.…”