Neural Circuits and Gliocomputation

Non-neuronal cells in the brain, such as microglia, astrocytes, NG2 glia, oligodendrocytes, pericytes, smooth muscle cells, and endothelial cells are each individual systems that receive complex input from the local brain tissue environment to produce signals that influence the nearby environment, including neurons1,2. Whereas neurons are much easier to study because their activity can be blindly captured with an electrode without ever visualizing the cell1, non-neuronal cells in the brain are much more difficult to study. These non-neuronal cells are often studied in vitro or ex vivo separated from their intact environment3-7, which limits the ability to understand how these different cells orchestrate complex interactions to produce synergistically enhanced functionality and performance. Two major technical advancements have enabled the study of glial and neurovascular cells in new ways. 1) advancements in in vivo optical imaging8,9, and 2) advancements in transgenic tools and genetically encoded indicators10. My lab incorporates a multimodal approach using these advancements to study neuronal and non-neuronal cells, such as oligodendrocytes11. This allows us to examine non-neuronal cell and neuronal subtype activity in their native environments and investigate integrated and synergistic processes that coordinate network activity, as well as understand how specific injuries and disease pathways have downstream effects on neural networks.

Although oligodendrocytes have been well established for their role in myelinating axons, early characterization was done under ex vivo and in vitro environments3-7. As a result, it has been dogmatized that the main purpose of myelination was to increase conduction velocity and enhance action potential timing. From a neurocomputational perspective however, this rationalization was unsatisfactory to explain activity-dependent myelination and why many axons remain unmyelinated. It was clear oligodendrocytes must play a neurocomputational role given profound behavioral and cognitive deficits associated with oligodendrocyte diseases. We took advantage of hypermyelination/hypomyelination animal models to determine the neurocomputational role of oligodendrocytes using laminar microelectrode arrays in the sensory cortex and a subcortical area called ‘CA1 hippocampus’.

This is the first investigation into the role of glial cells on neurocomputation of sensory cortical circuits in vivo. We found that in early stages of oligodendrocyte and myelin depletion there was no difference in neuronal loss or sensory-evoked action potential conduction velocity; however, there was significant loss in the ability of cortical neurons to maintain elevated firing rate activity in the presence of sustained sensory-input (>400 ms)12. Demyelination did not significantly impact latency of the first evoked action potential12, but greatly impacted the ability of neurons to sustain activity12. This makes sense because neurons are unable to metabolically sustain the energy cost of repolarizing the entire length of the axon when under constant rapid activation. Myelination reduces the ionic flux that occurs during action potential generation, which reduces the amount of metabolic cost (ATP) to power the Na/K Pumps to repolarize the membrane during periods of sustained elevated firing rate13. The metabolic cost for maintaining myelin (myelin lipid and protein production) is relatively high14, therefore, evolutionarily speaking, it makes sense to only make the metabolic investment to make myelin on axons with high metabolic activity where metabolic savings are maximized. We next investigated if this energy saving had an impact on sensory neurocomputation.

1)    We used Clemastine, a muscarinic receptor antagonist, to promote oligodendrogenesis and myelination. The advantages of Clemastine are that it targets oligodendrocytes specific signaling pathways mediated by the muscarinic receptors15, molecular mechanisms of gene regulation in oligodendrocyte are partly elucidated16, and it is effective on human NG2-glia, enhancing translational significance. The scientific premise is that Clemastine indirectly improves the health and activity of nearby neurons through oligodendrocytes. We showed that continuous administration of Clemastine starting 7 days prior to microelectrode implantation improved neuronal activity and better preserved inhibitory neuronal activity and neurocomputational capacity in the cortex, but not CA117.

2)    We found that conditionally knocking-out Fused in Sarcoma (FUS) in oligodendrocytes (FUSOLcKO) led to enhanced myelination of small diameter axons and improved persistence of hippocampal CA1 neuronal activity compared to wild-type controls. This finding was particularly surprising because prior studies with long-term implantation of microelectrode arrays were often met with degradation of electrophysiological recordings around 4-6 weeks; this severely limits memory and placidity studies that try to record from the same neurons over months. Most in vivo electrophysiological studies of CA1 have been carried out by reinserting electrodes each day, which limits recording from the same exact neurons every day or limits experimental design to studies that can be completed in 2-4 weeks. Our findings show that it is possible to study memory and plasticity if oligodendrocytes are treated.

Future Directions:

Taken together, we showed that depleting oligodendrocytes lead to faster fatiguing of sensory cortex neural activity in the presence of sustained sensory input, and enhanced oligodendrocyte activity led to preservation of inhibitory computational tone (clemastine) and hippocampal neuronal activity (FUSOLcKO). This opens up additional questions such as why do the muscarinic receptor pathway and the FUS pathway have different impacts in the cortex and CA1? Oligodendrocytes have long been hypothesized to primarily myelinate long excitatory axons, but growing evidence shows substantial myelination of inhibitory parvalbumin neurons. How does oligodendrocyte-excitatory neuron and oligodendrocyte-inhibitory neuron activity impact neurocomputation?

Oligodendrocytes as a neurocomputational unit only represents one of the non-neuronal cells we are actively investigating. In the interest of space, the investigation into other cell types are not detailed in this proposal. Other non-neuronal cells are also important because oligodendrocyte-neuron activity is heavily integrated with astrocytes, NG2-glia, microglia, pericytes, and metabolic activity. Our work heavily implicates metabolism as the key role for oligodendrocytes in neurocomputation. From a neurocomputational perspective, myelination increases the computational weights of the underlying axon’s computational processes while demyelination reduces those capacities, especially for sustained activity. Unlocking new understanding on the contribution of oligodendrocyte (and other non-neuronal cell) dysfunction to excitation-inhibition imbalance and psychiatric disorder treatment strategies can help many individuals in the coming decade. This is especially true since oligodendrocyte dysfunction has been implicated in many other mental illness and psychiatric disorders, like major depression, autism, anxiety18. It is anticipated that the list of conditions involving oligodendrocyte dysfunction will grow as sequencing studies continue to expand. In this way, targeting oligodendrocyte activity and other non-neuronal cells has the potential for significant impact on our understanding of mental illnesses and can contribute to the development of treatments and cures for multiple psychiatric conditions.

Reference

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11.    Chen, K., Wellman, S.M., Yaxiaer, Y., Eles, J.R. & Kozai, T.D. In vivo spatiotemporal patterns of oligodendrocyte and myelin damage at the neural electrode interface. Biomaterials 268, 120526 (2021).

12.    Wellman, S.M., et al. Cuprizone-induced oligodendrocyte loss and demyelination impairs recording performance of chronically implanted neural interfaces. Biomaterials, 119842 (2020).

13.    Rosko, L., Smith, V.N., Yamazaki, R. & Huang, J.K. Oligodendrocyte bioenergetics in health and disease. The Neuroscientist 25, 334-343 (2019).

14.    Harris, J.J. & Attwell, D. The energetics of CNS white matter. Journal of Neuroscience 32, 356-371 (2012).

15.    Li, Z., He, Y., Fan, S. & Sun, B. Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination. Neuroscience Bulletin 31, 617-625 (2015).

16.    Liu, J., et al. Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice. J Neurosci 36, 957-962 (2016).

17.    Chen, K., Cambi, F. & Kozai, T.D.Y. Pro-myelinating Clemastine administration improves recording performance of chronically implanted microelectrodes and nearby neuronal health. bioRxiv, 2023.2001. 2031.526463 (2023).

18.    Nazeri, A., Schifani, C., Anderson, J.A., Ameis, S.H. & Voineskos, A.N. In vivo imaging of gray matter microstructure in major psychiatric disorders: Opportunities for clinical translation. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging (2020).