Unravelling the Role Cortical Myelination Plays in Higher Brain Functions
by Swati Subramanian
Date of Examination:2021-02-09
Date of issue:2021-07-07
Advisor:Prof. Dr. Klaus-Armin Nave
Referee:Prof. Dr. Silvio Rizzoli
Referee:Prof. Dr. Nils Brose
Persistent Address:
http://dx.doi.org/10.53846/goediss-8448
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Abstract
English
Myelination is a process within the nervous system, where axons are ensheathed by lipid-rich, multi-spiral wraps called myelin. Its main role is to expedite impulse propagation within circuitries and allow for faster saltatory conduction at excitatory regions called the nodes of Ranvier by helping their formation. It begins prior to birth and continues well into adulthood, in humans. At every stage from infancy to adulthood, this process plays a crucial role in both physically and functionally shaping neuronal circuits. Despite being discovered centuries ago, its involvement in forming, fine-tuning and maintaining circuits has only taken centre stage in the recent years. A key question is whether myelinated axons are inherently less plastic, less prone to make new connections with other neurons. To address this question we studied the role of myelin in critical periods. In mice, central nervous system (CNS) myelination peaks between 4 and 8 weeks of age, and overlaps with brief windows of developmental experience-dependent plasticity, called critical periods. The functional role of this overlap is not well understood: is myelin closing the plasticity associated with critical periods? Is it part of the process? Whether this role is permissive or inhibitory is still debatable. To understand the role of myelination in critical periods I chose handedness as a test model. Handedness is established during childhood, when myelination is still progressing, and is dependent on a functional corpus callosum. The corpus callosum is a fibre path that connect both hemispheres and is heavily myelinated in adults. Previous studies in the lab have shown that adult mice lacking myelin do not show paw lateralization. First, to characterize the development of paw lateralization, I tested young wild type mice between 4 and 8 weeks of age using the paw preference behavioural paradigm. I found that wild type mice typically become lateralized by 8 weeks of age. To further assess whether myelination is important for this establishment, I tested young mutant mice lacking compact myelin in the CNS. While these mice are less lateralized than wild type, initially, with practice they become as lateralized as wild type mice. Their handedness, however, in contrast to that of wild type mice, tends to be unstable from test to test during this period. However, this is not observed in adult mice. To address the specific role of the corpus callosum in the establishment of handedness, I generated and tested mice 2 lacking compact myelin in the forebrain and, surprisingly, found no evidence of impairment in lateralization. The forebrain-specific dysmyelinated mice were of particular interest because they can be used to study the role of cortical myelination in higher cognitive functions. In a collaborative effort, colleagues tested these mice for a plethora of behavioural domains such as anxiety, social behaviour, motor deficits, sensorimotor gating, vision, hearing, catatonia and executive function, and found no deficits, except for mild signs of catatonia at older time-points. That too was no longer present at the latest time-point they were tested. Moreover, mice with a complete dysmyelination of the CNS tend to develop seizures that prove fatal at a very young age. Unlike in these mice, forebrain-specific dysmyelination does not affect the lifespan of the mice and hence may provide an interesting insight into adaptations within circuitries and gross morphology of a brain-region surviving without compact myelin. I characterized the general morphology of the mutant mice and found that, interestingly, these mice do not suffer from any major neuropathology or any obvious physiological shortages. Overall, the data suggests that lack of myelin in the CNS does not prevent apparent development of lateralization in childhood. That the observed lateralization is not stable suggests that this is not ‘true’ lateralization in the sense we understand it in humans, as a person’s trait but rather has a more functional and temporally local characteristic. Myelin, therefore, is crucial in the development of handedness and concomitantly plays a role over the critical period, preventing its closure. Interestingly, unlike mice without any myelin and trained only in adulthood, mice lacking myelin only in the forebrain and part of the corpus callosum had normal lateralization. Moreover, I introduce two new mouse models that lack compact myelin specifically in the forebrain to investigate the role of cortical myelination and its heterogeneity in higher brain functions.
Keywords: Myelination; Oligodendrocytes; PawPreference