On the stability of dendritic architecture : roles of Nogo receptor 1 and sleep
Authors: Brodin Alvin 
Published: January 2025

<p dir="ltr">The ability of the brain to rewire itself is central to its functioning. This plasticity must be tightly regulated to ensure the stability of memories and maintain normal levels of signalling. This thesis investigates two different systems contributing to the regulation of structural plasticity.</p><p dir="ltr">Nogo receptor 1 (NgR1) is a potent negative regulator of plasticity. First characterised in the setting of central nervous system injury, it is emerging as an important regulator of memory formation as well. Understanding how this system functions and is regulated could offer novel avenues for treatment of common and severe brain diseases.</p><p dir="ltr">In paper I we investigated how Nogo receptor 1 levels influence memory function and structural plasticity. Using transgenic mice, we found that constitutive overexpression of NgR1 impaired performance in the Morris water maze, while constitutive lack of NgR1 impaired novel object recognition. Further, overexpression of NgR1 limited the formation of dendritic spines. This paper adds to the growing evidence for a role for NgR1 in regulating memory formation and structural plasticity.</p><p dir="ltr">Given that NgR1 is strongly expressed in highly plastic brain regions, we hypothesised that there must be ways to bypass the growth inhibition of NgR1 to allow for lasting memory formation. In paper IV we find that a chemical LTP protocol induces rapid downregulation of dendritic NgR1 protein. Conversely, a chemical LTD protocol rapidly upregulates dendritic NgR1 protein. These findings suggest novel ways in which NgR1 levels are dynamically regulated to permit or inhibit memory formation.</p><p dir="ltr">Sleep is a well-conserved and costly behaviour, yet its function remains poorly understood. The synaptic homeostasis hypothesis is an influential theory that proposes that sleep serves to downscale synaptic weights, and several lines of evidence point to plastic changes in dendritic structure occurring during sleep. However, the evidence is conflicted regarding whether sleep results in a net growth or shrinkage of the dendritic tree. This is an important question to elucidate if we are to develop effective treatments for the ill effects of sleep loss.</p><p dir="ltr">In paper II we investigated how CA1 dendritic structure is affected by sleep deprivation. We measured dendritic length and dendritic spine density after 5 h sleep deprivation by gentle handling, and did not find any significant effects. In paper III we looked at the same issue but through a systematic review and meta- analysis. We included 30 studies in the meta-analysis, which were individually small and with high variability We found that current evidence does not indicate an effect on CA1 dendritic structure after 24 h or less of sleep deprivation. Chronic sleep deprivation of 72 h or longer does reduce CA1 spine density and dendritic length, but it remains unclear if this is solely due to sleep loss or to stress associated with the method of sleep deprivation.</p><p dir="ltr">Together, these studies advance our understanding of how structural plasticity is regulated.</p><h3>List of scientific papers</h3><p dir="ltr">I. Tobias E Karlsson, Gabriella Smedfors, <b>Alvin TS Brodin</b>, Elin Åberg, Anna Mattsson, Isabelle Högbeck, Katrin Wellfelt, Anna Josephson, Stefan Brené, Lars Olson. NgR1: A Tunable Sensor Regulating Memory Formation, Synaptic, and Dendritic Plasticity. Cereb Cortex. 2016 Apr;26(4):1804-17. <a href="https://doi.org/10.1093/cercor/bhw007" rel="noreferrer" target="_blank">https://doi.org/10.1093/cercor/bhw007</a></p><p dir="ltr">II. <b>Alvin TS Brodin</b>, Sarolta Gabulya, Katrin Wellfelt, Tobias E Karlsson. Five Hours Total Sleep Deprivation Does Not Affect CA1 Dendritic Length or Spine Density. Front Synaptic Neurosci. 2022 Mar 14;14:854160. <a href="https://doi.org/10.3389/fnsyn.2022.854160" rel="noreferrer" target="_blank">https://doi.org/10.3389/fnsyn.2022.854160</a></p><p dir="ltr">III. <b>Alvin TS Brodin</b>, Franziska Liesecke, Julia Spielbauer, Tobias E Karlsson. Effects of sleep deprivation on dendritic architecture: A systematic review and meta-analysis of rodent studies. [Manuscript]</p><p dir="ltr">IV. <b>Alvin TS Brodin</b>, Julia Spielbauer, Katrin Wellfelt, Lars Olson, Tobias E Karlsson. Localisation and regulation of Nogo-66 receptor 1 during chemical long term potentiation and depression. [Manuscript]</p>