BMAL1/ARNTL plays a critical, non-circadian role in secondary tissue damage after contusive SCI

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Circadian rhythms regulate a wide spectrum of biological processes of critical importance for organismal health. Perturbations of those rhythms underlie many pathologies including systemic inflammation, depression, and neurodegeneration. Mechanistically, circadian rhythms are driven by intrinsic oscillatory changes in gene expression that are orchestrated by several regulators of gene transcription and mRNA translation forming the core oscillator circuitry. Those key regulators, most importantly the non-redundant transcription/translation factor BMAL1/ARNTL, are active in most cells throughout the body and undergo circadian entrainment by external time cues such as light or feeding. At the organismal level, the pro-rhythmic role of the oscillator is widely recognized as a critical contributor to homeostasis. BMAL1 effects that are independent of the central rhythm include anti-oxidant protection in the brain, life span regulation, contributions to atherosclerosis and endoplasmic reticulum (ER) stress-sensitization of cancer cells. Those, or similar, tissue-specific functions of BMAL1 may affect the outcome after SCI. However, clock function at the molecular level has never been investigated in the context of SCI. Unexpectedly, we found that: (i) moderate contusive thoracic SCI upregulates BMAL1 in penumbral oligodendrocytes (OLs), coinciding with induction of the ER stress response (ERSR)-activated pro-apoptotic transcription factor CHOP and ER stress-mediated apoptosis of OLs, (ii) after SCI, Bmal1-/- mice show improved locomotor recovery and white matter sparing (WMS), as well as selective downregulation of Chop and its pro-apoptotic target gene death receptor 5 (Dr5) and reduced blood extravasation and inflammation, with extensive changes in microglia/macrophage (MM) and endothelial (EC)- specific gene expression. Also, pharmacological enhancement of the negative feedback inhibition of BMAL1 reduces ER stress toxicity in OPC cultures. These exciting findings suggest a novel role of BMAL1 in the pathogenesis of SCI which may include OL-cell autonomous regulation of CHOP-mediated OL apoptosis and/or EC/MM-cell autonomous modulation of post-SCI hemorrhage/vascular dysfunction/cytotoxic neuro- inflammation. Therefore, we will test the hypothesis that BMAL1 regulates OL, EC, and/or MM gene expression that contributes to SCI-associated white matter loss and impaired locomotor recovery. To test this hypothesis, we will: (i) determine the cell autonomous roles of OL-, MM-, and EC-BMAL1 in SCI-associated white matter damage and locomotor recovery, (ii) identify mechanism(s) that underlie BMAL1-mediated enhancement of SCI-driven white matter loss, and (iii) evaluate mediators of the negative feedback inhibition of BMAL1 as pharmacological targets for interventions to reduce SCI-associated white matter loss and locomotor impairment. We will use a moderate T9 SCI contusion model in wild type or cell type-selective Bmal1-/- mice and non-toxic, CNS-permeable drugs targeting the feedback regulation of BMAL1. This research may uncover novel, previously unrecognized contributions of BMAL1 to `secondary tissue injury after SCI.