Traumatic Brain Injury-related voiding dysfunction in mice is caused by damage to rostral pathways, altering inputs to the reflex pathways

Abstract

Brain degeneration, including that caused by traumatic brain injury (tBI) often leads to severe bladder dysfunction, including incontinence and lower urinary tract symptoms; with the causes remaining unknown. Male C57BL/6J mice underwent repetitive moderate brain injury (rmdTBI) or sham injury, then mice received either cis p-tau monoclonal antibody (cis mAb), which prevents brain degeneration in TBI mice, or control (IgG). Void spot assays revealed age-dependent incontinence in IgG controls 8 months after injury, while cis mAb treated or sham mice showed no dysfunction. No obvious bladder pathology occurred in any group. Urodynamic cystometry in conscious mice revealed overactive bladder, reduced maximal voiding pressures and incontinence in IgG control, but not sham or cis mAb treated mice. Hyperphosphorylated tau deposition and neural tangle-like pathology occurred in cortical and hippocampal regions only of IgG control mice accompanied with post-traumatic neuroinflammation and was not seen in midbrain and hindbrain regions associated with bladder filling and voiding reflex arcs. In this model of brain degeneration bladder dysfunction results from rostral, and not hindbrain damage, indicating that rostral brain inputs are required for normal bladder functioning. Detailed analysis of the functioning of neural circuits controlling bladder function in tBI should lead to insights into how brain degeneration leads to bladder dysfunction, as well as novel strategies to treat these disorders. Overactive bladder, incontinence and other bladder symptoms often occur in patients with neurodegenerative disease or brain injury, and can lead to significant debility, striking loss of self-esteem, depression, and the need for long term institutionalization 1-4. At present the mechanisms by which neurodegenerative diseases lead to severe bladder dysfunction remain entirely unclear. Although severe or/and moderate injuries most frequently sustained from single events falls, assaults, or roadside traffic accidents, which can lead to early death and profound disability 5,6 , military and sport-related injuries have received increasing attention in the past decade 7-10. Military-based brain injuries result in several

Chronic traumatic encephalopathy—a blueprint for the bridge between neurological and psychiatric disorders

“…Differences often occur in the duration and time between impacts across different models 110 . Importantly, many models also observe the long-term effects post injury, an important factor in trying to replicate CTE as a neuropathology [111][112][113] . Because of the similarity in the results of these established models, more research is needed to determine what factors induce pathological changes, including the type of mechanical force, injury frequency, and severity of injury.…”

Cystometric Measurements in Rats with an Experimentally Induced Traumatic Brain Injury and Voiding Dysfunction: A Time-Course Study

“…In the present study, results indicated that the RV was remarkably and significantly increased in TBI rats compared to that of NC rats. The PMC plays a crucial role in bladder inhibitory actions [8], and when this center is no longer intact, detrusor hyperreflexia occurs. Two PMCs are respectively responsible for bladder contractions and relaxation, which have reciprocal inhibitory effects.…”

“…In the acute stage of TBI, the common cognitive outcomes are decreased speed of information processing, attention problems, and confusion and in the chronic stage the outcomes extend to dizziness, sleep disturbance, anxiety, and depression. This chronic condition leads to the risky state of post-concussive syndrome [7,8]. Numerous methods are used to analyze outcomes of a TBI such as the fluid percussion model [9], weight-drop model (WDM) [10], controlled cortical-impact (CCI) model [11], and so on.…”

Tau nuclear translocation is a leading step in tau pathology process through P53 stabilization and nucleolar dispersion

“…Males are more susceptible to TBI consequences than females (Taylor et al, 2017), and in light of previous research (Albayram et al, 2017; Albayram et al, 2019; Guilhaume‐Correa et al, 2020; Kondo et al, 2015; Kondo, et al, 2015; Taylor et al, 2017; Xiong et al, 2013), we focused on adult male animals to obtain more thoughtful results. The animals were housed and cared for according to the protocol approved by the Royan Institutional Animal Care and Ethical Committee (IR.ACECR.ROYAN.REC.1397.233) in conformity with the National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals.…”