Traumatic brain injury induced motor deficits: novel neural and muscular mechanisms

Marlene Storm Andersen

Research output: ThesisPh.D. thesis

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Abstract

Traumatic brain injury (TBI) is one of the leading causes of adult disability, causing structural damage todifferent brain regions and thus resulting in motor impairments, which manifests as e.g., postural asymmetry.The motor impairments greatly affect the activity of daily life, however there is still no effective treatment torecover the motor functions. It is believed that one of the reasons for motor impairments are plastic changes inthe spinal cord, the mechanism behind is however still mostly unknown and is believed to be multiple. It islikely that the plastic changes of the spinal cord involve changes in the monoamine system, regulation ofneurotransmitters, and changes in reflexes. Brain injury may cause changes in the corticospinal tract, one ofthe major pathways for voluntary motor function, depending on the injury site, leading to reduced projectionsfrom motor cortex to the spinal cord. In addition, TBI could also induce changes in monosynaptic reflexes andpolysynaptic nociceptive withdrawal reflexes (NWRs), which may also play a role for the symptoms of motordeficits. Changes in the opioid system could also influence the postural asymmetry caused by TBI. Dependingon the type of opioids, an administration of specific opioid-agonist can induce postural asymmetry, whilecertain antagonists can reduce it. The serotonin receptors in the spinal cord plays an important role in regulationof motor control and have been shown to have impact on the motor deficits following a spinal cord injury.Similar change may happen following a TBI. Changes in the muscle tissue may be another mechanism ofmotor disfunctions and postural asymmetry. Studies on cerebral palsy, which is also a disorder where thecentral motor pathway has been damaged, showed an increase in the stiffness of the skeletal muscle and anupregulation of laminin and collagen in the extracellular matrix. Whether a TBI causes expression changes ofextracellular matrix in the affected limb muscle is unknown.

The overall aim of this thesis is to increase the knowledge of the plastic changes in the spinal cord and peripheral tissue following a TBI. We want to investigate the formation of postural asymmetry following a TBI and the possible underlying mechanisms, which include changes in the polysynaptic NWRs of the hindlimb, changes of serotonin (5-HT)2A and 2C receptors in the spinal cord, and changes of the extracellular matrix of skeletal muscles in the hindlimbs. In addition, we want to uncover the role of the opioid systems in the formation of hindlimb postural asymmetry following TBI by using different kinds of opioid receptor
antagonist.

In manuscript I, we showed that a TBI induced postural asymmetry of the hindlimbs, created asymmetric changes in the hindlimb NWRs, and increased resistance to stretching in the affected hindlimb. The asymmetric hindlimb posture was retained after complete spinal transection. Furthermore, the TBI results in changes in expression and co-expression pattern of neuroplasticity genes in the lumbar spinal cord.

In manuscript II, we showed that the non-selective opioid antagonist naloxone as well as selective opioid antagonists (naltrindole, nor-binaltorphimine and β-funaltrexamine) blocked TBI-induced formation of hindlimb postural asymmetry. Furthermore, we showed that the administration of naloxone created an asymmetric NWRs between ipis- and contralesional side in brain injured rats. Lastly, we showed that TBI created a dysregulation of opioid gene expression compared to neuroplasticity-related gene expression.

In manuscript III, we showed that the formation of hindlimb asymmetry following a TBI changed over a period of 28 days. Furthermore, a walking test revealed a change in the walking pattern not only in the stride length but also in the paw placement pattern. An investigation of the serotonin 2A and 2C receptors did however not show significant expression changes in TBI rats in comparison with sham-operated rats, indicating that serotonin 2A and 2C receptors do not influence the formation of postural asymmetry by a TBI.

Lastly, in manuscript IV, we found that TBI induced an increase in expression of the extracellular matrix protein laminin in four hindlimb muscles (BP, EDL, PL, and VL) following a TBI. However, no changes were found in the expression of another extracellular matrix protein collagen.

In conclusion, the results show that several mechanisms are involved in the formation of hindlimb postural asymmetry, which include changes of the withdrawal reflexes, opioid and neuroplasticity gene expression in the spinal cord, and expression changes of the extracellular matrix proteins. Moreover, the opioid systems are involved in the formation and maintenance of hindlimb postural asymmetry. Thus, further investigation of the
opioid system may lead to pharmacological therapies through this system.
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Zhang, Mengliang, Principal supervisor
  • Bakalkin, Georgy, Co-supervisor, External person
  • Schouenborg, Jens, Co-supervisor, External person
  • Watanabe, Hiroyuki, Co-supervisor
Publisher
DOIs
Publication statusPublished - 16. Feb 2023

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