1 INTRODUCTION
Traumatic brain injury (TBI) causes structural damage to multiple brain
regions leading to sensorimotor impairments such as muscle weakness,
spasticity and contractions (Feldman &
Levin, 2016; Jamal, Leplaideur, Rousseau,
Chochina, Moulinet-Raillon & Bonan, 2018;
Roelofs, van Heugten, de Kam, Weerdesteyn
& Geurts, 2018; Wilson et al., 2017). A
unilateral TBI of cortical and subcortical structures often result in
the formation of postural asymmetry with contralateral motor deficits
including hemiplegia and hemiparesis
(Jamal, Leplaideur, Rousseau, Chochina,
Moulinet-Raillon & Bonan, 2018; Roelofs,
van Heugten, de Kam, Weerdesteyn & Geurts, 2018;
Wilson et al., 2017). Motor impairment on
the affected side contributes to dynamic control asymmetry in favor of
the less affected leg, weight-bearing asymmetry and impaired body sway
control. The TBI-induced motor impairments are defined as the loss of
symmetrical limb reflexes and functions, and a loss of pre-injury
abilities. Along with the reinstatement of pre-injury patterns, the
symmetric pattern of limb functions and sensorimotor reflexes is used as
a measure of functional recovery
(Fujimoto, Longhi, Saatman, Conte,
Stocchetti & McIntosh, 2004; Schallert,
Fleming, Leasure, Tillerson & Bland, 2000). Neuroplastic
rearrangements in supraspinal and spinal neurocircuitries induced by
aberrant asymmetric activity of descending neural tracts may underlie
motor impairments. In contrast to adaptive changes in the brain,
knowledge on the brain injury-induced spinal neuroplasticity is limited
(Grau, 2014;
Sist, Fouad & Winship, 2014;
Tan, Chakrabarty, Kimura & Martin, 2012;
Wolpaw, 2012).
Spinal cord neuroplasticity or “pathological spinal memory” was
proposed as a mechanism of motor impairment after injury to the
cerebellum (Chamberlain, Halick & Gerard,
1963; DiGiorgio, 1929). In these
studies, a unilateral cerebellar lesion caused asymmetric hindlimb
posture with flexion of the ipsilesional limb that persisted after
complete spinal transection. Consistently, changes in spinal reflexes
induced by lateral spinal cord lesion were found to retain after
complete spinal transection, and paralleled by asymmetry in locomotion
(Frigon, Barriere, Leblond & Rossignol,
2009; Rossignol & Frigon, 2011).
Hindlimb postural asymmetry (HL-PA) was also induced by a large
unilateral brain lesion (Varlinskaia,
Rogachii, Klement’ev & Vartanian, 1984) and the localized focal lesion
of the hindlimb representation area of the sensorimotor cortex
(Bakalkin et al., 2018;
Zhang, Watanabe, Sarkisyan, Thelin,
Schouenborg & Bakalkin, 2018). The HL-PA was manifested as differences
in the position of the ipsi- and contralesional hindlimbs. In contrast
to cerebellar or lateral spinal cord injuries, the contralesional
hindlimb was flexed. Formation of HL-PA with contralesional flexion
correlated with motor deficits of the same limb
(Bakalkin et al., 2018;
Zhang, Watanabe, Sarkisyan, Thelin,
Schouenborg & Bakalkin, 2018), and asymmetry of the hindlimb
nociceptive withdrawal reflexes. The cortical injury also modified gene
expression in the ipsi- and contralesional halves of lumbar spinal cord,
and impaired coordination of gene expression between these halves. Thus,
asymmetric changes in the hindlimb posture and nociceptive withdrawal
reflexes may be encoded by molecular processes in lumbar spinal
circuits. Overall the postural symmetry phenomenon recapitulates
symptoms of asymmetric motor deficits observed in human subjects.
Furthermore, it represents a promising translational animal model to
unravel spinal mechanisms of unilateral motor deficits such as
hemiplegia and hemiparesis and to identify pharmacological targets to
interfere with a “pathological spinal memory trace”. The employment of
this model for pharmacological purposes thus far has been limited by the
absence of data on whether a clinically relevant brain injury e.g. a
focal, unilateral TBI may induce the same phenomenon, and on spinal
neurotransmitter systems mediating effects of brain injury on asymmetry
formation.
The endogenous opioid system includes µ-, δ- and κ-opioid receptors and
endogenous opioid peptides endorphins, enkephalins and dynorphins.
Opioid receptors are expressed in dorsal and ventral spinal domains and
involved in regulation of sensory processes and motor functions
(Clarke, Galloway, Harris, Taylor & Ford,
1992; Steffens & Schomburg, 2011;
Wang et al., 2018). Opioid peptides and
synthetic opioid agonists may induce HL-PA in intact rats thus mimicking
effects of a unilateral brain lesion
(Bakalkin & Kobylyansky, 1989;
Chazov, Bakalkin, Yarigin, Trushina, Titov
& Smirnov, 1981). Unusual was the left-right side specificity of the
effects; bremazocine and dynorphin, the -agonists and Met-enkephalin,
the endogenous µ-/δ-agonist induced flexion of the left hindlimb,
whereas Leu-enkephalin, a δ-agonist caused the right limb to flex.
In this study, we examined whether a unilateral controlled cortical
impact (CCI) delivered on the sensorimotor cortex, a model of clinical
focal TBI, induces HL-PA as a readout of asymmetric functional
impairments; whether HL-PA is encoded at the spinal level, and whether
the CCI-induced development of HL-PA and its fixation is mediated
through opioid receptors.