Endocrine signaling mediates asymmetric motor deficits after unilateral brain injury

Abstract

26A paradigm in neurology is that brain injury-induced motor deficits (e.g. hemiparesis and 27 hemiplegia) arise due to aberrant activity of descending neural pathways. We discovered that a 28 unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic 29 spinal cord produces hindlimb postural asymmetry with contralateral flexion, and asymmetric 30 changes in nociceptive hindlimb withdrawal reflexes and gene expression patterns in lumbar spinal 31 cord. The injury-induced postural effects were abolished by prior hypophysectomy and were 32 mimicked by transfusion of serum from animals with unilateral brain injury. Antagonists of the 33 opioid and vasopressin receptors blocked formation of hindlimb postural asymmetry suggesting 34 that these neurohormones mediate effects of brain injury on lateralized motor responses. Our data 35 indicate that descending neural control of spinal circuits is complemented by a previously 36 unknown humoral signaling from injured brain to the contra-and ipsilesional hindlimbs, and 37 suggest the existence of a body side-specific neuroendocrine regulation in bilaterally symmetric 38 animals. 39 In this study we challenge the neurological paradigm by investigating whether a unilaterally 62 injured brain may signal to the lumbar spinal cord through non-spinal mechanism. We applied a 63 "reversed strategy" protocol in which brain injury was performed after complete transection of the 64 spinal cord at a superior thoracic level. 65 66 Results 67Brain injury induces postural asymmetry in rats with transected spinal cord 68 We first demonstrated that the unilateral injury of the hindlimb representation area of the 69 sensorimotor cortex in rats induces formation of HL-PA (Figure 1A,D,E; Figure 1-figure 70 supplement 1). The effect was evident under pentobarbital anesthesia within 5 min after the lesion 71 and lasted for 14 days. The HL-PA median values and probability to develop HL-PA greater than 72 the 1 mm threshold were markedly higher in rats with UBI (n = 8) compared to those with sham 73 surgery (sham; n = 7). The UBI rats displayed a contralesional hindlimb flexion which correlated 74 with motor deficits of the same limb in the beam-working and ladder rung tests (UBI, n = 11/12; 75 sham, n = 8) (Figure 1B,C). The UBI rats showed the high number of slips of the contralesional 76 hindlimb compared to the ipsilesional limb, and to both hindlimbs in rats with sham surgery. 77 Consistent with earlier studies (Chamberlain et al., 1963; DiGiorgio, 1929; Hultborn & Malmsten, 78 1983; Rossignol & Frigon, 2011;Wolpaw, 2012), the HL-PA was retained after complete 79 transection of the spinal cord performed at the T2-T3 level (Figure 1-figure supplement 1E-G). 80 We hypothesized that the HL-PA is maintained either due to neuroplastic changes in the lumbar 81 spinal cord induced through the descending neural tracts before spinalization, or due to non-spinal 82 cord mediated signaling from the injured brain to the lumbar neural circui...

Ipsilesional versus contralesional postural deficits induced by unilateral brain trauma: a side reversal by opioid mechanism

“…The HL-PA is a proxy for the analysis of postural impairments and represents a translational model of ‘hemiplegic posture’ ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Lukoyanov et al , 2020 ; Zhang et al , 2020 ). The HL-PA induced by a unilateral brain injury was evident in un-anesthetized decerebrate animals and in animals under anaesthesia that were used to measure the asymmetry size ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Lukoyanov et al , 2020 ; Zhang et al , 2020 ).…”

“…The HL-PA is a proxy for the analysis of postural impairments and represents a translational model of ‘hemiplegic posture’ ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Lukoyanov et al , 2020 ; Zhang et al , 2020 ). The HL-PA induced by a unilateral brain injury was evident in un-anesthetized decerebrate animals and in animals under anaesthesia that were used to measure the asymmetry size ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Lukoyanov et al , 2020 ; Zhang et al , 2020 ). As previously established, the stretch and postural limb reflexes were substantially decreased under anaesthesia ( Zhou et al , 1998 ; Fuchigami et al , 2011 ) and abolished immediately and for days after spinal cord transection ( Miller et al , 1996 ; Musienko et al , 2010 ; Frigon et al , 2011 ).…”

“…After completion of all surgical procedures, the wounds were closed by 3-0 suture (AgnTho’s, Sweden) and rats were kept under an infrared radiation lamp to maintain body temperature during monitoring of postural asymmetry. In a subset of rats, the 3- to 4-mm spinal cord segment was dissected and removed; the following microscopic and functional analyses demonstrated that the transection was complete, and that the brain injury-induced HL-PA was of the same size and direction as before the spinal transection (for details, see Lukoyanov et al , 2020 ).…”

“…In a subset of the rats, HL-PA was assessed by the hands-off method as described previously ( Lukoyanov et al , 2020 ). Briefly, silk threads were glued to the nails of the middle three toes of both hindlimbs, and their other ends were tied to hooks attached to the movable platform that was operated by a micromanipulator.…”

“…In contrast to cerebellar or spinal cord injuries, the contralesional hindlimb was flexed after injury to the sensorimotor cortex. The HL-PA was associated with impairment of contralesional hindlimb in the beam walking and ladder rung tests ( Lukoyanov et al , 2020 ). The asymmetry induced by a right-side brain injury was abolished by pancuronium, a curare-mimetic muscle relaxant but not eliminated by bilateral lumbar dorsal rhizotomy, suggesting neurogenic mechanisms that depend on the efferent drive but not on afferent input.…”