Unilateral traumatic brain injury of the left and right hemisphere produces the left hindlimb response in rats

Abstract

Traumatic brain injury and stroke result in hemiplegia, hemiparesis, and asymmetry in posture. The effects are mostly contralateral; however, ipsilesional deficits may also develop. We here examined whether ablation brain injury and controlled cortical impact (CCI), a rat model of clinical focal traumatic brain injury, both centered over the left or right sensorimotor cortex, induced hindlimb postural asymmetry (HL-PA) with contralesional or ipsilesional limb flexion. The contralesional hindlimb was flexed after left or right side ablation injury. In contrast, both the left and right CCI unexpectedly produced HL-PA with flexion on left side. The flexion persisted after complete spinal cord transection suggesting that CCI triggered neuroplastic processes in lumbar neural circuits enabling asymmetric muscle contraction. Left limb flexion was exhibited under pentobarbital anesthesia. However, under ketamine anesthesia, the body of the left and right CCI rats bent laterally in the coronal plane to the ipsilesional side suggesting that the left and right injury engaged mirror-symmetrical motor pathways. Thus, the effects of the left and right CCI on HL-PA were not mirror-symmetrical in contrast to those of the ablation brain injury, and to the left and right CCI produced body bending. Ipsilateral effects of the left CCI on HL-PA may be mediated by a lateralized motor pathway that is not affected by the left ablation injury. Alternatively, the left-side-specific neurohormonal mechanism that signals from injured brain to spinal cord may be activated by both the left and right CCI but not by ablation injury.

Keywords: Contralateral response; Ipsilateral response; Postural asymmetry; Stroke; Traumatic brain injury.

Fig. 1

Controlled cortical impact (CCI) and unilateral ablation brain injury (UBI) of the hindlimb motor cortex. a Schematic representation of the sensorimotor cortex of the rat brain (modified from (Tandon et al. 2008)). b Expanded cortex. Green circle denotes the intended lesion area although the actual lesion area slightly varied among the rats. Red rectangle denotes the intended lesion area although the actual lesion area slightly varied among the rats. Vertical purple line indicates the bregma plane. Scales above and on the right side indicate the distance in mm relative to the bregma rostrocaudally and to the midline mediolaterally, respectively. c Five consecutive Nissl-stained cortical sections show the lesion site on the right cortex in two-dimension from a CCI rat. d Five consecutive Nissl-stained cortical sections show the lesion site on the right cortex in two-dimension from a UBI rat. Caudal is to the left and rostral is to the right for all the panels. The numbers below c and d indicate the position of the first and the last section in the figure relative to the bregma. Scale bar = 2 mm

Fig. 2

The left and right CCI-induced body bending revealed under ketamine anesthesia. Rats with sham injury (a, d) or CCI (b, c, e, and f) were analyzed on Day 4 (a, b, d and e) or Day 7 (c, f). CCI and sham surgery were performed either on the left (a–c) or (d–f) right side. Rats were categorized as symmetric (not bent), or laterally bent from the neck to the tail to the left or to the right in the coronal plane. The number of rats is shown in Table 1. All rats in each group displayed virtually the same either symmetric or asymmetric body posture at each of the 10, 20, and 30 min time points after ketamine administration

Fig. 3

The HL-PA induced by the left- (L-) or right- (R-) side CCI, and by the left- or right side UBI. a Experimental design. HL-PA was analyzed before [shown as (−)] and 60 min after [shown as (+)] spinal cord transection at the T2-3 level on the Day 3 or Day 4 after CCI, UBI or sham injury; the effects of the left CCI are shown. b, c The magnitude of HL-PA (MPA) and HL-PA size in millimeters (mm), respectively. In c, negative and positive HL-PA values are assigned to rats with the left and right hindlimb flexion, respectively. d, e Differences (contrasts) between the CCI and sham injury groups, and between the UBI and sham injury groups in the asymmetry magnitude and its size, respectively. The number of animals is given in Table 2. The MPA, HL-PA, and the contrasts are plotted as median (black circles), 95% highest posterior density continuous intervals (black lines) and posterior density from Bayesian regression. *Significant differences (contrasts) between the groups: 95% highest posterior density continuous intervals did not include zero value, and adjusted P values identified by Bayesian regression were ≤ 0.05. Adjusted P values are shown in Online Resource 1 and Online Resource 2

Fig. 4

The probability of contralesional flexion in the left- (L-) and right- (R-) side CCI and the left- and right-side UBI groups. a The probability is plotted as median (black circles), 95% highest posterior density continuous intervals (black lines) and posterior density from Bayesian regression. *Significant differences (contrasts) between the groups: 95% highest posterior density continuous intervals did not include zero value, and adjusted P values identified by Bayesian regression were ≤ 0.05. Adjusted P values are shown in Online Resource 3. For details, see legend to Fig. 3

Fig. 5

Hypothetical neural and neurohormonal mechanisms of contralesional and ipsilesional responses induced by the left and right CCI, and the left and right UBI. a–c Descending motor tracts may mediate effects of the brain injury on body bending and HL-PA. a Lateral body bending directed to the ipsilesional side after the left- and right-side CCI, and c formation of the contralesional hindlimb flexion after the left- and right-side UBI may be mediated by decussating neural tracts that are mirror-symmetrical. b Ipsilateral and decussating contralateral motor pathways may be engaged in formation of HL-PA with left hindlimb flexion after the left- and right-side CCI, respectively; the left CCI in contrast to the left UBI and right CCI may activate the ipsilateral motor pathway. This pathway may control hindlimb responses but not body bending, and may be anatomically asymmetric because the right CCI instead produces the contralesional hindlimb flexion. d, e Two groups of neurohormones and neuropeptides may produce HL-PA with flexion of the left or right hindlimb, respectively (Bakalkin et al. ; Watanabe et al. 2020, 2021). Activity of these left and right postural asymmetry inducing factors (PAFs) may be balanced in the symmetric brain, while CCI and UBI may impair the balance and shift an equilibrium in PAFs activity to favor the factors producing either the contralesional or ipsilesional hindlimb response. Some of the PAFs, for example, endogenous opioid peptides dynorphins and Met-enkephalin are involved in tissue injury, pain and stress, and overproduced after brain trauma and spinal cord injury (Hauser et al. ; Hussain et al. ; Maximyuk et al. ; Smeets et al. 2015). The overproduction or excessive release of these injury-associated PAFs may be similar after the left and right side CCI. Similarly with synthetic dynorphins and Met-enkephalin that induce hindlimb flexion on the left side in animals with intact brain, the endogenous injury-associated PAFs may induce a unilateral response, namely the left hindlimb flexion (Bakalkin et al. ; Watanabe et al. 2020). In comparison with the CCI, the UBI does not produce a severe brain damage and, therefore, may not activate the injury-associated PAFs, while the side-specific PAFs may be generated and enable formation of the contralesional hindlimb flexion (Bakalkin et al. ; Watanabe et al. 2020)