Restoration of Contralateral Representation in the Mouse Somatosensory Cortex after Crossing Nerve Transfer

Avulsion of spinal nerve roots in the brachial plexus (BP) can be repaired by crossing nerve transfer via a nerve graft to connect injured nerve ends to the BP contralateral to the lesioned side. Sensory recovery in these patients suggests that the contralateral primary somatosensory cortex (S1) is activated by afferent inputs that bypassed to the contralateral BP. To confirm this hypothesis, the present study visualized cortical activity after crossing nerve transfer in mice through the use of transcranial flavoprotein fluorescence imaging. In naïve mice, vibratory stimuli applied to the forepaw elicited localized fluorescence responses in the S1 contralateral to the stimulated side, with almost no activity in the ipsilateral S1. Four weeks after crossing nerve transfer, forepaw stimulation in the injured and repaired side resulted in cortical responses only in the S1 ipsilateral to the stimulated side. At eight weeks after crossing nerve transfer, forepaw stimulation resulted in S1 cortical responses of both hemispheres. These cortical responses were abolished by cutting the nerve graft used for repair. Exposure of the ipsilateral S1 to blue laser light suppressed cortical responses in the ipsilateral S1, as well as in the contralateral S1, suggesting that ipsilateral responses propagated to the contralateral S1 via cortico-cortical pathways. Direct high-frequency stimulation of the ipsilateral S1 in combination with forepaw stimulation acutely induced S1 bilateral cortical representation of the forepaw area in naïve mice. Cortical responses in the contralateral S1 after crossing nerve transfer were reduced in cortex-restricted heterotypic GluN1 (NMDAR1) knockout mice. Functional bilateral cortical representation was not clearly observed in genetically manipulated mice with impaired cortico-cortical pathways between S1 of both hemispheres. Taken together, these findings strongly suggest that activity-dependent potentiation of cortico-cortical pathways has a critical role for sensory recovery in patients after crossing nerve transfer

Visual Map Shifts based on Whisker-Guided Cues in the Young Mouse Visual Cortex

Mice navigate nearby space using their vision and whiskers, and young mice learn to integrate these heterogeneous inputs in perceptual space. We found that cortical responses were depressed in the primary visual cortex of young mice after wearing a monocular prism. This depression was uniformly observed in the primary visual cortex and was eliminated by whisker trimming or lesions in the posterior parietal cortex. Compensatory visual map shifts of responses elicited via the eye that had worn the prism were also observed. As a result, cortical responses elicited via each eye were clearly separated when a visual stimulus was placed in front of the mice. A comparison of response areas before and after prism wearing indicated that the map shifts were produced by depression with spatial eccentricity. Visual map shifts based on whisker-guided cues may serve as a model for investigating the cellular and molecular mechanisms underlying higher sensory integration in the mammalian brain

Bilaterality index in mice with or without crossing nerve transfer.

<p>The bilaterality index in mice with crossing nerve transfer surgery using three different methods is significantly greater than that in naïve mice (P<0.0001, respectively). The bilaterality index is not significantly different between mice operated in an end-to-end fashion, with or without sequential nerve cut. However, the index in mice operated in an end-to-side fashion was significantly larger than that in mice operated in an end-to-end fashion with (P<0.002) or without sequential nerve cut (P<0.007). Numbers in the parentheses show the numbers of mice.</p

Cortical responses before and after crossing nerve transfer.

<p>(A) Cortical responses elicited by vibratory stimulation applied to the left forepaw in a naïve mouse. In the left diagram (a), peripheral nerves are shown on the back of a mouse to avoid left-right confusion. The middle panel (b) shows the original fluorescence image. In the right panel (c), neural activity is apparent in the contralateral right S1, while the ipsilateral left S1 is only weakly activated. (B) Cortical responses after crossing nerve transfer. The diagram (a) and cortical responses elicited by vibratory stimulation applied to the left forepaw at 4 weeks (b), 8 weeks (c and d), 8 months (e) and 12 months (f) after crossing nerve transfer. The cortical responses shown in (c) were almost completely lost after the nerve graft was cut in the same mouse (d).</p

Crossing nerve transfer in cPcdhα knockout mice.

<p>(A) Cortical responses elicited by transcranial stimulation of the left S1 in control cPcdhα +/+ (a) and cPcdhα −/− mice (b). Responses in a cortex-restricted GluN1 +/− mouse are also shown for comparison (c). (B) Bilaterality index of cortical responses elicited by transcranial stimulation of the left S1 in cPcdhα +/+, cPcdhα −/−, and cortex-restricted GluN1 +/− mice. (C) Cortical responses elicited by left forepaw stimulation at 8 weeks after crossing nerve transfer in cPcdhα +/+ (a) and cPcdhα −/− mice (b). (D) Bilaterality index after crossing nerve transfer in cPcdhα +/+ and cPcdhα −/− mice.</p

Bilateral cortical representation induced by direct cortical stimulation.

<p>(A) Cortical responses elicited by left forepaw stimulation before (a), within 20 min (b) and more than 40 min (c) after cessation of direct stimulation applied to the ipsilateral left S1 paired with left forepaw stimulation in the same mouse. These experiments were performed in naïve mice. The black dot in (a–c) shows the direct cortical stimulation site. (B) Amplitudes of cortical responses elicited by left forepaw stimulation in the ipsilateral left S1 (red) and contralateral right S1 (blue).</p

Crossing nerve transfer surgery.

<p>The cut ends of the left median (MN) and ulnar nerves (UN) were connected to the right brachial plexus (BP) via a sciatic nerve graft at 8 weeks of age. The left radial (RN) and musculocutaneous nerves (McN) were cut at the same time, or at 15 weeks of age (sequential nerve cut). Imaging was performed at 16 weeks of age.</p

Crossing nerve transfer in cortex-restricted heterozygous GluN1 knockout mice.

<p>(A) Cortical responses elicited by left forepaw stimulation after crossing nerve transfer in control GluN1 +/+ (a) and cortex-restricted GluN1 +/− mice (b). (B) Amplitudes of cortical responses recorded in the ipsilateral left S1 after crossing nerve transfer. Control GluN1 +/+ mice expressed Cre alone, LoxP alone, or neither, and cortex-restricted GluN1 +/− mice expressed both Cre and LoxP. (C) Amplitudes of cortical responses recorded in the contralateral right S1 after crossing nerve transfer. (D) Bilaterality index after crossing nerve transfer in control GluN1 +/+ and cortex-restricted GluN1 +/− mice. The index in naïve mice is also shown for comparison.</p

Activity-dependent mechanisms underlying bilateral cortical representation.

<p>(A) Neural circuits prior to crossing nerve transfer. Cortico-cortical inputs from the left S1 to the right S1 are not necessarily synchronous to other non-thalamic inputs to the right S1, because sensory inputs from both forepaws are not necessarily synchronous. In contrast, thalamic inputs to the right S1 are synchronous to other non-thalamic inputs to the right S1. (B) Neural circuits after crossing nerve transfer. Cortico-cortical inputs from the left S1 to the right S1 are now synchronous to other non-thalamic inputs to the right S1, so that the cortico-cortical inputs can be synchronized with postsynaptic activities in the right S1. Cortico-cortical synapses from the left S1 to the right S1 are potentiated according to the Hebbian rule.</p