Enhanced visual experience rehabilitates the injured brain inXenopustadpoles in an NMDAR-dependent manner

Abstract

Traumatic brain injuries introduce functional and structural circuit deficits that must be repaired for an organism to regain function. We developed an injury model in which Xenopus laevis tadpoles are given a penetrating stab wound that damages the optic tectal circuit and impairs visuomotor behavior. In tadpoles, as in other systems, injury induces neurogenesis. The newly generated neurons are thought to integrate into the existing circuit; however, whether they integrate via the same mechanisms that govern normal neuronal maturation during development is not understood. Development of the functional visuomotor circuit in Xenopus is driven by sensory activity. We hypothesized that enhanced visual experience would improve recovery from injury by facilitating integration of newly generated neurons into the tectal circuit. We labeled newly generated neurons in the injured tectum by green fluorescent protein expression and examined their circuit integration using electrophysiology and in vivo imaging. Providing animals with brief bouts of enhanced visual experience starting 24 h after injury increased synaptogenesis and circuit integration of new neurons and facilitated behavioral recovery. To investigate mechanisms of neuronal integration and behavioral recovery after injury, we interfered with N-methyl-d-aspartate (NMDA) receptor function. Ifenprodil, which blocks GluN2B-containing NMDA receptors, impaired dendritic arbor elaboration. GluN2B blockade inhibited functional integration of neurons generated in response to injury and prevented behavioral recovery. Furthermore, tectal GluN2B knockdown blocked the beneficial effects of enhanced visual experience on functional plasticity and behavioral recovery. We conclude that visual experience-mediated rehabilitation of the injured tectal circuit occurs by GluN2B-containing NMDA receptor-dependent integration of newly generated neurons. NEW & NOTEWORTHY Recovery from brain injury is difficult in most systems. The study of regenerative animal models that are capable of injury repair can provide insight into cellular and circuit mechanisms underlying repair. Using Xenopus tadpoles, we show enhanced sensory experience rehabilitates the injured visual circuit and that this experience-dependent recovery depends on N-methyl-d-aspartate receptor function. Understanding the mechanisms of rehabilitation in this system may facilitate recovery in brain regions and systems where repair is currently impossible.

A Focal Impact Model of Traumatic Brain Injury in Xenopus Tadpoles Reveals Behavioral Alterations, Neuroinflammation, and an Astroglial Response

“…We focused on visually-directed behavior because injury to the optic tectum is expected to disrupt the processing of visual inputs and visually-driven motor responses [ 14 ]. This approach was pioneered in earlier studies from Cline and colleagues, which investigated neural regeneration in the optic tectum of pre-metamorphic tadpoles using a surgical ablation injury model [ 15 , 33 ]. These studies showed that local injury in the dorsolateral midbrain leads to a sharp decline in visual avoidance.…”

“…The capacity for visual avoidance recovers gradually and has returned to baseline at 7 days post-injury. Recovery of distinct behavioral responses requires proliferation of neural progenitors to replenish neurons at the injury site [ 15 ], as well as NMDAR-dependent neuronal activity to integrate new neurons into existing neural circuits [ 33 ]. While this work elucidates the neural regenerative response characteristic of pre-metamorphic tadpoles, regenerative capacity is essentially lost with the activation of thyroid hormone (TH)-dependent processes at metamorphosis (reviewed in [ 34 ].…”

“…4.7c—Visual Avoidance: Visual avoidance behavior was assessed using an assay modified from [ 15 , 33 ]. Tadpoles were screened on Day 0 for the optomotor response to evaluate ability to respond to visual stimuli.…”

BRCA1 and ELK-1 regulate Neural Progenitor Cell Fate in the Optic Tectum in response to Visual Experience in Xenopus laevis tadpoles

“…In the tadpole, visual stimulation increases the integration of newly generated neurons into the tectal circuit by regulating neuronal structural development, synaptic connectivity and biophysical properties that affect neuronal firing (Aizenman and Cline, 2007;Gambrill et al, 2019;Sharma and Cline, 2010;Sin et al, 2002). Several studies indicate that visual experience also regulates multipotent neural progenitor proliferation, cell fate and neuronal differentiation (Bestman et al, 2012;Sharma and Cline, 2010;Sierra et al, 2015;Song et al, 2012).…”

BRCA1 and ELK-1 regulate neural progenitor cell fate in the optic tectum in response to visual experience in Xenopus laevis tadpoles

“…Xenopus laevis tadpoles are an excellent system to investigate how sensory experience modulates neural development because tadpoles receive and respond to patterned visual stimuli while neurogenesis and circuit assembly are occurring. In tadpoles, visual stimulation increases integration of newly generated neurons into the tectal circuit by regulating neuronal structural development, synaptic connectivity, and biophysical properties that affect neuronal firing ( 6 – 8 ). Visual experience also regulates neural progenitor proliferation, cell fate, and neuronal differentiation.…”