Exercise-induced Nogo-A influences rodent motor learning in a time-dependent manner.

Jörg H Stehle,Zhiyuan Sheng,Martin E Schwab,Oliver Weinmann,Juha Hernesniemi,Joseph S Neimat,Philipp Bechstein,Ajmal Zemmar,Laura Hausmann

doi:10.1371/journal.pone.0250743

Abstract

The adult, mature central nervous system (CNS) has limited plasticity. Physical exercising can counteract this limitation by inducing plasticity and fostering processes such as learning, memory consolidation and formation. Little is known about the molecular factors that govern these mechanisms, and how they are connected with exercise. In this study, we used immunohistochemical and behavioral analyses to investigate how running wheel exercise affects expression of the neuronal plasticity-inhibiting protein Nogo-A in the rat cortex, and how it influences motor learning in vivo. Following one week of exercise, rats exhibited a decrease in Nogo-A levels, selectively in motor cortex layer 2/3, but not in layer 5. Nogo-A protein levels returned to baseline after two weeks of running wheel exercise. In a skilled motor task (forelimb-reaching), administration of Nogo-A function-blocking antibodies over the course of the first training week led to improved motor learning. By contrast, Nogo-A antibody application over two weeks of training resulted in impaired learning. Our findings imply a bimodal, time-dependent function of Nogo-A in exercise-induced neuronal plasticity: While an activity-induced suppression of the plasticity-inhibiting protein Nogo-A appears initially beneficial for enhanced motor learning, presumably by allowing greater plasticity in establishing novel synaptic connections, this process is not sustained throughout continued exercise. Instead, upregulation of Nogo-A over the course of the second week of running wheel exercise in rats implies that Nogo-A is required for consolidation of acquired motor skills during the delayed memory consolidation process, possibly by inhibiting ongoing neuronal morphological reorganization to stabilize established synaptic pathways. Our findings suggest that Nogo-A downregulation allows leaning to occur, i.e. opens a ‘learning window’, while its later upregulation stabilizes the learnt engrams. These findings underline the importance of appropriately timing of application of Nogo-A antibodies in future clinical trials that aim to foster memory performance while avoiding adverse effects.

Highlights

While the central nervous system (CNS) exhibits a high degree of plasticity during early development, it becomes increasingly hard-wired and more stable with age
We found Nogo-A expression is regulated in a stringently time-dependent, biphasic manner: it is downregulated in the motor cortex immediately following exercise to promote CNS plasticity, as described [29], and is upregulated again at later stages to serve its known function as a memory consolidator [27,28,29]
Semiquantitative densitometric analyses of immunofluorescence images (Relative Optical Density [relative optical density (ROD)], see Table 1) revealed a significant downregulation of Nogo-A after 7 days of voluntary running (Fig 1a, 1e and 1g; [ROD + standard error of the mean (SEM)]: [0.385 ± 0.011] for sedentary controls vs. [0.298 ± 0.011] for exercised animals; P = 0.001; n = 7) in M1 L2/3, a layer which is known as the substrate for neuronal plasticity within the motor cortex [32, 38], but not in M1 L5, which does not contribute to plasticity to the same degree as layer 2/3 [38] (Fig 1a, 1e and 1g; [ROD + SEM]: [0.385 ± 0.015] for sedentary controls vs. [0.359 ± 0.015] for exercised animals; P = 0.72; n = 7)

Summary

Introduction

While the central nervous system (CNS) exhibits a high degree of plasticity during early development, it becomes increasingly hard-wired and more stable with age Exercise can counteract this limitation, and maintain or even induce plasticity in the adult CNS, e.g. by increasing the number of new neurons [1,2,3], by neovascularisation [4], by enhancing synaptic plasticity and plasticity-related genes [5, 6], by increasing dendritic complexity and spine density [7], improving cognitive function [8], learning and memory [9] and functional recovery [10]. Effects of Nogo-A on brain plasticity have been shown in the murine motor cortex [26]: While on the one hand, downregulation of Nogo-A enhanced acquisition of novel motor tasks [14, 26], on the other hand upregulation of Nogo-A signaling is required to consolidate memories [27,28,29]

Methods

Results

Conclusion