Conditioning lesions enhance axonal regeneration of descending brain neurons in spinal‐cord‐transected larval lamprey

Abstract

In larval lamprey, with increasing recovery times after a transection of the rostral spinal cord, there is a gradual recovery of locomotor behavior, and descending brain neurons regenerate their axons for progressively greater distances below the transection site. In the present study, spinal cord "conditioning lesions" (i.e., transections) were performed in the spinal cord at 30% body length (BL; normalized distance from the head) or 50% BL. After various "lesion delay times" (D), a more proximal spinal cord "test lesion" (i.e., transection) was performed at 10% BL, and then, after various recovery times (R), horseradish peroxidase was applied to the spinal cord at 20% BL to determine the extent of axonal regeneration of descending brain neurons. Conditioning lesions at 30% BL, lesion delay times of 2 weeks, and recovery times of 4 weeks (D-R = 2-4 group) resulted in a significant enhancement of axonal regeneration for the total numbers of descending brain neurons as well as neurons in certain brain cell groups compared to control animals without conditioning lesions. Experiments with hemiconditioning lesions, which reduce interanimal variability, confirmed that conditioning lesions do significantly enhance axonal regeneration and indicate that axotomy rather than diffusible factors released at the injury site is primarily involved in this enhancement. Results from the present study suggest that conditioning lesions "prime" descending brain neurons via cell body responses and enhance subsequent axonal regeneration, probably by reducing the initial delay and/or increasing the initial rate of axonal outgrowth. Indexing termsaxotomy; reticulospinal neurons; spinal cord injury; conditioning lesion; test lesion When neurons are axotomized, they often are "primed" for possible subsequent axonal regeneration. If the axons of these neurons then receive a second "test lesion," often proximal to the first "conditioning lesion" (CL), regeneration can be enhanced compared with that of neurons without previous CLs. This phenomenon of enhanced axonal regeneration is called the "CL effect" (Forman et al., 1980). Because most studies of CL effects have been performed on nerves (e.g., sciatic nerve or optic nerve), crush injuries usually are employed for both the conditioning and the test lesions.After an initial CL, there are a series of morphological, physiological, and biochemical changes in axotomized neurons (McQuarrie and Grafstein, 1982;Redshaw and Bisby, 1987 Perry et al., 1987;Jacob and McQuarrie, 1991;Tetzlaff et al., 1996). Investigating the effects of CLs potentially might clarify the mechanisms that regulate neural regeneration, and it might then be possible to manipulate these mechanisms to enhance axonal regeneration. For example, a CL of the peripheral branch of neurons in dorsal root ganglia (DRG) raises cAMP levels and promotes axonal regeneration of the central branches of these neurons, and this effect can be mimicked by injection of cAMP in DRG (Qiu et al., 2002).The effects of CLs have been invest...

Differential responses to increasing numbers of mild traumatic brain injury in a rodent closed‐head injury model

“…While we may speculate that compensatory mechanisms may become operative following 3 mTBI (Cho and So ; Zhang et al . ), it is important to note that there was no statistically significant difference in cognitive function between animals following 2 and 3 mTBI and this in itself warrants further investigation. Additionally, longitudinal studies comprising careful and complete monitoring of patients who have experienced one or more mTBI will be required to ascertain whether cognitive deficits are lessened with an additional injury in humans.…”

“…The phenomena is reminiscent of a conditioning effect, where an injury can provide protective effects via a predisposition to faster neural regeneration (Cho and So ; Zhang et al . ). Repetitive mTBI can condition the brain such that an additional more severe injury does not lead to expected motor deficits (Allen et al .…”

Determining of Apoptosis at in vitro Conditioned DRG Neurons with TUNEL Method

“…While, this regeneration occurs highly effective in the peripheral nervous system, in adult central nervous system quietly reduced regeneration capacity (Dahlin, 2004;Doron-Mandel et al, 2015). Once a peripheral nerve has been damaged and then the same nerve is reinjured a second time, a faster and more effective regeneration is observed compared with the nerve injured once, this phenomenon is called "Conditioning lesion effect" (Zhang et al, 2004). Many studies have been carried out to search this effect, it is known that most of the sciatic nerve fibers last at L4-L5 Dorsal Root Ganglions (DRGs) because of this, these studies are focused on these DRG neurons.…”

Regeneration in the Era of Functional Genomics and Gene Network Analysis

“…Thus, there is already evidence from the candidate- gene approach that regeneration in the lamprey shares some elements with the normal developmental program and that there are different transcriptional responses post-injury. Interestingly, the regenerative process in lamprey spinal cord, as in mammals, is influenced by age, temperature, conditioning lesion, and cAMP, as well as by electric fields; indicating that at least some of the networks governing regeneration are shared across species—a point we will return to later in the article (Borgens et al , 1981; Cohen et al , 1989, 1999; Zhang et al , 2004; Jin et al , 2009). In the next section, we look at the specific components of a GRN analysis in the lamprey RS neurons, which would go beyond the candidate-gene approach to allow us to define in a comprehensive manner the molecular mechanisms underlying CNS regeneration.…”