Cortical electrical stimulation in female rats with a cervical spinal cord injury to promote axonal outgrowth

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Traumatic spinal cord injury (SCI) affects approximately 40 people per million annually in North America (Furlan, Sakakibara, Miller, & Krassioukov, 2013) and often leaves individuals irrevocably injured because of, among other issues, a lack of axonal repair. Treatments aimed at inducing axonal outgrowth (whether for axonal regeneration and/or collateralization) have, to date, failed to translate into significant functional improvement from animal models to individuals with SCI.
Axonal outgrowth in the adult spinal cord is hampered by both extrinsic inhibitory factors (e.g., myelin‐associated inhibitors and chondroitin sulfate proteoglycans) (Cajal, 1928; Filbin, 2003; Jones, Yamaguchi, Stallcup, & Tuszynski, 2002) as well as mature neurons having a reduced intrinsic capacity for regeneration. Many factors contribute to this decreased ability to regrow including decreased expression of growth‐associated proteins (e.g., GAP‐43), microtubule‐associated proteins, and cAMP levels (Filbin, 2003; Han, Shukla, Subramanian, & Hoffman, 2004; Hannila & Filbin, 2008; Ming et al., 1997; Song, Ming, & Poo, 1997; Wei et al., 2016). Thus, increasing neuronal innate regenerative abilities is likely necessary to promote robust neuronal outgrowth and regeneration that will translate into behavioral improvements (Nikulina, Tidwell, Dai, Bregman, & Filbin, 2004). One clinically applicable method of increasing the innate outgrowth capacity of an axon is via electrical stimulation (ES). ES has been demonstrated to influence neuronal outgrowth (Al‐Majed, Brushart, & Gordon, 2000; Al‐Majed, Neumann, Brushart, & Gordon, 2000; Brus‐Ramer, Carmel, Chakrabarty, & Martin, 2007; Carmel, Kimura, Berrol, & Martin, 2013; Carmel & Martin, 2014; Udina et al., 2008) and thus overcome axon growth inhibitors near SCI sites through its effect on the expression of growth factors such as BDNF and endogenous second messengers such as calcium and cAMP (Al‐Majed, Brushart, et al., 2000; Udina et al., 2008). Both cAMP and calcium have been demonstrated to play a major role in growth cone motility and the upregulation and expression of immediate‐early genes involved in regeneration (Kater & Mills, 1991; Kocsis, Rand, Lankford, & Waxman, 1994; Ming et al., 1997). In fact, increasing intracellular neuronal cAMP and BDNF levels through ES even prior to injury have been demonstrated to enhance axonal outgrowth post injury in the peripheral nervous system. This increased outgrowth likely occurs by allowing time for the upregulation and transcription of genes involved in neuronal outgrowth (Al‐Majed, Brushart, et al., 2000; Neumann, Bradke, Tessier‐Lavigne, & Basbaum, 2002; Udina et al., 2008). In this manner, with ES occurring prior to neuronal injury, the cell is then thought to be in a progrowth primed state for when the injury does occur. On the basis of these mechanisms for peripheral nerve outgrowth post injury, we hypothesized that ES of the central nervous system (CNS) post SCI would promote neuronal axon outgrowth.
To date, ES in the injured spinal cord has largely been confined to spinal cord stimulation at the site of the injury to promote regeneration of axons into the lesion (Borgens, Blight, & McGinnis, 1987; Borgens, Blight, Murphy, & Stewart, 1986; Borgens et al., 1993), as well as caudal to the lesion to modulate the excitability of neuronal networks and central pattern generators (Angeli, Edgerton, Gerasimenko, & Harkema, 2014; Capogrosso et al., 2016; Harkema et al., 2011; Moraud et al., 2016). More recently, cortical ES has been used to stimulate uninjured corticospinal tract (CST) neurons following unilateral lesions to promote sprouting toward the denervated, contralateral side (Carmel et al., 2013; Carmel, Kimura, & Martin, 2014; Carmel & Martin, 2014). The cortical ES performed in the latter experiments occurred at a relatively higher frequency (333 Hz) comparison with that performed to promote outgrowth within the peripheral nervous system (PNS) post injury (20 Hz).

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