Spinal cord injury drives chronic brain changes

Ignacio Jure, Florencia Labombarda,

1 Laboratorio de Bioquímica Neuroendocrina, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina

2 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

Spinal cord injury drives chronic brain changes

Ignacio Jure1, Florencia Labombarda1,2,＊

1 Laboratorio de Bioquímica Neuroendocrina, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina

2 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

How to cite this article:Jure I, Labombarda F (2017) Spinal cord injury drives chronic brain changes. Neural Regen Res 12(7):1044-1047.

Only a few studies have considered changes in brain structures other than sensory and motor cortex aer spinal cord injury, although cognitive impairments have been reported in these patients. Spinal cord injury results in chronic brain neuroin fl ammation with consequent neurodegeneration and cognitive decline in rodents. Regarding the hippocampus, neurogenesis is reduced and reactive gliosis increased.ese longterm abnormalities could explain behavioral impairments exhibited in humans patients suffering from spinal cord trauma.

spinal cord injury; brain neurodegeneration; neuroin fl ammation

Accepted: 2017-06-19

Introduction

Spinal cord injury (SCI) produces an extensive brain reorganization of the sensorimotor cortex due to cortical circuit dea ff erentation (Nardone et al., 2013). Concomitantly with the cortical plastic changes SCI leads to the atrophy not only of spinal cord (Lundell et al., 2011) but also of the sensorimotor cortex and corticospinal tract (CST) (Jurkiewicz et al., 2006; Wrigley et al., 2009). In particular, human magnetic resonance imaging (MRI) studies using voxel-based morphometry and diffusion tensor imaging have revealed that grey matter volume decreases in primary somatosensory (S1) and motor cortex (M1) in chronic SCI, which is consistent with atrophy and/or neuronal loss (Jurkiewicz et al., 2006; Wrigley et al., 2009; Freund et al., 2011, 2013a, b). In addition, these studies have demonstrated that axonal and myelin integrity of CST is reduced following spinal cord trauma (Wrigley et al., 2009; Freund et al., 2012, 2013b). Concerning the survival of cortical axotomized motoneurons there is no uniform consensus. A number of reports on SCI animal models have shown apoptotic neurons on Lamina V of primary motor cortex (Hains et al., 2003; Lee et al., 2004) while others have demonstrated that the number of large pyramidal neurons remains invariable (Wannier et al., 2005; Brock et al., 2010; Nielson et al., 2011). Despite this controversy regarding the survival of the upper-motoneuron both positions agree with the fact that those neurons suffer changes as atrophy and shrinkage following SCI (Tseng and Prince, 1996; Wannier et al., 2005; Brock et al., 2010; Nielson et al., 2011).

Crucially, the decrease of CST integrity and cortical grey matter volume is directly correlated with spinal cord atrophy in humans (Freund et al., 2012, 2013a) suggesting that trauma-induced spinal degenerative process spreads towards the brain.

According to human MRI studies SCI can cause progressive reduction in grey matter volume not only in the sensorimotor cortex but also in regions not directly connected to the injury site, such as insular, cerebellar, medial prefrontal, anterior cingulate and temporal cortices, which are crucial for the processing of emotional information and the modulation of attentional states (Nicotra et al., 2006; Wrigley et al., 2009).

In this regard there have been several reports about long-term cognitive impairments in humans after SCI. Standardized neuropsychological tests have identi fi ed performance impairments in span memory, executive functioning, memory function, concentration ability, attention, processing speed, and learning (Roth et al., 1989; Murray et al., 2007; Lazzaro et al., 2013; Craig et al., 2015). As comorbid traumatic brain injury (TBI) can result in cognitive impairments, it is worth mentioning that the stated reports exclude people with concomitant TBI. Sixty percent of spinal cord injured patients su ff er not only from cognitive impairment but also from depression (Shin et al., 2012) and anxiety (Post and van Leeuwen, 2012) conditions which result in a general decrease in quality of life (Boakye et al., 2012). A prospective longitudinal neuropsychological study has shown that cognitive impairment in spinal cord injured patients was associated with elevated depressive mood, anxiety and fatigue only when patients returned to society, where there is less support and substantial challenges (Craig et al., 2015).

Since human behavior is very complex, factors other than TBI might also contribute to lower cognitive performance such as chronic pain, taking multiple medication and alcohol and substance abuse. In this context, Faden and colleagues´ work is very signi fi cant as it reveals that SCI in both mouse and rat causes impairment of spatial and retention memory and depressive-like behavior as demonstrated by diminished performance in the Morris water maze, Y-maze, novel objective recognition, sucrose preference and tail suspension tests (Wu et al., 2014a, b). One recent report has provided evidence for a relationship between the up-regulation of peripheral and hippocampal cytokine levels andthe increase of depression or anxiety-like signs following rodent spinal cord contusion (Maldonado-Bouchard et al., 2016).

Interestingly, glia reactivity is related to SCI intensity. Severe lesions induce reactive microglia and astrogliosis in all DG sub-regions. However, reactive microglia and astrogliosis develop only in the hilus and in the molecular layer respectively aer moderate SCI while no changes are observed in the mildly injured rats (Jure et al., 2017). In accordance with our result, a recent report has shown microglia activation only after moderate and severe SCI and not in mildly injured mice in the cerebral cortex and hippocampus (Wu et al., 2016). Widespread brain neuroin fl ammation could lead to remote neurodegeneration after SCI. Indeed, neuroinfl ammation and microglia activation are common landmarks following normal aging, neurodegenerative diseases, chronic stress, and brain ischemia (Sierra et al., 2014). In this regard isolated thoracic SCI in both rat and mouse models has resulted in signi fi cant neuronal loss in the hippocampus, cortex, and thalamus only in the chronic phase but not at early time points (Wu et al., 2014a, b). Stereological analyses have demonstrated that moderate and severe - but not mild- SCI reduces neuronal survival and increases neuronal endoplasmic reticulum stress in important brain regions associated with cognitive decline and depression (Wu et al., 2016). In summary it could be stated that on the one hand there are no signs of either neuronal loss or neuroinflammation in mildly injured rats and on the other hand, neuroin fl ammation arises both in the acute and chronic phases preceding neurodegeneration which appears only at late time points, suggesting that inflammation leads to SCI-induced brain neurodegeneration.

Convincing work has demonstrated that the brain is affected by SCI. However, exact mechanisms underlying those changes are completely unknown. On the one hand, the systemic immune function is markedly altered aer SCI and this mechanism could affect the brain (Popovich and McTigue, 2009; Schwab et al., 2014) and on the other hand, corticosterone released in the acute phase after SCI could model the brain producing long-term alterations. It is well documented that the hippocampus and cerebral cortex are vulnerable to glucocorticoid actions (Lucassen et al., 2015). Finally, BDNF and other molecules that participate in neuron-glia communication as chemokines (Cardona et al., 2006; Wu et al., 2014b; Gundersen et al., 2015) could be involved in brain changes following SCI. In this regard, BDNF is known to regulate adult neurogenesis at the SGZ (Lee etal., 2002; Scharfman et al., 2005; Fumagalli et al., 2009) and it has been shown that reduced hippocampal neurogenesis is correlated with the decrease of BDNF protein levels (Felix et al., 2012). However, other reports found that this factor remains unchanged aer 4 and 12 weeks of injury (Fumagalli et al., 2009).

Regarding chemokines, CCL21 is produced by spinal cord neurons after nerve damage or glutamate exposure (Hulsebosch et al., 2009) and is delivered at more distant sites resulting in microglia activation and neuropathic pain generation (Zhao et al., 2007). In addition, CCL21 is up-regulated in neurons both in the acute and chronic phases after SCI in the thalamus, hippocampus and cerebral cortex (Wu et al., 2014a, 2016). Consistent with these results, the microglia activator CCL2 (Zhang et al., 2017) and its receptor CCR2 are chronically expressed in neurons aer severe spinal contusion in the thalamus, hippocampus and periaqueductal gray matter, brain circuits associated with pain and emotional or memory functions (Knerlich-Lukoschus et al., 2011).

In conclusion, SCI results in chronic brain neuroinflammation that is remarkably similar to that reported aer TBI producing a progressive delayed neurodegeneration and functional deficits as cognitive impairment and depressive-like behavior (Faden et al., 2016).ose long-term brain abnormalities and the reported diffuse neuroinflammation associated could explain behavioral impairments exhibited in patients suffering from spinal cord trauma (Davidoff et al., 1992; Dowler et al., 1997; Lazzaro et al., 2013). Future rehabilitation strategies should be oriented to improving not only sensorimotor skills but also cognitive function. Given that SCI drives chronic brain changes, it will be necessary to consider cognitive and emotional patient impairments as a consequence of SCIper seand not as a consequence of the lifestyle resulting from the disability.erefore, future therapies should include the inhibition of post-traumatic brain inflammatory response to avoid cognitive and emotional de fi cits.

Author contributions:IJ and FL have conceived and participated in article preparation.

Con fl icts of interest:None declared.

Open access statement:

Contributor agreement:A statement of “Publishing Agreement” has been signed by an authorized author on behalf of all authors prior to publication.

Plagiarism check:This paper has been checked twice with duplication-checking soware ienticate.

Peer review:A double-blind and stringent peer review process has been performed to ensure the integrity, quality and signi fi cance of this paper.

Open peer reviewers:Michele Fornaro, Midwestern University, USA; Gregory Hawryluk,e University of Utah, USA.

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Copyedited by Jackson C, Li HF, Liu ZF, Song LP, Liu WJ, Zhao M

Florencia Labombarda, Ph.D., fl orlabombarda@gmail.com.

10.4103/1673-5374.211177

＊< class="emphasis_italic">Correspondence to: Florencia Labombarda, Ph.D., fl orlabombarda@gmail.com.