<p>Neuropathic Pain Causes Memory Deficits and Dendrite Tree Morphology Changes in Mouse Hippocampus</p>

Abstract

Introduction: Neuropathic pain manifests in a diverse combination of sensory symptoms and disorders of higher nervous activity, such as memory deficiency, anxiety, depression, anhedonia, etc. This suggests the participation of brain structures, including the hippocampus, in the pathogenesis of neuropathic pain. The elucidation of central sensitization mechanisms underlying neuropathic pain cognitive and affective symptoms may be useful in the development of new and effective treatments for these common disorders. The study aims to elucidate the effect of chronic neuropathic pain on cognitive function and underlying neuronal plasticity in the hippocampus. Methods: Chronic constriction injury of mouse right hind limb sciatic nerve was used as a model of neuropathic pain. The presence of neuropathic pain was confirmed by the thermal and mechanical allodynia. The morphology of the CA1 pyramidal neurons and the dentate gyrus (DG) granule neurons were studied using Golgi-Cox staining. The hippocampal proteins concentration was determined by immunohistochemistry and ELISA. Results: Behavioral testing revealed reduced locomotor activity as well as impaired working and long-term memory in mice with a ligated nerve. We revealed changes in the dendritic tree morphology in CA1 and the dentate gyrus hippocampal subregions. We found the atrophy of the CA1 pyramidal neurons and an increase in the dendritic tree complexity in DG. Moreover, changes in the density of dendritic spines were observed in these regions. In addition, we revealed increased expression of the Arc protein in DG granule neurons and decreased surface expression of AMPA receptors within the hippocampus. Decreased AMPA receptors expression underlies observed altered dendrite arborization and dendritic spines morphology. Discussion: We found that pain information entering the hippocampus causes neuronal plasticity changes. The changes in neurite arborization, dendritic length and dendritic spines morphology as well as protein expression are observed within the hippocampal regions involved in the processing of pain information. Moreover, changes in the dendrite morphology in hippocampal subregions are different due to the anatomical and functional heterogeneity of the hippocampus. Apparently, the detected morphological and biochemical changes can underlie the observed hippocampus-dependent behavioral and cognitive impairment in animals with neuropathic pain.

Optimized Golgi-Cox Staining Validated in the Hippocampus of Spared Nerve Injury Mouse Model

“…To validate our modified method, we used SNI mice-a model for neuropathic pain (Richner et al, 2011). Previous reports associate this model with altered neuronal plasticity and pain-related protein expression in the hippocampus, as well as morphological changes (Metz et al, 2009;Tyrtyshnaia and Manzhulo, 2020). Our results are consistent with that of previous reports that SNI mice exhibit a significant reduction in the number of intersections, total dendritic length, and the number of dendrites.…”

Sculpting Dendritic Spines during Initiation and Maintenance of Neuropathic Pain

“…In addition to dendritic spine dysgenesis in the spinal cord, neuropathic pain produces spine changes in higher brain regions, including the hippocampus. Similar to the structural changes in the spinal cord, neuropathic pain after chronic constriction injury induced alterations in dendritic tree morphology as well as altering the type and number of dendritic spines in the mouse hippocampus (Tsai et al, 2009;Tyrtyshnaia and Manzhulo, 2020). This finding suggests that neuropathic pain produces aberrant structural plasticity in diverse neuronal structures involved in the processing of sensory information (Tsai et al, 2009).…”

“…This finding suggests that neuropathic pain produces aberrant structural plasticity in diverse neuronal structures involved in the processing of sensory information (Tsai et al, 2009). The dysregulation of spines in the hippocampus might explain the connection between chronic neuropathic pain and the development of anxiety and depression, which are often comorbid in patients with neuropathic pain (Woo, 2010;Golden et al, 2013;Lee et al, 2018;Tyrtyshnaia and Manzhulo, 2020). Acute increases in dendritic spine turnover of primary cortical somatosensory circuits accompany neuropathic pain after peripheral nerve injury (S. K. Kim et al, 2016).…”

Neural Plasticity in the Brain during Neuropathic Pain

“…Interestingly, a study reported that the generation of new neurons in the amygdala was promoted during neuropathic pain [129]. The hippocampus displayed changes in dendritic spine morphology and neurogenesis rates following nerve injury [130,131]. These alterations are related to several molecules, such as tumor necrosis factor-alpha [132] and glycogen synthase kinase-3 beta [133].…”