Anxiety- and Depression-Like Behavior and Impaired Neurogenesis Evoked by Peripheral Neuropathy Persist following Resolution of Prolonged Tactile Hypersensitivity

Abstract

Pain and depression are frequently associated with and often persist after resolution of an initial injury. Identifying the extent to which depression remains causally associated with ongoing physical discomfort during chronic pain, or becomes independent of it, is an important problem for basic neuroscience and psychiatry. Difficulty in distinguishing between effects of ongoing aversive sensory input and its long-term consequences is a significant roadblock, especially in animal models. To address this relationship between localized physical discomfort and its more global consequences, we investigated cellular and behavioral changes during and after reversing a mouse model of neuropathic pain. Tactile allodynia produced by placing a plastic cuff around the sciatic nerve resolved within several days when the cuff was removed. In contrast, the changes in elevated O-maze, forced-swim, Y-maze spontaneous alternation and novel-object recognition test performance that developed after nerve cuff placement remained for at least 3 weeks after the nerve cuffs were removed, or 10 -15 d following complete normalization of mechanical sensitivity. Hippocampal neurogenesis, measured by doublecortin and proliferating cell nuclear antigen expression, was also suppressed after nerve cuff placement and remained suppressed 3 weeks after cuff removal. FosB expression was elevated in the central nucleus of the amygdala and spinal cord dorsal horn only in mice with ongoing allodynia. In contrast, FosB remained elevated in the basolateral amygdala of mice with resolved nociception and persisting behavioral effects. These observations suggest that different processes control tactile hypersensitivity and the behavioral changes and impaired neurogenesis that are associated with neuropathic allodynia.

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

“…34,[57][58][59][60] Remote hippocampal neurogenesis also is inhibited in some chronic pain models evoked by peripheral nerve injury that is associated with depression. 35,37 Assessments of neurogenesis in the brain after SCI have been controversial. Significant long-term reduction of neurogenesis in the hippocampal SGZ has been reported at 90 days after a cervical spinal cord hemisection injury in adult rats, 36 whereas Franz and colleagues reported no alteration of neurogenesis in the brain at 42 days after rats thoracic moderate contusion.…”

“…[32][33][34] Remote impaired neurogenesis has been shown after peripheral neuropathy and spinal cord lesions. 18,[35][36][37] However, the relationship between injury severity and the development of hippocampal neurogenesis following SCI is less clear. Brain inflammation can affect neurogenesis and depression.…”

Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

“…Neurogenesis which has been shown to be involved in cognitive impairment and depression in humans and in a variety of rodent models, is a function of serotonergic regulation and may affect the response to antidepressants in both cognitive and affective behavioral domains (Adeosun et al, 2014;Alenina and Klempin, 2015;Anacker, 2014;Biscaro et al, 2012;Braun and Jessberger, 2014;Chadwick et al, 2011;Cho et al, 2015;Dimitrov et al, 2014;Gundersen et al, 2013;Hill et al, 2015;Jiang et al, 2015;Lin and Wang, 2014;Mendez-David et al, 2013;Morais et al, 2014;O'Leary and Cryan, 2014;Parihar et al, 2013;Pereira Dias et al, 2014;Ransome et al, 2012;Rotheneichner et al, 2014;Schoenfeld and Cameron, 2015;Seib et al, 2013;Serafini et al, 2014;Shetty, 2014;Suarez-Pereira et al, 2015;Yau et al, 2014). In young adult mice, antidepressants increase stem cell proliferation (Hodes et al, 2010;Santarelli et al, 2003;Tanti et al, 2013).…”

Fish Neurogenesis in Context: Assessing Environmental Influences on Brain Plasticity within a Highly Labile Physiology and Morphology

“…However, it is clear that such injury can lead to dramatic changes in behavior, and some authors have tied these behavioral effects to stressinduced changes in neurogenesis [Dimitrov et al, 2014]. In birds and mammals, which have relatively little capacity to regenerate, one can assess injury-induced changes in brain cell proliferation separately from changes in somatic cell proliferation since injury does not cause a prolonged period of cell proliferation at the wound site.…”