New neurons restore structural and behavioral abnormalities in a rat model of PTSD

Abstract

Post-traumatic stress disorder (PTSD) has been associated with anxiety, memory impairments, enhanced fear, and hippocampal volume loss, although the relationship between these changes remain unknown. Single-prolonged stress (SPS) is a model for PTSD combining three forms of stress (restraint, swim, and anesthesia) in a single session that results in prolonged behavioral effects. Using pharmacogenetic ablation of adult neurogenesis in rats, we investigated the role of new neurons in the hippocampus in the long-lasting structural and behavioral effects of SPS. Two weeks after SPS, stressed rats displayed increased anxiety-like behavior and decreased preference for objects in novel locations regardless of the presence or absence of new neurons. Chronic stress produced by daily restraint for 2 or 6 hours produced similar behavioral effects that were also independent of ongoing neurogenesis. At a longer recovery time point, one month after SPS, rats with intact neurogenesis had normalized, showing control levels of anxiety-like behavior. However, GFAP-TK rats, which lacked new neurons, continued to show elevated anxiety-like behavior and enhanced serum corticosterone response to anxiogenic experience. Volume loss in ventral CA1 paralleled increases in anxiety-like behavior, occurring in all rats exposed to SPS at the early time point and only rats lacking adult neurogenesis at the later time point. In chronic stress experiments, volume loss occurred broadly throughout the dentate gyrus and CA1 after 6-hour daily stress but was not apparent in any hippocampal subregion after 2-hr daily stress. No effect of SPS was seen on cell proliferation in the dentate gyrus, but the survival of young neurons born a week after stress was decreased. Together, these data suggest that new neurons are functionally important for recovery of normal behavior and hippocampal structure following a strong acute stress and point to the ventral CA1 region as a potential key mediator of stress-induced anxiety-like behavior.

Adult neurogenesis alters response to an aversive distractor in a labyrinth maze without affecting spatial learning or memory

“…DCX, a marker of immature granule neurons (Brown et al, 2003;Snyder et al, 2009), was used to qualitatively assess the presence of ongoing neurogenesis in WT and TK rats. As expected, based on previous work using this transgenic rat model (Cahill, Cole, Yu, Clemans-Gibbon, & Snyder, 2018;Galinato et al, 2018;Karlsson et al, 2018;Opendak et al, 2016;Schoenfeld et al, 2019), treatment with valganciclovir completely eliminated new neurons in TK rats but not WT rats ( Figure 1). All wild type rats had numerous DCX+ cells, and all TK rats had ≤1 DCX+ cells per section, so no rats were excluded for problems with genotyping or drug treatment.…”

“…The increase in corticosterone release following mint exposure and the known effects of new neurons on stress responses (Opendak et al, 2016; Schoenfeld et al, 2019; Snyder et al, 2011) suggest that mint odor may alter behavior by acting as a stressor. However, corticosterone release occurs in response to emotional arousal regardless of whether the provoking stimulus is a stressor/threat (Koolhaas et al, 2011; Woodson, Macintosh, Fleshner, & Diamond, 2003).…”

P2X7 Receptor Signaling in Stress and Depression

“…According to the neurogenic hypothesis of depression, impaired adult hippocampal neurogenesis would be inhibited by stress, and be a causal factor for triggering depressive episodes; while antidepressant treatments would induce therapeutic effect by restoring normal hippocampal neurogenesis [171]. There are studies suggesting that decreased neurogenesis is not a major contributor to the MDD development, but it may be associated to cognitive impairments induced by stress and observed in patients with depression [172,173]. In line with this prospect, mice lacking adult hippocampal neurogenesis are not more susceptible to stress [174] or do not present more depressive-related behavior [175,176].…”

In Vivo Expression of Reprogramming Factor OCT4 Ameliorates Myelination Deficits and Induces Striatal Neuroprotection in Huntington’s Disease

“…We tried to check at 2 weeks post-treatment not only how the newly generated cells by OCT4 committed to their fate according to the microenvironment of early-HD stage but also these cells affect early behavior recovery. Because newly proliferated cells in adult concerned behavior at a later time point, more than a month after the injury [ 43 ]. We suggest that newly generated NSCs and OPCs by OCT4 affect early behavior recovery at 8 weeks of age.…”

“…Namely, in situ expression of OCT4 in the SVZ increased the number of newly generated NSCs (Nestin + BrdU + cells) and OPCs (NG2 + BrdU + cells) but not the number of newly generated neurons (βIII-tubulin + BrdU + cells) and astrocytes (GFAP + BrdU + cells) in HD mice at 6 weeks of age ( Figure 2 A–D). Newly proliferated cells in adult affected behavior at a later time point, more than a month after injury [ 43 ]. Therefore, we suggest that the increased number of NSCs and OPCs during initial 2 weeks affected the recovery of neuromuscular function at 8 weeks of age.…”