Chronic restraint stress impairs neurogenesis and hippocampus‐dependent fear memory in mice: possible involvement of a brain‐specific transcription factor Npas4

Abstract

Stress is defined in biological systems as any condition that seriously perturbs physiological/psychological homeostasis and well known to affect the function and morphology of the hippocampus (Kim and Diamond 2002). The exact underlying cellular mechanisms that mediate the inhibitory effect of stress are largely unknown. However, stress reduces the expression of several growth factors and neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1, nerve growth factor, epidermal growth factor, and vascular endothelial growth factor, that can all influence neurogenesis (Lucassen et al. 2010). Address correspondence and reprint requests to Dr Kiyofumi Yamada, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. E-mail: kyamada@med.nagoya-u.ac.jp 1 These authors contributed equally to this study.Abbreviations used: BDNF, brain-derived neurotrophic factor; BrdU, 5-Bromo-2¢-deoxyuridine; DCX, doublecortin; DG, dentate gyrus; GCL, granule cell layer; GFAP, glial fibrillary acidic protein; NeuN, neuronal nuclei; Npas4, neuronal PAS domain protein 4; PBS, phosphate-buffered saline; SGZ, subgranular zone; Sox-2, SRY-related HMG box 2. AbstractNeurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2¢-deoxyuridine-and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosteroneinduced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.

α2δ Ligands Act as Positive Modulators of Adult Hippocampal Neurogenesis and Prevent Depression-Like Behavior Induced by Chronic Restraint Stress

“…It was suggested that a reduction in neurogenesis after chronic stress exposure might underlie impaired hippocampal plasticity and might contribute to symptoms of depression (Warner-Schmidt and Duman, 2006;Pittenger and Duman, 2008;Lucassen et al, 2010). The chronic restraint stress test is frequently used to evaluate whether drugs can prevent depression-like symptoms (Luo et al, 2005;Yun et al, 2010). Behavioral efficacy of antidepressants is usually demonstrated by using two common paradigms of chronic stress-induced behavioral responses, namely, the forced swim test (FST) and the tail suspension test (TST) (Porsolt, 2000;Bourin et al, 2005;Cryan and Holmes, 2005).…”

Memory development: implications for adults recalling childhood experiences in the courtroom

“…Long-term stress has particularly deleterious effects on structures (e.g., hippocampus, basolateral nucleus of the amygdala) rich in glucocorticoid receptors 83 . One consequence of long-term stress is poorer consolidation of emotional information, including through inhibition of neurogenesis, at least in rodents [84][85][86][87] , primates 88 , and possibly humans [89][90] . Although the role of adult neurogenesis in memory consolidation in humans is hotly debated [89][90] , there is evidence 91 that in adult humans, new neurons are added each day to the hippocampus at a rate commensurate with that found in nonhuman animal studies.…”

“…Regardless, there is evidence that the inhibition of neurogenesis leads to poorer storage (and hence retention) of stressful memories in nonhuman animals [84][85][86][87][88]93 . Some of these negative effects of early life stress in human [94][95] and nonhuman 96 animals can be ameliorated by modifying the environment (e.g., by removing the stressor, social enrichment), but this effect depends not only on the timing of these changes but also on the timing, duration, intensity, and frequency of exposure to stressors during development.…”

Neuronal Per Arnt Sim (PAS) Domain Protein 4 (NPAS4) Regulates Neurite Outgrowth and Phosphorylation of Synapsin I

“…Lin et al (13) have reported that NPAS4 regulates the development of GABAergic inhibitory synapses in an activity-dependent manner and suggested its homeostatic role in the balance between excitatory and inhibitory neuronal activities in the brain. We previously reported that reduced Npas4 mRNA levels may contribute to impairments in adult neurogenesis in the hippocampus, memory and emotional behaviors induced by social isolation or restriction stress (16,17). Recent studies (18,19) revealed that NPAS4 is important in memory formation and consolidation.…”