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Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress.

Schloesser RJ, Lehmann M, Martinowich K, Manji HK, Herkenham M - Mol. Psychiatry (2010)

Bottom Line: It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression.Our data show two main findings.First, living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and second, these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Pathophysiology, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

ABSTRACT
The subgranular zone of the adult hippocampal dentate gyrus contains a pool of neural stem cells that continuously divide and differentiate into functional granule cells. It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression. The survival of newly born hippocampal neurons is decreased by chronic psychosocial stress and increased by exposure to enriched environments. These observations suggest the existence of a link between hippocampal neurogenesis, stress-induced behavioral changes, and the beneficial effects of enriched environment. To show causality, we subjected transgenic mice with conditionally suppressed neurogenesis to psychosocial stress followed by environmental enrichment. First, we showed that repeated social defeat coupled with chronic exposure to an aggressor produces robust and quantifiable indices of submissive and depressive-like behaviors; second, subsequent exposure to an enriched environment led to extinction of the submissive phenotype, while animals exposed to an impoverished environment retained the submissive phenotype; and third, enrichment was not effective in reversing the submissive and depressive-like behaviors in transgenic mice lacking neurogenesis. Our data show two main findings. First, living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and second, these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neurogenesis.

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Diagram depicting experimental groups and study design (a). An initial cohort consisting of control and NG- mice were first housed for 14 days under social conflict (SC) conditions during which time aggressive encounters were scored for 5 min day–1. Following SC induction, all animals were removed from the SC living condition and divided into four groups: 1. Control animals living under EE conditions, 2. NG- animals living under EE conditions, 3. Control animals living under IE conditions and 4. NG- animals living under IE conditions. Following 3 weeks of either the EE or IE condition, all groups were re-exposed to SC for 14 days during which aggressive encounters were scored for 5 min day–1. In addition, all groups underwent a behavioral battery during the final week of the SC condition (a). SC induction period (b–d): Chronic psychosocial stress and daily social defeat induce subordinate/submissive phenotype in Ctrl and NG- mice. The induction of submissive behavior was determined by; (b) percentage of conflicts won, (c) the number of approaches by the intruder mouse towards the resident dominant CD-1 mouse and (d) time spent immobile. As NG- (n=22) and control (n=22) mice accumulated social conflict defeats, aggressive behaviors declined and immobility increased. Ctrl and NG- mice showed no significant differences in the development of submissive behavior. SC Re-exposure (e–g): In previously submissive male mice, hippocampal neurogenesis and environmental enrichment opposes the development of subordinate phenotype during re-exposure to chronic psychosocial stress. Compared with all other groups, EE Ctrl mice showed; (d) a significant increase in percentage of conflicts won (significant effect of group [F3,41=73.66; P<0.001], day [F13,29=2.581; P<0.02] and a significant interaction between group × day [F13,29=2.053; P<0.01], (e) a significant increase in approaches towards resident CD-1 mouse (significant effect of group [F3,41=22.54; P<0.001], and (f) a significant decrease in time spent immobile during conflict sessions (significant effect of group [F3,41=25.302; P<0.001], day [F13,29=2.966; P<0.01]. *indicates significant difference (P<0.05) between EE Ctrl and all other treatment groups. **indicates significant difference (P<0.05) between EE Ctrl and IE Ctrl/IE NG- groups. ***indicates significant difference (P<0.05) between Ctrl and NG- groups. N=11 per group. Data are expressed as mean±s.e.m. (h) EE exposed groups show higher levels of exploration in the first 15 min in a novel environment compared with all other treatment groups (significant effect of treatment: F3,19=5.268, P<0.01). n=6 per group. (i) Only animals living in EE with intact neurogenesis showed preference for saccharine (values above 50% [horizontal line] indicate preference for saccharine solution above chance) (significant effect of treatment: F3,38=3.539, P=0.0235). n=10–11 per group. (j) In the light–dark box test, animals that had lived in EE with intact neurogenesis spend less time in the dark compartment compared with all other groups (significant effect of treatment: F3,39=12.41, P<0.0001). n=10–11 per group. Results are expressed as mean±s.e.m. *indicates significantly different (P<0.05) from all other treatment groups. One-way ANOVA followed by Newman Keuls post hoc test.
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fig4: Diagram depicting experimental groups and study design (a). An initial cohort consisting of control and NG- mice were first housed for 14 days under social conflict (SC) conditions during which time aggressive encounters were scored for 5 min day–1. Following SC induction, all animals were removed from the SC living condition and divided into four groups: 1. Control animals living under EE conditions, 2. NG- animals living under EE conditions, 3. Control animals living under IE conditions and 4. NG- animals living under IE conditions. Following 3 weeks of either the EE or IE condition, all groups were re-exposed to SC for 14 days during which aggressive encounters were scored for 5 min day–1. In addition, all groups underwent a behavioral battery during the final week of the SC condition (a). SC induction period (b–d): Chronic psychosocial stress and daily social defeat induce subordinate/submissive phenotype in Ctrl and NG- mice. The induction of submissive behavior was determined by; (b) percentage of conflicts won, (c) the number of approaches by the intruder mouse towards the resident dominant CD-1 mouse and (d) time spent immobile. As NG- (n=22) and control (n=22) mice accumulated social conflict defeats, aggressive behaviors declined and immobility increased. Ctrl and NG- mice showed no significant differences in the development of submissive behavior. SC Re-exposure (e–g): In previously submissive male mice, hippocampal neurogenesis and environmental enrichment opposes the development of subordinate phenotype during re-exposure to chronic psychosocial stress. Compared with all other groups, EE Ctrl mice showed; (d) a significant increase in percentage of conflicts won (significant effect of group [F3,41=73.66; P<0.001], day [F13,29=2.581; P<0.02] and a significant interaction between group × day [F13,29=2.053; P<0.01], (e) a significant increase in approaches towards resident CD-1 mouse (significant effect of group [F3,41=22.54; P<0.001], and (f) a significant decrease in time spent immobile during conflict sessions (significant effect of group [F3,41=25.302; P<0.001], day [F13,29=2.966; P<0.01]. *indicates significant difference (P<0.05) between EE Ctrl and all other treatment groups. **indicates significant difference (P<0.05) between EE Ctrl and IE Ctrl/IE NG- groups. ***indicates significant difference (P<0.05) between Ctrl and NG- groups. N=11 per group. Data are expressed as mean±s.e.m. (h) EE exposed groups show higher levels of exploration in the first 15 min in a novel environment compared with all other treatment groups (significant effect of treatment: F3,19=5.268, P<0.01). n=6 per group. (i) Only animals living in EE with intact neurogenesis showed preference for saccharine (values above 50% [horizontal line] indicate preference for saccharine solution above chance) (significant effect of treatment: F3,38=3.539, P=0.0235). n=10–11 per group. (j) In the light–dark box test, animals that had lived in EE with intact neurogenesis spend less time in the dark compartment compared with all other groups (significant effect of treatment: F3,39=12.41, P<0.0001). n=10–11 per group. Results are expressed as mean±s.e.m. *indicates significantly different (P<0.05) from all other treatment groups. One-way ANOVA followed by Newman Keuls post hoc test.

Mentions: Male mice develop social hierarchies based on agonistic (aggressive) encounters. Although all participants initially display overt aggressive behavior, winners and losers emerge after repeated interactions. In the SC paradigm (see Figure 4a for an experimental timeline), a stable dominant-subordinate hierarchy formed over time, and repeated defeats rendered the test mice chronically submissive. The extent and form of agonistic interaction during the SC induction period was similar for the Ctrl and NG- groups (Figure 4b–d and Supplementary Figure 1). Initially, both Ctrl and NG- mice displayed an equally strong aggressive phenotype directed towards the CD-1 mouse as shown by elevated approaches towards the CD-1 mouse (Figure 4c), brief time spent immobile (Figure 4d), and high number of tail rattles (Supplementary Figure 1c). Aggressive behaviors in both groups rapidly declined and were absent by the seventh day of the induction period as social defeats accumulated. Immobility behavior offers a striking example of the powerful effect of SC on behavior. On days 1–3, mice in both groups spent less than 50 s of the 5-min encounter immobile (Figure 4d). However, immobility time increased to ∼100 s on days 6–8, and by day 11, mice in both groups spent the majority of the session immobile. Both groups also showed similar decreases in latency to conflict, number of explorations and relatively constant numbers of conflicts, and withdrawals across the sessions (Supplementary Figure 1).


Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress.

Schloesser RJ, Lehmann M, Martinowich K, Manji HK, Herkenham M - Mol. Psychiatry (2010)

Diagram depicting experimental groups and study design (a). An initial cohort consisting of control and NG- mice were first housed for 14 days under social conflict (SC) conditions during which time aggressive encounters were scored for 5 min day–1. Following SC induction, all animals were removed from the SC living condition and divided into four groups: 1. Control animals living under EE conditions, 2. NG- animals living under EE conditions, 3. Control animals living under IE conditions and 4. NG- animals living under IE conditions. Following 3 weeks of either the EE or IE condition, all groups were re-exposed to SC for 14 days during which aggressive encounters were scored for 5 min day–1. In addition, all groups underwent a behavioral battery during the final week of the SC condition (a). SC induction period (b–d): Chronic psychosocial stress and daily social defeat induce subordinate/submissive phenotype in Ctrl and NG- mice. The induction of submissive behavior was determined by; (b) percentage of conflicts won, (c) the number of approaches by the intruder mouse towards the resident dominant CD-1 mouse and (d) time spent immobile. As NG- (n=22) and control (n=22) mice accumulated social conflict defeats, aggressive behaviors declined and immobility increased. Ctrl and NG- mice showed no significant differences in the development of submissive behavior. SC Re-exposure (e–g): In previously submissive male mice, hippocampal neurogenesis and environmental enrichment opposes the development of subordinate phenotype during re-exposure to chronic psychosocial stress. Compared with all other groups, EE Ctrl mice showed; (d) a significant increase in percentage of conflicts won (significant effect of group [F3,41=73.66; P<0.001], day [F13,29=2.581; P<0.02] and a significant interaction between group × day [F13,29=2.053; P<0.01], (e) a significant increase in approaches towards resident CD-1 mouse (significant effect of group [F3,41=22.54; P<0.001], and (f) a significant decrease in time spent immobile during conflict sessions (significant effect of group [F3,41=25.302; P<0.001], day [F13,29=2.966; P<0.01]. *indicates significant difference (P<0.05) between EE Ctrl and all other treatment groups. **indicates significant difference (P<0.05) between EE Ctrl and IE Ctrl/IE NG- groups. ***indicates significant difference (P<0.05) between Ctrl and NG- groups. N=11 per group. Data are expressed as mean±s.e.m. (h) EE exposed groups show higher levels of exploration in the first 15 min in a novel environment compared with all other treatment groups (significant effect of treatment: F3,19=5.268, P<0.01). n=6 per group. (i) Only animals living in EE with intact neurogenesis showed preference for saccharine (values above 50% [horizontal line] indicate preference for saccharine solution above chance) (significant effect of treatment: F3,38=3.539, P=0.0235). n=10–11 per group. (j) In the light–dark box test, animals that had lived in EE with intact neurogenesis spend less time in the dark compartment compared with all other groups (significant effect of treatment: F3,39=12.41, P<0.0001). n=10–11 per group. Results are expressed as mean±s.e.m. *indicates significantly different (P<0.05) from all other treatment groups. One-way ANOVA followed by Newman Keuls post hoc test.
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fig4: Diagram depicting experimental groups and study design (a). An initial cohort consisting of control and NG- mice were first housed for 14 days under social conflict (SC) conditions during which time aggressive encounters were scored for 5 min day–1. Following SC induction, all animals were removed from the SC living condition and divided into four groups: 1. Control animals living under EE conditions, 2. NG- animals living under EE conditions, 3. Control animals living under IE conditions and 4. NG- animals living under IE conditions. Following 3 weeks of either the EE or IE condition, all groups were re-exposed to SC for 14 days during which aggressive encounters were scored for 5 min day–1. In addition, all groups underwent a behavioral battery during the final week of the SC condition (a). SC induction period (b–d): Chronic psychosocial stress and daily social defeat induce subordinate/submissive phenotype in Ctrl and NG- mice. The induction of submissive behavior was determined by; (b) percentage of conflicts won, (c) the number of approaches by the intruder mouse towards the resident dominant CD-1 mouse and (d) time spent immobile. As NG- (n=22) and control (n=22) mice accumulated social conflict defeats, aggressive behaviors declined and immobility increased. Ctrl and NG- mice showed no significant differences in the development of submissive behavior. SC Re-exposure (e–g): In previously submissive male mice, hippocampal neurogenesis and environmental enrichment opposes the development of subordinate phenotype during re-exposure to chronic psychosocial stress. Compared with all other groups, EE Ctrl mice showed; (d) a significant increase in percentage of conflicts won (significant effect of group [F3,41=73.66; P<0.001], day [F13,29=2.581; P<0.02] and a significant interaction between group × day [F13,29=2.053; P<0.01], (e) a significant increase in approaches towards resident CD-1 mouse (significant effect of group [F3,41=22.54; P<0.001], and (f) a significant decrease in time spent immobile during conflict sessions (significant effect of group [F3,41=25.302; P<0.001], day [F13,29=2.966; P<0.01]. *indicates significant difference (P<0.05) between EE Ctrl and all other treatment groups. **indicates significant difference (P<0.05) between EE Ctrl and IE Ctrl/IE NG- groups. ***indicates significant difference (P<0.05) between Ctrl and NG- groups. N=11 per group. Data are expressed as mean±s.e.m. (h) EE exposed groups show higher levels of exploration in the first 15 min in a novel environment compared with all other treatment groups (significant effect of treatment: F3,19=5.268, P<0.01). n=6 per group. (i) Only animals living in EE with intact neurogenesis showed preference for saccharine (values above 50% [horizontal line] indicate preference for saccharine solution above chance) (significant effect of treatment: F3,38=3.539, P=0.0235). n=10–11 per group. (j) In the light–dark box test, animals that had lived in EE with intact neurogenesis spend less time in the dark compartment compared with all other groups (significant effect of treatment: F3,39=12.41, P<0.0001). n=10–11 per group. Results are expressed as mean±s.e.m. *indicates significantly different (P<0.05) from all other treatment groups. One-way ANOVA followed by Newman Keuls post hoc test.
Mentions: Male mice develop social hierarchies based on agonistic (aggressive) encounters. Although all participants initially display overt aggressive behavior, winners and losers emerge after repeated interactions. In the SC paradigm (see Figure 4a for an experimental timeline), a stable dominant-subordinate hierarchy formed over time, and repeated defeats rendered the test mice chronically submissive. The extent and form of agonistic interaction during the SC induction period was similar for the Ctrl and NG- groups (Figure 4b–d and Supplementary Figure 1). Initially, both Ctrl and NG- mice displayed an equally strong aggressive phenotype directed towards the CD-1 mouse as shown by elevated approaches towards the CD-1 mouse (Figure 4c), brief time spent immobile (Figure 4d), and high number of tail rattles (Supplementary Figure 1c). Aggressive behaviors in both groups rapidly declined and were absent by the seventh day of the induction period as social defeats accumulated. Immobility behavior offers a striking example of the powerful effect of SC on behavior. On days 1–3, mice in both groups spent less than 50 s of the 5-min encounter immobile (Figure 4d). However, immobility time increased to ∼100 s on days 6–8, and by day 11, mice in both groups spent the majority of the session immobile. Both groups also showed similar decreases in latency to conflict, number of explorations and relatively constant numbers of conflicts, and withdrawals across the sessions (Supplementary Figure 1).

Bottom Line: It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression.Our data show two main findings.First, living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and second, these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Pathophysiology, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

ABSTRACT
The subgranular zone of the adult hippocampal dentate gyrus contains a pool of neural stem cells that continuously divide and differentiate into functional granule cells. It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression. The survival of newly born hippocampal neurons is decreased by chronic psychosocial stress and increased by exposure to enriched environments. These observations suggest the existence of a link between hippocampal neurogenesis, stress-induced behavioral changes, and the beneficial effects of enriched environment. To show causality, we subjected transgenic mice with conditionally suppressed neurogenesis to psychosocial stress followed by environmental enrichment. First, we showed that repeated social defeat coupled with chronic exposure to an aggressor produces robust and quantifiable indices of submissive and depressive-like behaviors; second, subsequent exposure to an enriched environment led to extinction of the submissive phenotype, while animals exposed to an impoverished environment retained the submissive phenotype; and third, enrichment was not effective in reversing the submissive and depressive-like behaviors in transgenic mice lacking neurogenesis. Our data show two main findings. First, living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and second, these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neurogenesis.

Show MeSH
Related in: MedlinePlus