Environmental enrichment initiated in adolescence restores the reduced expression of synaptophysin and GFAP in the hippocampus of chronically stressed rats in a sex‐specific manner
Εvgenia Dandi,
Paschalis Theotokis,
Maria Christina Petri
et al.
Abstract:This study aims at investigating whether environmental enrichment (EE) initiated in adolescence can alter chronic unpredictable stress (CUS)‐associated changes in astroglial and synaptic plasticity markers in male and female rats. To this end, we studied possible alterations in hippocampal glial fibrillary acidic protein (GFAP) and synaptophysin (SYN) in CUS rats previously housed in EE. Wistar rats on postnatal day (PND) 23 were housed for 10 weeks in standard housing (SH) or enriched conditions. On PND 66, a… Show more
“…Specifically, the learning impairments previously found exclusively in CUS males could be associated with the decreases found in SYN and CB 1 receptor expression in the CA3 and CA1 hippocampal areas. Meanwhile, the decreases in SYN and CB 1 receptor expression in CA1 observed in females may explain the increase in depressive behavior detected only in females [38,39]. In support of the present findings, existing evidence highlights the role of eCBs in modulating synaptic function and contributing to synaptic plasticity through retrograde signaling to CB 1 and CB 2 receptors [58].…”
Section: Discussionsupporting
confidence: 88%
“…Based on our findings, the adverse effects of CUS on cognitive function and emotional behavior [38], which were also linked to a region and sex-specific decrease in the expression of glial fibrillary acidic protein (GFAP) and synaptophysin (SYN) in the hippocampus [39], may be mediated by alterations in the CB 1 receptor expression. Specifically, the learning impairments previously found exclusively in CUS males could be associated with the decreases found in SYN and CB 1 receptor expression in the CA3 and CA1 hippocampal areas.…”
Section: Discussionmentioning
confidence: 71%
“…The DAB signal was blindly quantified and analyzed using the ImageJ/Fiji software (version 1.2). The mean percentage of CB 1 -positive tissue area per hippocampal region was calculated as an indicator of CB 1 immunoreactivity (for more details, see [39]).…”
Section: Tissue Processingmentioning
confidence: 99%
“…The enriched environment (EE), described as "a new way of endogenous pharmacotherapy" [37], acts protectively against the negative effects induced by stressful experiences [38][39][40] and exerts significant molecular, anatomical and functional changes in the brain [41]. In animal studies, the EE condition refers to the housing of more than two same-sex animals in large cages equipped with various objects of varying shapes and sizes along with running wheels.…”
Stress-related mental disorders have become increasingly prevalent, thus endangering mental health worldwide. Exploring stress-associated brain alterations is vital for understanding the possible neurobiological mechanisms underlying these changes. Based on existing evidence, the brain endogenous cannabinoid system (ECS) plays a significant role in the stress response, and disruptions in its function are associated with the neurobiology of various stress-related disorders. This study primarily focuses on investigating the impact of chronic unpredictable stress (CUS) on the expression of hippocampal cannabinoid type 1 (CB1) receptors, part of the ECS, in adult male and female Wistar rats. Additionally, it explores whether environmental enrichment (EE) initiated during adolescence could mitigate the CUS-associated alterations in CB1 expression. Wistar rats, shortly after weaning, were placed in either standard housing (SH) or EE conditions for a duration of 10 weeks. On postnatal day 66, specific subgroups of SH or EE animals underwent a 4-week CUS protocol. Western blot (WB) analysis was conducted in the whole hippocampus of the left brain hemisphere to assess total CB1 protein expression, while immunohistochemistry (IHC) was performed on the right hemisphere to estimate the expression of CB1 receptors in certain hippocampal areas (i.e., CA1, CA3 and dentate gyrus-DG). The WB analysis revealed no statistically significant differences in total CB1 protein levels among the groups; however, reduced CB1 expression was found in specific hippocampal sub-regions using IHC. Specifically, CUS significantly decreased CB1 receptor expression in the CA1 and DG of both sexes, whereas in CA3 the CUS-associated decrease was limited to SH males. Interestingly, EE housing proved protective against these reductions. These findings suggest a region and sex-specific endocannabinoid response to chronic stress, emphasizing the role of positive early experiences in the protection of the adolescent brain against adverse conditions later in life.
“…Specifically, the learning impairments previously found exclusively in CUS males could be associated with the decreases found in SYN and CB 1 receptor expression in the CA3 and CA1 hippocampal areas. Meanwhile, the decreases in SYN and CB 1 receptor expression in CA1 observed in females may explain the increase in depressive behavior detected only in females [38,39]. In support of the present findings, existing evidence highlights the role of eCBs in modulating synaptic function and contributing to synaptic plasticity through retrograde signaling to CB 1 and CB 2 receptors [58].…”
Section: Discussionsupporting
confidence: 88%
“…Based on our findings, the adverse effects of CUS on cognitive function and emotional behavior [38], which were also linked to a region and sex-specific decrease in the expression of glial fibrillary acidic protein (GFAP) and synaptophysin (SYN) in the hippocampus [39], may be mediated by alterations in the CB 1 receptor expression. Specifically, the learning impairments previously found exclusively in CUS males could be associated with the decreases found in SYN and CB 1 receptor expression in the CA3 and CA1 hippocampal areas.…”
Section: Discussionmentioning
confidence: 71%
“…The DAB signal was blindly quantified and analyzed using the ImageJ/Fiji software (version 1.2). The mean percentage of CB 1 -positive tissue area per hippocampal region was calculated as an indicator of CB 1 immunoreactivity (for more details, see [39]).…”
Section: Tissue Processingmentioning
confidence: 99%
“…The enriched environment (EE), described as "a new way of endogenous pharmacotherapy" [37], acts protectively against the negative effects induced by stressful experiences [38][39][40] and exerts significant molecular, anatomical and functional changes in the brain [41]. In animal studies, the EE condition refers to the housing of more than two same-sex animals in large cages equipped with various objects of varying shapes and sizes along with running wheels.…”
Stress-related mental disorders have become increasingly prevalent, thus endangering mental health worldwide. Exploring stress-associated brain alterations is vital for understanding the possible neurobiological mechanisms underlying these changes. Based on existing evidence, the brain endogenous cannabinoid system (ECS) plays a significant role in the stress response, and disruptions in its function are associated with the neurobiology of various stress-related disorders. This study primarily focuses on investigating the impact of chronic unpredictable stress (CUS) on the expression of hippocampal cannabinoid type 1 (CB1) receptors, part of the ECS, in adult male and female Wistar rats. Additionally, it explores whether environmental enrichment (EE) initiated during adolescence could mitigate the CUS-associated alterations in CB1 expression. Wistar rats, shortly after weaning, were placed in either standard housing (SH) or EE conditions for a duration of 10 weeks. On postnatal day 66, specific subgroups of SH or EE animals underwent a 4-week CUS protocol. Western blot (WB) analysis was conducted in the whole hippocampus of the left brain hemisphere to assess total CB1 protein expression, while immunohistochemistry (IHC) was performed on the right hemisphere to estimate the expression of CB1 receptors in certain hippocampal areas (i.e., CA1, CA3 and dentate gyrus-DG). The WB analysis revealed no statistically significant differences in total CB1 protein levels among the groups; however, reduced CB1 expression was found in specific hippocampal sub-regions using IHC. Specifically, CUS significantly decreased CB1 receptor expression in the CA1 and DG of both sexes, whereas in CA3 the CUS-associated decrease was limited to SH males. Interestingly, EE housing proved protective against these reductions. These findings suggest a region and sex-specific endocannabinoid response to chronic stress, emphasizing the role of positive early experiences in the protection of the adolescent brain against adverse conditions later in life.
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