Abstract TP104: Post Stroke Depressive-Like Behaviors in Middle-Aged Female Rats is Associated With Gut Dysbiosis and Improved by Mir363-3p

Background: Post-stroke depression (PSD) occurs in one-third of stroke survivors, is more prevalent in women, and negatively impacts quality of life and recovery. Our previous work showed that acyclic middle-aged female rats display depressive behaviors after stroke, and IV treatment with mir363-3p attenuates these behaviors. Serotonin has been implicated in affective behaviors, and loss of this neurotransmitter is also associated with decreased neurogenesis in the hippocampus. The present study determined (a) whether stroke affected tryptophan, a gut metabolite, and precursor for serotonin, and cell proliferation in the hippocampus and (b) whether serum tryptophan levels and hippocampal cell proliferation was restored by mir363-3p. Methods: Ischemic stroke was induced by stereotaxic delivery of endothelin-1 to the MCA of middle-aged female rats. Animals received a single injection of mir363-3p or scrambled oligos 4h after stroke. Depressive-like behaviors were assessed by the Effort-based sucrose consumption test, Social Interaction and Forced Swim Test 3 months after stroke. Blood was collected at termination. Serum tryptophan levels were quantified by ELISA. Bacterial composition was analyzed by 16S sequencing of fecal samples. Ki67 immunohistochemistry was performed on brain tissue collected at termination and quantified within the dentate gyrus by two blind observers. Results: Animals subjected to stroke exhibited depressive-like behaviors and had decreased tryptophan levels as compared to sham treated animals. This is also accompanied by microbiota dysbiosis as measured by an elevated ratio of Firmicutes to Bacteroidetes. Mir363-3p treatment increased tryptophan levels as compared to scrambled controls and were no different from sham (non-stroke) animals. Moreover, miR363-3p treated rats exhibit a significantly more dentate gyrus-specific Ki67 expression a proliferation marker. Conclusions: Together, these data indicate that miR363-3p attenuates post stroke depression via a mechanism that prevents microbiota dysbiosis and increases hippocampal cell proliferation.

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Post-Stroke Social Isolation Reduces Cell Proliferation in the Dentate Gyrus and Alters miRNA Profiles in the Aged Female Mice Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22010099 ◽

2020 ◽

Vol 22 (1) ◽

pp. 99

Author(s):

Aleah Holmes ◽

Yan Xu ◽

Juneyoung Lee ◽

Michael E. Maniskas ◽

Liang Zhu ◽

...

Keyword(s):

Cell Proliferation ◽

Dentate Gyrus ◽

Social Isolation ◽

Census Data ◽

Elderly Women ◽

Stroke Recovery ◽

Tissue Loss ◽

Female Mice ◽

Post Stroke ◽

The Brain

Social isolation and loneliness are risk factors for stroke. Elderly women are more likely to be isolated. Census data shows that in homeowners over the age of 65, women are much more likely to live alone. However, the underlying mechanisms of the detrimental effects of isolation have not been well studied in older females. In this study, we hypothesized that isolation impairs post-stroke recovery in aged female mice, leading to dysregulated microRNAs (miRNAs) in the brain, including those previously shown to be involved in response to social isolation (SI). Aged C57BL/6 female mice were subjected to a 60-min middle cerebral artery occlusion and were randomly assigned to either single housing (SI) or continued pair housing (PH) immediately after stroke for 15 days. SI immediately after stroke led to significantly more brain tissue loss after stroke and higher mortality. Furthermore, SI significantly delayed motor and sensory recovery and worsened cognitive function, compared to PH. A decrease in cell proliferation was seen in the dentate gyrus of SI mice assessed by bromodeoxyuridine (BrdU) labeling. miRNAome data analysis revealed changes in several miRNAs in the brain, such as miR-297a-3p and miR-200c-3p, which are known to regulate pathways involved in cell proliferation. In conclusion, our data suggest that SI can lead to a poor post-stroke recovery in aged females and dysregulation of miRNAs and reduced hippocampal cell proliferation.

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Abstract P757: Social Isolation After Stroke Reduces Cell Proliferation and Alters Brain MiRNA Profiles in the Aged Female Mice

Stroke ◽

10.1161/str.52.suppl_1.p757 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Aleah Holmes ◽

Yan Xu ◽

Juneyoung Lee ◽

Liang Zhu ◽

Venugopal Reddy Venna ◽

...

Keyword(s):

Cell Proliferation ◽

Social Isolation ◽

Elderly Women ◽

Epidemiological Studies ◽

Stroke Recovery ◽

Tissue Loss ◽

Adhesive Tape ◽

Female Mice ◽

Post Stroke ◽

Hippocampal Cell

Background: Social isolation (SI) and loneliness are risk factors for stroke. Epidemiological studies have shown that women tend to have a higher risk of stroke at later age and elderly women are more likely to be isolated. The mechanisms underlying the detrimental effects of SI have not been well studied in older females. We hypothesized that SI in aged female mice would lead to impaired post-stroke recovery and could lead to differential regulation of microRNAs (miRNAs). Methods: In this study, aged C57BL/6N female mice were subjected to a 60-minute middle cerebral artery occlusion (MCAO) and were randomly assigned to either single housing (SI) or continued pair housing (PH) immediately after stroke for 15 days. Infarct size, mortality and recovery was assessed using open field, the adhesive-tape removal task and the Y-maze test. MiRNAs were comprehensively analyzed by miRNAome analysis on stroke brain, and changes in hippocampal cell proliferation was assessed from perfused brain sections. Results: Importantly, SI immediately after stroke led to significantly larger tissue loss and higher mortality in aged females, it also significantly delayed motor/sensory recovery in the adhesive removal test and impaired overall locomotor activity. In addition, these mice also demonstrated worse post-stroke cognitive function. In parallel, brains of these mice showed reduced miR-297a-3p expression and increased miR-18a-3p and miR-200c-3p expression with SI compared to PH cohort and reduced hippocampal cell proliferation. Conclusion: The results from this study suggest that SI after stroke can increase mortality and significantly impair post-stroke recovery in aged female mice. These worse outcomes are in parallel to the significant changes in several miRNAs and reduced hippocampal cell proliferation.

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Abstract WP96: The Histone Deacetylase Inhibitor, Sodium Butyrate, Exhibits Biphasic Neuroprotective Mechanisms in the Acute Phase of Ischemic Stroke in Middle-Aged Female Rats

Stroke ◽

10.1161/str.48.suppl_1.wp96 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Min Jung Park ◽

Farida Sohrabji

Keyword(s):

Histone Deacetylase ◽

Acute Phase ◽

Sodium Butyrate ◽

Hdac Inhibitor ◽

Female Rats ◽

Middle Aged ◽

Peripheral Tissues ◽

Post Stroke ◽

Sensory Motor ◽

Anti Inflammatory

Introduction: Sodium butyrate (NaB) is a histone deacetylase (HDAC) inhibitor exhibiting anti-inflammatory and neuroprotective effects in a rat ischemic model of a myocardial ischemia as well as stroke. Although clinical evidence shows that older women are at higher risk for stroke occurrence and greater stroke severity, no studies have evaluated the effectiveness of NaB either in females or in older animals. Methods: To determine the effects of NaB on stroke in older females, acyclic middle-aged Sprague-Dawley female rats (10-12 months old, constant diestrus) were subject to middle cerebral artery occlusion (MCAo) by intracerebral injection of recombinant endothelin-1. Rats were treated with NaB (300 mg/kg, i.p.) at 6h and 30h following ET-1 injection. Animals were tested for sensory motor performance pre and post stroke. Subsequently, rats were sacrificed at the early (2d) or late (5d) acute phase after MCAo. Serum and tissue samples were collected for biochemical analyses. Results: NaB treatment reduced infarct volume and ameliorated stroke-induced sensory motor impairment in middle-aged female rats post MCAo. At the early acute phase, NaB treatment decreased brain lipid peroxides, and reduced serum levels of GFAP, a marker of blood brain barrier permeability. NaB also reduced expression of the inflammatory cytokine IL-1beta in circulation and IL-18 in the ischemic hemisphere. At the late acute phase, NaB treatment further suppressed MCAo-induced increase of IL-1beta, IL-17A, and IL-18 in brain lysates (cortex and striatum) from the ischemic hemisphere, and decreased ischemia-induced upregulation of IL-1beta and IL-18 in circulation, indicating a potent anti-inflammatory effect of the HDAC inhibitor. Moreover, NaB treatment also increased expression of IGF-1, a known neuroprotectant, in peripheral tissues including serum, liver, and spleen. Conclusions: These data provide the first evidence that delayed (> 6h) NaB treatment post-stroke is neuroprotective in older female rats. Importantly, these data also show that in addition to its well-known anti-inflammatory actions, NaB may exert a biphasic effect after stroke, operating initially to reduce oxidative stress in the brain, and later, elevating IGF-1 expression in peripheral tissues.

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Inverse relationship between adult hippocampal cell proliferation and synaptic rewiring in the dentate gyrus

Hippocampus ◽

10.1002/hipo.20445 ◽

2008 ◽

Vol 18 (9) ◽

pp. 879-898 ◽

Cited By ~ 33

Author(s):

Markus Butz ◽

Gertraud Teuchert-Noodt ◽

Keren Grafen ◽

Arjen van Ooyen

Keyword(s):

Cell Proliferation ◽

Dentate Gyrus ◽

Inverse Relationship ◽

Hippocampal Cell

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Zizyphus Enhances Cell Proliferation and Neuroblast Differentiation in the Subgranular Zone of the Dentate Gyrus in Middle-Aged Mice

Journal of Medicinal Food ◽

10.1089/jmf.2010.1123 ◽

2011 ◽

Vol 14 (3) ◽

pp. 195-200 ◽

Cited By ~ 6

Author(s):

In Koo Hwang ◽

Ki-Yeon Yoo ◽

Dae Young Yoo ◽

Jung Hoon Choi ◽

Choong Hyun Lee ◽

...

Keyword(s):

Cell Proliferation ◽

Dentate Gyrus ◽

Subgranular Zone ◽

Middle Aged ◽

Aged Mice ◽

Neuroblast Differentiation

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Maternal diet of polyunsaturated fatty acid altered the cell proliferation in the dentate gyrus of hippocampus and influenced glutamatergic and serotoninergic systems of neonatal female rats

Lipids in Health and Disease ◽

10.1186/s12944-016-0236-1 ◽

2016 ◽

Vol 15 (1) ◽

Cited By ~ 26

Author(s):

Mimi Tang ◽

Min Zhang ◽

Hualin Cai ◽

Huande Li ◽

Pei Jiang ◽

...

Keyword(s):

Cell Proliferation ◽

Fatty Acid ◽

Dentate Gyrus ◽

Polyunsaturated Fatty Acid ◽

Maternal Diet ◽

Female Rats

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Induction of cell proliferation and neuroblasts in the subgranular zone of the dentate gyrus by aqueous extract from Platycodon grandiflorum in middle-aged mice

Neuroscience Letters ◽

10.1016/j.neulet.2008.07.057 ◽

2008 ◽

Vol 444 (1) ◽

pp. 97-101 ◽

Cited By ~ 8

Author(s):

Ki-Yeon Yoo ◽

Ok Kyu Park ◽

In Koo Hwang ◽

Hua Li ◽

Shi Yong Ryu ◽

...

Keyword(s):

Cell Proliferation ◽

Dentate Gyrus ◽

Aqueous Extract ◽

Subgranular Zone ◽

Middle Aged ◽

Platycodon Grandiflorum ◽

Aged Mice

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Mir363-3p attenuates post-stroke depressive-like behaviors in middle-aged female rats

Brain Behavior and Immunity ◽

10.1016/j.bbi.2019.01.003 ◽

2019 ◽

Vol 78 ◽

pp. 31-40 ◽

Cited By ~ 4

Author(s):

Aditya Panta ◽

Sivani Pandey ◽

Irma N. Duncan ◽

Shaelynn Duhamel ◽

Farida Sohrabji

Keyword(s):

Female Rats ◽

Middle Aged ◽

Post Stroke

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Abstract T MP119: Forced Swim Test as an Index of Post-Stroke Depression in Rats

Stroke ◽

10.1161/str.45.suppl_1.tmp119 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Allison Kunze ◽

Dannielle Zierath ◽

Tessa Barclay ◽

Kyra J Becker

Keyword(s):

Forced Swim Test ◽

Plasma Concentrations ◽

Response To Therapy ◽

Maximal Velocity ◽

Lewis Rats ◽

Post Stroke ◽

Swim Test ◽

Sd Rats ◽

Forced Swim ◽

Post Stroke Depression

Background: Depression is common after stroke. The Porsolt Forced Swim Test (FST) is used to screen for depression and response to therapy in rodent models. The duration of immobility is considered to be an indication of learned helplessness. In this study we aimed to characterize post-stroke depression using the FST. Methods: Male Lewis (N=6), Wistar (N=5), and Sprague Dawley (SD; N=11) rats were subjected to the FST (10 minutes) prior to 2 hours middle cerebral artery occlusion (MCAO) and then again at 28 days after MCAO. Sham-operated animals were used as controls. The latency to immobility and the duration of immobility were assessed along with the maximum velocity of movement. Blood was obtained at the time of sacrifice and assayed for interleukin (IL)-1α, IL-1β and IL-10. Statistics are non-parametric; data are displayed as median and interquartile range. Results: Prior to stroke, the latency to immobility was similar in all strains, but the duration of immobility was greater in Lewis rats (201 [159, 294] secs; P =0.039) than in Wistar (148 [106, 184] secs) and SD rats (136 [112, 200] secs). The maximal velocity of movement in Lewis rats (47 [42, 55] cm/sec; P =0.007) was faster than Wistar (29 [25, 41] cm/sec) and SD (39 [34, 46] cm/sec) rats. In comparison to strain matched sham-operated animals, stroke was associated with an increase in the period of immobility (P=0.088), a decrease in latency to immobility ( P =0.019) and an increase in the maximal velocity of movements ( P =0.033) in Lewis rats. No significant differences in FST behavior were seen in Wistar or SD rats. Plasma concentrations of IL-1α (P=0.001) and IL-10 (P=0.011) were highest in Lewis rats at the time of sacrifice. The duration of immobility was most highly correlated with IL-1β (r=0.663, P =0.003) and IL-10 (r=0.575, P =0.013). Summary: At baseline, Lewis rats exhibit more depressive behavior than Wistar and SD rats, and stroke appears to enhance these differences. The change in behavior on the FST is associated with an increase in markers of systemic inflammation. The FST could be used to study interventions for post-stroke depression.

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