Sex-Dependent Effects of Environmental Enrichment on Spatial Memory and Brain-Derived Neurotrophic Factor (BDNF) Signaling in a Developmental “Two-Hit” Mouse Model Combining BDNF Haploinsufficiency and Chronic Glucocorticoid Stimulation

Abstract Haploinsufficiency of RAI1 is responsible for Smith-Magenis Syndrome (SMS), a childhood neurodevelopmental disorder associated with hyperphagia, obesity, and autistic features. We previously showed that constitutive inactivation of one or both copies of Rai1 in the germline or developing brain induces SMS-like neurobehavioral deficits and obesity in mice. By contrast, the postnatal function of Rai1 is unclear. Here, we globally deleted one or both copies of Rai1 during two postnatal developmental windows by generating an inducible Rai1 knockout mouse model. We found that delayed Rai1 deletion at 3 or 8 weeks of age had no effect on neurobehavioral functions but resulted in adult-onset obesity and decreased expression of brain-derived neurotrophic factor (Bdnf) in the hypothalamus. Remarkably, genetic overexpression of human Bdnf in Rai1 heterozygous mice reversed SMS-like obesity, hyperphagia, metabolic syndrome-like features, and hyposociability. Increasing Bdnf signaling in the paraventricular nucleus of the hypothalamus (PVH) or the ventromedial nucleus of the hypothalamus (VMH) was sufficient to mediate the anti-obesity effect. Our work identifies the function of Rai1 in different temporal windows after birth and provides in vivo evidence that increasing Bdnf signaling is therapeutically effective in a preclinical mouse model of SMS.

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A Novel Knockout Mouse Model of the Noncoding Antisense Brain-Derived Neurotrophic Factor (Bdnf) Gene Displays Increased Endogenous Bdnf Protein and Improved Memory Function Following Exercise

SSRN Electronic Journal ◽

10.2139/ssrn.3733188 ◽

2020 ◽

Author(s):

Farzaneh Modarresi ◽

Roya Pedram-Fatemi ◽

Seyedeh Fatemeh Razavipour ◽

Natalie Ricciardi ◽

Madina Makhmutova ◽

...

Keyword(s):

Mouse Model ◽

Neurotrophic Factor ◽

Knockout Mouse ◽

Memory Function ◽

Brain Derived Neurotrophic Factor ◽

Knockout Mouse Model ◽

I Gene

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Modulation of Brain-Derived Neurotrophic Factor (BDNF) Signaling Pathway by Culinary Sage (Salvia officinalis L.)

International Journal of Molecular Sciences ◽

10.3390/ijms22147382 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7382

Author(s):

Nancy Chiang ◽

Shahla Ray ◽

Jade Lomax ◽

Sydney Goertzen ◽

Slavko Komarnytsky ◽

...

Keyword(s):

Liquid Chromatography ◽

Neurotrophic Factor ◽

High Performance ◽

Memory Function ◽

Brain Derived Neurotrophic Factor ◽

Salvia Officinalis ◽

C6 Glioma Cells ◽

Medicinal Uses ◽

Bdnf Signaling ◽

Salvia Officinalis L

Culinary sage (Salvia officinalis L.) is a common spice plant in the mint family (Lamiaceae) well known for its distinctive culinary and traditional medicinal uses. Sage tea has been used traditionally as a brain-enhancing tonic and extracts from sage have been reported to have both cognitive and memory enhancing effects. Brain-derived neurotrophic factor (BDNF) is an endogenous signaling molecule involved in cognition and memory function. In this study, activity-guided fractionation employing preparative reverse-phase high performance liquid chromatography (RP-HPLC) of culinary sage extracts led to the discovery of benzyl 6-O-β-D-apiofuranosyl-β-D-glucoside (B6AG) as a natural product that upregulates transcription of neurotrophic factors in C6 glioma cells. Purified B6AG showed a moderate dose response, with upregulation of BDNF and with EC50 at 6.46 μM. To better understand the natural variation in culinary sage, B6AG was quantitated in the leaves of several commercial varieties by liquid chromatography-mass spectrometry (LC-MS). The level of B6AG in dried culinary sage was found to range from 334 ± 14 to 698 ± 65 μg/g. This study provided a foundation for future investigations, including quantitative inquiries on the distribution of B6AG within the different plant organs, explorations in optimizing post-harvest practices, and aid in the development of sage varieties with elevated levels of B6AG.

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Social Defeat Stress during Early Adolescence Confers Resilience against a Single Episode of Prolonged Stress in Adult Rats

Cells ◽

10.3390/cells10020360 ◽

2021 ◽

Vol 10 (2) ◽

pp. 360

Author(s):

Giulia Federica Mancini ◽

Enrico Marchetta ◽

Irene Pignani ◽

Viviana Trezza ◽

Patrizia Campolongo

Keyword(s):

Spatial Memory ◽

Early Adolescence ◽

Neurotrophic Factor ◽

Social Defeat ◽

Brain Derived Neurotrophic Factor ◽

Plasma Corticosterone ◽

Social Defeat Stress ◽

Single Episode ◽

Second Hit ◽

Prolonged Stress

Early-life adverse experiences (first hit) lead to coping strategies that may confer resilience or vulnerability to later experienced stressful events (second hit) and the subsequent development of stress-related psychopathologies. Here, we investigated whether exposure to two stressors at different stages in life has long-term effects on emotional and cognitive capabilities, and whether the interaction between the two stressors influences stress resilience. Male rats were subjected to social defeat stress (SDS, first hit) in adolescence and to a single episode of prolonged stress (SPS, second hit) in adulthood. Behavioral outcomes, hippocampal expression of brain-derived neurotrophic factor, and plasma corticosterone levels were tested in adulthood. Rats exposed to both stressors exhibited resilience against the development of stress-induced alterations in emotional behaviors and spatial memory, but vulnerability to cued fear memory dysfunction. Rats subjected to both stressors demonstrated resilience against the SDS-induced alterations in hippocampal brain-derived neurotrophic factor expression and plasma corticosterone levels. SPS alone altered locomotion and spatial memory retention; these effects were absent in SDS-exposed rats later exposed to SPS. Our findings reveal that exposure to social stress during early adolescence influences the ability to cope with a second challenge experienced later in life.

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