Sex-specific behavioral and structural alterations caused by early-life stress in C57BL/6 and BTBR mice

Reshetnikov, Vasiliy V.; Ayriyants, Kseniya A.; Ryabushkina, Yulia; Bobkov, Nikolai; Bondar, Natalia P.

doi:10.1016/j.bbr.2021.113489

Cited by 24 publications

(8 citation statements)

References 68 publications

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“…However, we found a significant main effect of genotype on total travel throughout the 30-minute period ( Figure 4B ; F(1, 36) = 22.795, p < 0.001), as well as during the 0-5 minute ( Figure 4C ; F(1,36) = 73.848, p < 0.001) and 5-10 minute periods ( Figure 4C ; F(1,36) = 58.489, p < 0.001). In the open field, BTBR mice walked a longer distance in 30 minutes compared to C57 mice ( Figure 4B , p < 0.001) as well as in the 0-5 minute ( Figure 4C , p < 0.001) and 5-10 minute periods ( Figure 4C , F(1,36) = 28.306, p < 0.001), suggesting that BTBR mice showed high locomotor activity within the beginning 10 minutes of the open field experiment, which is consistent with previously reported results ( Reshetnikov et al., 2021 ).…”

Section: Resultssupporting

confidence: 91%

GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice

Liu

Gao

et al. 2022

Front. Cell. Infect. Microbiol.

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Autism spectrum disorder (ASD) is considered a heterogeneous neurodevelopmental disorder characterized by significant social, communication, and behavioral impairments. The gut microbiota is increasingly considered a promising therapeutic target in ASD. Farnesoid X receptor (FXR) has recently been shown to modulate the gut microbiota. We hypothesized that FXR agonist GW4064 could ameliorate behavioral deficits in an animal model for autism: BTBR T+Itpr3tf/J (BTBR) mouse. As expected, administration of GW4064 rescued the sociability of BTBR mice in the three-chamber sociability test and male-female social reciprocal interaction test, while no effects were observed in C57BL/6J mice. We also found that GW4064 administration increased fecal microbial abundance and counteracted the common ASD phenotype of a high Firmicutes to Bacteroidetes ratio in BTBR mice. In addition, GW4064 administration reversed elevated Lactobacillus and decreased Allobaculum content in the fecal matter of BTBR animals. Our findings show that GW4064 administration alleviates social deficits in BTBR mice and modulates selective aspects of the composition of the gut microbiota, suggesting that GW4064 supplementation might prove a potential strategy for improving ASD symptoms.

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Section: Resultssupporting

confidence: 91%

GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice

Liu

Gao

et al. 2022

Front. Cell. Infect. Microbiol.

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“…While many neurodevelopmental milestones occur postbirth in rats ( Zeiss, 2021 ), the timing of our manipulation was selected to coincide with previous studies in which developmental disruptions between gestational day 11 and 21 produce robust neuropsychiatric alterations in adulthood, including autism-like and schizophrenia-like phenotypes ( Lodge, 2013 ; Perez et al, 2014 ; Donegan et al, 2018 , 2020 ). Indeed, lower total brain volume has been observed in rodent models of autism and early-life stress ( Golden et al, 2021 ; Reshetnikov et al, 2021 ). Further, loss of brain volume in specific brain regions is observed in a variety of psychiatric illnesses ( Angelescu et al, 2021 ; Steuber et al, 2021 ; Su et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

Elam¹,

Donegan

Hsieh

et al. 2022

eNeuro

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Opioid misuse among pregnant women is rapidly increasing in the United States. The number of maternal opioid-related diagnoses increased by 131% in the last 10 years, resulting in an increased number of infants exposed to opioids in utero and a subsequent increase in infants developing neonatal abstinence syndrome (NAS). The most prescribed treatment to combat maternal opioid use disorder is buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist. Buprenorphine treatment effectively reduces NAS but has been associated with disrupted cortical development and neurodevelopmental consequences in childhood. Less is known about the long-term neurodevelopmental consequences following buprenorphine exposure in utero . Previous research has shown that gestational buprenorphine exposure can induce anxiety-like and depressive-like phenotypes in adult rats, suggesting that exposure to buprenorphine in utero may render individuals more susceptible to psychiatric illness in adulthood. A common pathology observed across multiple psychiatric illnesses is dopamine system dysfunction. Here, we administered the highly-abused opioid, oxycodone (10 mg/kg, i.p.) or a therapeutic used to treat opioid use disorder, buprenorphine (1 mg/kg, i.p) to pregnant Sprague Dawley rats from gestational day 11 through 21, then examined neurophysiological alterations in the mesolimbic dopamine system and dopamine-dependent behaviors in adult offspring. We found that gestational exposure to buprenorphine or oxycodone increases dopamine neuron activity in adulthood. Moreover, prenatal buprenorphine exposure disrupts the afferent regulation of dopamine neuron activity in the ventral tegmental area (VTA). Taken together, we posit that gestational buprenorphine or oxycodone exposure can have profound effects on the mesolimbic dopamine system in adulthood.

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“…A growing body of research indicates that early-life stress or prenatal stress may affect mouse and human behavior sex-dependently [73]. Biological gender has also been revealed to play a role in sexdependent stress vulnerability and resilience to stress [74], brain sex differentiation via neuroimmunological function, and epigenetic modi cation [75].…”

Section: Discussionmentioning

confidence: 99%

Microglia involvement in the schizophrenia occurrence in male offspring with maternal dexamethasone exposure

Rim

Park

You

et al. 2022

Preprint

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Background: Fetal microglia are particularly sensitive cells to the changes in utero environment and show sex-biased differences in shape and function. Maternal stress hormone induction can affect fetal microglial functions including alterations in synaptic pruning and cytokine secretion. It may contribute to psychiatric outcomes in offspring such as schizophrenia and depression. Methods: We administered a 50 µg/kg dexamethasone (DEX) to dams subcutaneously from gestational days 16 to 18. To characterize behaviors of maternal DEX exposed offspring, we assessed depressive-like and schizophrenia-relevant behaviors among 5 week old (adolescence), 10 week old (adult), and orchiectomized group respectively. Using quantitative real-time polymerase chain reaction, western blotting, and rapid Golgi staining, microglial morphology and synaptic pruning were assessed. Results: Prenatal exposure to dexamethasone (PN-DEX) induced SCZ-relevant behavior in male mice and depressive-like behavior in female mice. SCZ-relevant behavioral patterns were induced in 10 week old (10 W) male mice but not in 5 week old (5 W) male mice. Microglia in the medial prefrontal cortex (mPFC) and the striatum (STR) of 10 W males prenatally treated with dexamethasone (10 W PN-DEX-M) showed hyper-ramified morphology and dramatically reduced spine density in mPFC. Immunofluorescence studies indicated that microglia in the mPFC of the 10 W PN-DEX-M group interacted with pre-synaptic Bassoon and post-synaptic density 95 (PSD95) puncta. PN-DEX-M also showed significantly changed dopamine system proteins. A testosterone surge was not observed in parallel to SCZ-relevant behavior in 10 W PN-DEX-M. Furthermore, females prenatally treated with dexamethasone (PN-DEX-F) displayed depressive-like behavior, in addition to HPA axis activation and inflammatory microglial phenotypes in their hippocampus (HPC).Conclusions: Our study demonstrated that maternal DEX exposure induces sex-biased abnormal behavior as well as SCZ-relevant behavior in male offspring, and depressive-like behaviors in female offspring. We propose that altered microglial function, such as increased synaptic pruning, may be involved in the occurrence of SCZ-relevant behavior in PN-DEX-M and sex-biased abnormal behavior in the PN-DEX model.

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Sex-specific behavioral and structural alterations caused by early-life stress in C57BL/6 and BTBR mice

Cited by 24 publications

References 68 publications

GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice

GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice

Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

Microglia involvement in the schizophrenia occurrence in male offspring with maternal dexamethasone exposure

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