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1. The Role of Serotonergic Gene Methylation in Regulating Anxiety-Related Personality Traits in Chimpanzees

   https://doi.org/10.3390/biology11111673  

   Staes, Nicky; Guevara, Elaine E.; Hopkins, William D.; Schapiro, Steven J.; Eens, Marcel; Sherwood, Chet C.; Bradley, Brenda J. (November 2022, Biology)

   While low serotonergic activity is often associated with psychological disorders such as depression, anxiety, mood, and personality disorders, variations in serotonin also contribute to normal personality differences. In this study, we investigated the role of blood DNA methylation levels at individual CpG sites of two key serotonergic genes (serotonin receptor gene 1A, HTR1A; serotonin transporter gene, SLC6A4) in predicting the personalities of captive chimpanzees. We found associations between methylation at 9/48 CpG sites with four personality dimensions: Dominance, Reactivity/Dependability, Agreeableness, and Openness. Directionality of effects were CpG location-dependent and confirmed a role of serotonergic methylation in reducing anxiety (Dominance) and aggression-related personality (Reactivity/Undependability) while simultaneously promoting prosocial (Agreeableness) and exploratory personalities (Openness). Although early-life adversity has been shown to impact serotonergic methylation patterns in other species, here, atypical early social rearing experiences only had a modest impact on CpG methylation levels in this chimpanzee sample. The precise environmental factors impacting serotonergic methylation in chimpanzees remain to be identified. Nevertheless, our study suggests a role in shaping natural variation in animal personalities. The results of this study offer a basis for future hypothesis-driven testing in additional populations and species to better understand the impact of ecology and evolution on complex behavioral traits. 

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2. An acute dose of intranasal oxytocin rapidly increases maternal communication and maintains maternal care in primiparous postpartum California mice

   https://doi.org/10.1371/journal.pone.0244033  

   Guoynes, Caleigh D.; Marler, Catherine A. (April 2021, PLOS ONE)

   Rosenfeld, Cheryl S. (Ed.)

   Maternal-offspring communication and care are essential for offspring survival. Oxytocin (OXT) is known for its role in initiation of maternal care, but whether OXT can rapidly influence maternal behavior or ultrasonic vocalizations (USVs; above 50 kHz) has not been examined. To test for rapid effects of OXT, California mouse mothers were administered an acute intranasal (IN) dose of OXT (0.8 IU/kg) or saline followed by a separation test with three phases: habituation with pups in a new testing chamber, separation via a wire mesh, and finally reunion with pups. We measured maternal care, maternal USVs, and pup USVs. In mothers, we primarily observed simple sweep USVs, a short downward sweeping call around 50 kHz, and in pups we only observed pup whines, a long call with multiple harmonics ranging from 20 kHz to 50 kHz. We found that IN OXT rapidly and selectively enhanced the normal increase in maternal simple sweep USVs when mothers had physical access to pups (habituation and reunion), but not when mothers were physically separated from pups. Frequency of mothers’ and pups’ USVs were correlated upon reunion, but IN OXT did not influence this correlation. Finally, mothers given IN OXT showed more efficient pup retrieval/carrying and greater total maternal care upon reunion. Behavioral changes were specific to maternal behaviors (e.g. retrievals) as mothers given IN OXT did not differ from controls in stress-related behaviors (e.g. freezing). Overall, these findings highlight the rapid effects and context-dependent effect a single treatment with IN OXT has on both maternal USV production and offspring care. 

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3. A Novel Non-Invasive Murine Model of Neonatal Hypoxic-Ischemic Encephalopathy Demonstrates Developmental Delay and Motor Deficits with Activation of Inflammatory Pathways in Monocytes

   https://doi.org/10.3390/cells13181551  

   Lemanski, Elise A; Collins, Bailey A; Ebenezer, Andrew T; Anilkumar, Sudha; Langdon, Victoria A; Zheng, Qi; Ding, Shanshan; Franke, Karl Royden; Schwarz, Jaclyn M; Wright-Jin, Elizabeth C (September 2024, Cells)

   Neonatal hypoxic-ischemic encephalopathy (HIE) occurs in 1.5 per 1000 live births, leaving affected children with long-term motor and cognitive deficits. Few animal models of HIE incorporate maternal immune activation (MIA) despite the significant risk MIA poses to HIE incidence and diagnosis. Our non-invasive model of HIE pairs late gestation MIA with postnatal hypoxia. HIE pups exhibited a trend toward smaller overall brain size and delays in the ontogeny of several developmental milestones. In adulthood, HIE animals had reduced strength and gait deficits, but no difference in speed. Surprisingly, HIE animals performed better on the rotarod, an assessment of motor coordination. There was significant upregulation of inflammatory genes in microglia 24 h after hypoxia. Single-cell RNA sequencing (scRNAseq) revealed two microglia subclusters of interest following HIE. Pseudobulk analysis revealed increased microglia motility gene expression and upregulation of epigenetic machinery and neurodevelopmental genes in macrophages following HIE. No sex differences were found in any measures. These results support a two-hit noninvasive model pairing MIA and hypoxia as a model for HIE in humans. This model results in a milder phenotype compared to established HIE models; however, HIE is a clinically heterogeneous injury resulting in a variety of outcomes in humans. The pathways identified in our model of HIE may reveal novel targets for therapy for neonates with HIE. 

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4. Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain

   https://doi.org/10.3390/ijms23020620  

   Nguyen, Nam Phuong; Helmbrecht, Hawley; Ye, Ziming; Adebayo, Tolulope; Hashi, Najma; Doan, My-Anh; Nance, Elizabeth (January 2022, International Journal of Molecular Sciences)

   Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates. 

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5. The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury

   https://doi.org/10.1177/0271678X20908523  

   Novorolsky, Robyn J; Nichols, Matthew; Kim, Jong S; Pavlov, Evgeny V; J Woods, Joshua; Wilson, Justin J; Robertson, George S (January 2020, Journal of Cerebral Blood Flow & Metabolism)

   The mitochondrial calcium (Ca2+) uniporter (MCU) mediates high-capacity mitochondrial Ca2+ uptake implicated in ischemic/reperfusion cell death. We have recently shown that inducible MCU ablation in Thy1-expressing neurons renders mice resistant to sensorimotor deficits and forebrain neuron loss in a model of hypoxic/ischemic (HI) brain injury. These findings encouraged us to compare the neuroprotective effects of Ru360 and the recently identified cell permeable MCU inhibitor Ru265. Unlike Ru360, Ru265 (2-10 µM) reached intracellular concentrations in cultured cortical neurons that preserved cell viability, blocked the protease activity of Ca2+-dependent calpains and maintained mitochondrial respiration and glycolysis after a lethal period of oxygen-glucose deprivation (OGD). Intraperitoneal (i.p.) injection of adult male C57Bl/6 mice with Ru265 (3 mg/kg) also suppressed HI-induced sensorimotor deficits and brain injury. However, higher doses of Ru265 (10 and 30 mg/kg, i.p.) produced dose-dependent increases in the frequency of seizure-like behaviours and the duration of clonic convulsions. Ru265 is proposed to promote convulsions by reducing Ca2+ buffering and energy production in highly energetic interneurons that suppress brain seizure activity. These findings support the potential therapeutic utility of MCU inhibition in the acute management of ischemic stroke but also indicate that such clinical translation will require drug delivery strategies which mitigate the pro-convulsant effects of Ru265. 

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