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1. Transcriptional profiles of non-neuronal and immune cells in mouse trigeminal ganglia

   https://doi.org/10.3389/fpain.2023.1274811  

   Mecklenburg, Jennifer; Shein, Sergey A; Malmir, Mostafa; Hovhannisyan, Anahit H; Weldon, Korri; Zou, Yi; Lai, Zhao; Jin, Yu-Fang; Ruparel, Shivani; Tumanov, Alexei V; et al (October 2023, Frontiers in Pain Research)

   Non-neuronal cells constitute 90%–95% of sensory ganglia. These cells, especially glial and immune cells, play critical roles in the modulation of sensory neurons. This study aimed to identify, profile, and summarize the types of trigeminal ganglion (TG) non-neuronal cells in naïve male mice using published and our own data generated by single-cell RNA sequencing, flow cytometry, and immunohistochemistry. TG has five types of non-neuronal cells, namely, glial, fibroblasts, smooth muscle, endothelial, and immune cells. There is an agreement among publications for glial, fibroblasts, smooth muscle, and endothelial cells. Based on gene profiles, glial cells were classified as myelinated and non-myelinated Schwann cells and satellite glial cells.Mpzhas dominant expression in Schwann cells, andFabp7is specific for SCG. Two types of Col1a2⁺fibroblasts located throughout TG were distinguished. TG smooth muscle and endothelial cells in the blood vessels were detected using well-defined markers. Our study reported three types of macrophages (Mph) and four types of neutrophils (Neu) in TG. Mph were located in the neuronal bodies and nerve fibers and were sub-grouped by unique transcriptomic profiles withCcr2,Cx3cr1, andIba1as markers. A comparison of databases showed that type 1 Mph is similar to choroid plexus-low (CP^lo) border-associated Mph (BAMs). Type 2 Mph has the highest prediction score with CP^hiBAMs, while type 3 Mph is distinct. S100a8⁺Neu were located in the dura surrounding TG and were sub-grouped by clustering and expressions ofCsf3r,Ly6G,Ngp,Elane, andMpo. Integrative analysis of published datasets indicated that Neu-1, Neu-2, and Neu-3 are similar to the brain Neu-1 group, while Neu-4 has a resemblance to the monocyte-derived cells. Overall, the generated and summarized datasets on non-neuronal TG cells showed a unique composition of myeloid cell types in TG and could provide essential and fundamental information for studies on cell plasticity, interactomic networks between neurons and non-neuronal cells, and function during a variety of pain conditions in the head and neck regions. 

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2. Sex-Linked Growth Disorder and Aberrant Pituitary Gene Expression in Nestin-Cre-Mediated Egr1 Conditional Knockout Mice

   https://doi.org/10.3390/biology12070966  

   Swilley, Cody; Lin, Yu; Zheng, Yuze; Xu, Xiguang; Liu, Min; Zimmerman, Kurt; Xie, Hehuang (July 2023, Biology)

   Genes that regulate hormone release are essential for maintaining metabolism and energy balance. Egr1 encodes a transcription factor that regulates hormone production and release, and a decreased in growth hormones has been reported in Egr1 knockout mice. A reduction in growth hormones has also been observed in Nestin-Cre mice, a model frequently used to study the nervous system. Currently, it is unknown how Egr1 loss or the Nestin-Cre driver disrupt pituitary gene expression. Here, we compared the growth curves and pituitary gene expression profiles of Nestin-Cre-mediated Egr1 conditional knockout (Egr1cKO) mice with those of their controls. Reduced body weight was observed in both the Nestin-Cre and Egr1cKO mice, and the loss of Egr1 had a slightly more severe impact on female mice than on male mice. RNA-seq data analyses revealed that the sex-related differences were amplified in the Nestin-Cre-mediated Egr1 conditional knockout mice. Additionally, in the male mice, the influence of Egr1cKO on pituitary gene expression may be overridden by the Nestin-Cre driver. Differentially expressed genes associated with the Nestin-Cre driver were significantly enriched for genes related to growth factor activity and binding. Altogether, our results demonstrate that Nestin-Cre and the loss of Egr1 in the neuronal cell lineage have distinct impacts on pituitary gene expression in a sex-specific manner. 

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3. Peripheral Anomalies in USH2A Cause Central Auditory Anomalies in a Mouse Model of Usher Syndrome and CAPD

   https://doi.org/10.3390/genes12020151  

   Perrino, Peter A.; Newbury, Dianne F.; Fitch, R. Holly (February 2021, Genes)

   null (Ed.)

   Central auditory processing disorder (CAPD) is associated with difficulties hearing and processing acoustic information, as well as subsequent impacts on the development of higher-order cognitive processes (i.e., attention and language). Yet CAPD also lacks clear and consistent diagnostic criteria, with widespread clinical disagreement on this matter. As such, identification of biological markers for CAPD would be useful. A recent genome association study identified a potential CAPD risk gene, USH2A. In a homozygous state, this gene is associated with Usher syndrome type 2 (USH2), a recessive disorder resulting in bilateral, high-frequency hearing loss due to atypical cochlear hair cell development. However, children with heterozygous USH2A mutations have also been found to show unexpected low-frequency hearing loss and reduced early vocabulary, contradicting assumptions that the heterozygous (carrier) state is “phenotype free”. Parallel evidence has confirmed that heterozygous Ush2a mutations in a transgenic mouse model also cause low-frequency hearing loss (Perrino et al., 2020). Importantly, these auditory processing anomalies were still evident after covariance for hearing loss, suggesting a CAPD profile. Since usherin anomalies occur in the peripheral cochlea and not central auditory structures, these findings point to upstream developmental feedback effects of peripheral sensory loss on high-level processing characteristic of CAPD. In this study, we aimed to expand upon the mouse behavioral battery used in Perrino et al. (2020) by evaluating central auditory brain structures, including the superior olivary complex (SOC) and medial geniculate nucleus (MGN), in heterozygous and homozygous Ush2a mice. We found that heterozygous Ush2a mice had significantly larger SOC volumes while homozygous Ush2a had significantly smaller SOC volumes. Heterozygous mutations did not affect the MGN; however, homozygous Ush2a mutations resulted in a significant shift towards more smaller neurons. These findings suggest that alterations in cochlear development due to USH2A variation can secondarily impact the development of brain regions important for auditory processing ability. 

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4. Age-related hearing loss persisted in mice that had demonstrated improved healthspan, reduced inflammaging and extended lifespan following expression of the naked mole-rat transgene for hyaluronan synthase 2

   https://doi.org/10.3389/fragi.2026.1936677  

   Owens, Connor E; Borruso, Aiden J; Place, Kevin A; Seluanov, Andrei; Gorbunova, Vera; White, Patricia M; Place, Ned J (August 2026, Frontiers in Aging)

   BackgroundApproximately one in three adults aged 65–74 years reports hearing difficulty, including age-related hearing loss (AHL, presbycusis). The C57BL/6 mouse is widely used in preclinical AHL research because it develops AHL relatively early. Calorie restriction (CR) attenuates AHL and improves healthspan and longevity in this strain. A recently developed transgenic C57BL/6 mouse expressing naked mole-rat hyaluronan synthase 2 (nmrHas2), which produces very high molecular mass hyaluronan (vHMM-HA), also exhibits improved healthspan, reduced inflammaging, and increased longevity. Therefore, we evaluatednmrHas2mice for evidence of alleviated AHL. ObjectiveTo determine whether AHL is attenuated innmrHas2 mice. MethodsThis study supplemented a larger investigation ofnmrHas2and female reproductive aging. Tamoxifen administered at 1 month induced ubiquitousnmrHas2expression innmrHas2+females;nmrHas2−controls received tamoxifen or vehicle. Auditory brainstem response (ABR) testing was performed approximately 2 weeks before mice reached 3 or 12 months of age. Cochleae and reproductive tissues were collected following euthanasia approximately 2 weeks later. ResultsABR thresholds to clicks and six tones (4–32 kHz) showed marked hearing loss from 3 to 12 months of age in bothnmrHas2+mice and controls, with no evidence thatnmrHas2attenuated AHL. CochlearnmrHas2expression innmrHas2+mice was confirmed by quantitative RT-PCR. ConclusionUbiquitousnmrHas2expression did not attenuate AHL in C57BL/6 mice despite previously reported benefits for other aging phenotypes. These findings contrast with CR, suggesting that vHMM-HA and CR influence aging through distinct mechanisms. 

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5. Role of Surfactant Protein D in Experimental Otitis Media

   https://doi.org/10.1159/000513605  

   Abdel-Razek, Osama; Liu, Tianyi; Chen, Xinghua; Wang, Qiushi; Vanga, Gautam; Wang, Guirong (September 2021, Journal of Innate Immunity)

   Surfactant protein D (SP-D) is a C-type collectin and plays an important role in innate immunity and homeostasis in the lung. This study studied SP-D role in the nontypeable Haemophilus influenzae (NTHi)-induced otitis media (OM) mouse model. Wild-type C57BL/6 (WT) and SP-D knockout (KO) mice were used in this study. Mice were injected in the middle ear (ME) with 5 μL of NTHi bacterial solution (3.5 × 10⁵ CFU/ear) or with the same volume of sterile saline (control). Mice were sacrificed at 3 time points, days 1, 3, and 7, after treatment. We found SP-D expression in the Eustachian tube (ET) and ME mucosa of WT mice but not in SP-D KO mice. After infection, SP-D KO mice showed more intense inflammatory changes evidenced by the increased mucosal thickness and inflammatory cell infiltration in the ME and ET compared to WT mice (p < 0.05). Increased bacterial colony-forming units and cytokine (IL-6 and IL-1β) levels in the ear washing fluid of infected SP-D KO mice were compared to infected WT mice. Molecular analysis revealed higher levels of NF-κB and NLRP3 activation in infected SP-D KO compared to WT mice (p < 0.05). In vitro studies demonstrated that SP-D significantly induced NTHi bacterial aggregation and enhanced bacterial phagocytosis by macrophages (p < 0.05). Furthermore, human ME epithelial cells showed a dose-dependent increased expression of NLRP3 and SP-D proteins after LPS treatment. We conclude that SP-D plays a critical role in innate immunity and disease resolution through enhancing host defense and regulating inflammatory NF-κB and NLRP3 activation in experimental OM mice. 

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