Center for Glial Neuronal Interactions

The Salton Sea is a drying salt lake in an arid region with high aerosol particulate-matter concentrations. This region is plagued by a high incidence of asthma, attributed in part to the aerosols surrounding the Sea. But the connection between the Sea and asthma may be more than simple calculations of dust concentrations. While dusts might contain toxic substances that impact the lungs of residents, the complex dynamics related to the environmental degradation of the Salton Sea may be generating additional toxins relevant to public health, such as microcystins produced by algal blooms. This collection of pollutants may be driving inflammatory responses in the lungs of residents through multiple mechanisms. As such, examination of the full range of potential environmental triggers of lung inflammation promises to yield a better understanding of key mechanisms driving the high incidence of asthma in local residents. Our discussion provides a perspective aiming to re-frame the issue in the context of the historical theory of “miasma” and the linkages between environmental change and health impacts.

The onset of parental care in female mammals is associated with plasticity in neural processing of infant-related sensory stimuli, which enhances mothers’ ability to detect and care for their offspring; however, little is known about sensory plasticity in fathers. We tested the hypothesis that parenthood alters neural responses to olfactory and auditory stimuli from infants in male and female California mice (Peromyscus californicus), a biparental rodent. Virgins and new parents of both sexes were exposed to a combination of a chemosensory stimulus (pup-scented or unscented cotton [control]) and an auditory stimulus (pup vocalizations or white noise [control]). Brains were collected one hour later and stained immunohistochemically for Fos, an index of neural activity. We quantified Fos in the main olfactory bulbs (MOB), a region essential to receiving olfactory information, and medial preoptic area (MPOA), a region critical for parental behavior. We predicted that Fos in MOB and MPOA would be greater in parents than virgins, especially after exposure to pup stimuli. We found that in females, MPOA and MOB Fos did not differ between virgins and mothers or across treatment groups. In contrast, fathers had lower expression of Fos in MOB but higher expression in MPOA, compared to virgin males. Moreover, Fos in MPOA was higher in males exposed to pup vocalizations and pup scent compared to those exposed exclusively to pup vocalizations. Fos in MPOA was also higher in males exposed to scent or both scent and vocalization stimuli compared to males exposed to control stimuli. These findings suggest that the onset of parenthood alters activity in the MOB and MPOA, especially in response to pup vocalizations and scents, in males but not females in this biparental rodent.

In many biparental mammalian species, such as California mice (Peromyscus cali- fornicus), new fathers exhibit affiliative behavior toward unfamiliar infants, whereas reproductively naïve males show highly variable behavioral responses to infants. The sources of this variation are unknown. We investigated the effects of acute stress on pup-directed behavior in reproductively naïve male California mice. Each mouse underwent three 10-minute tests with an unfamiliar pup at 48-hour intervals. Males in the stressed group (N=22) were stressed using subcutane- ous oil injections, a common experimental stressor used in rodents, immediate- ly before each of the first two tests. The controls (N=22) were left undisturbed to avoid any experimentally induced stress. Compared to controls, stressed mice spent significantly less time performing paternal behavior in tests 1 and 2, while only marginal differences were seen in test 3. In tests 2 and 3, signifi- cantly fewer stressed mice interacted with the pup than controls. These findings suggest that acute stress experienced by reproductively naïve males might con- tribute to both short-term and long-term differences in pup-directed behavior.

A zoonotic Babesia species previously referred to as Babesia sp. MO1 is formally described and named here as Babesia hegotelforum sp. nov. This taxon is distinct from Babesia divergens based on genome-wide sequence divergence, phylogenetic placement, host associations, and clinical presentation. The parasite infects erythrocytes of humans, and eastern cottontail rabbits (Sylvilagus floridanus), and is transmitted by Ixodes dentatus. The holotype consists of a Giemsa-stained thin blood smear and cryopreserved infected erythrocytes from the cloned isolate BML-Bh-B12 at ≤10 passages in continuous in vitro culture. Paratype material includes five additional clones (BML-Bh-H1, BML-Bh-F12, BML-Bh-H6, BML-Bh-A3, and BML-Bh-F1) derived from BEI Resources strain NR-50441, along with the original mixed isolate NR-50441. This species description meets the requirements of the International Code of Zoological Nomenclature and establishes Babesia hegotelforum sp. nov. as a distinct species of clinical and epidemiological significance in North America.

Neural crest (NC) cells are multipotent cells unique to vertebrates that arise early in development, at the edge of the neural plate, and subsequently undergo an epithelial to mesenchymal transition, migrate throughout the body, and differentiate into many different derivatives, contributing to the formation of many organs and systems. NC induction research from multiple modeling organisms has identified critical roles for a few signaling pathways, including Wnt, BMP, FGF, Notch/ Delta, Indian Hedgehog, and Endothelin signaling (Prasad et al., 2019). Given the limitations of human embryo studies, pluripotent stem cell models of human NC formation have provided a resourceful alternative (Lee et al., 2007). Intriguingly, while TGFβ inhibition had not been identified as a signaling requirement for NC formation in any in vivo model organism, several pluripotent stem cell (PSC) models of human NC induction rely on TGFβ inhibition (Chambers et al., 2009). To address this issue, we evaluate the role of TGFβ in NC formation using our human (hNC) model that depends on WNT signaling and does not require TGFβ inhibition (Leung et al., 2016, Gomez et al., 2019). We report that under our model, TGFβ signaling is required, and that moderate levels of TGFβ and pSMAD2 levels are necessary for optimal NC formation (with negative effects seen upon strong activation or inhibition). Moreover, we demonstrate that PSC cultured in mTeSR1 immediately prior to hNC induction instead required TGFβ modulation in addition to WNT signaling activation to render hNC. Using the chick embryo as an in vivo vertebrate model, we further provide evidence of expression and requirement of relevant TGFβ signaling components during NC formation. This study identifies an important role for TGFβ signaling in early NC development, opening the door for novel players as effectors mediating the multiple signals integrated during early neural crest development.

OBJECTIVE: Elevated kurtosis values have been observed in subcortical grey matter structures of patients with neurodegenerative diseases. Here, we examined relationships between iron measures and kurtosis in iron-rich subcortical grey matter structures.Please check and confirm the affiliation 4 for the author "Xiaoping P. Hu".Affiliation 4 for Xiaoping P. Hu was incorrect since he is not associated with that department. We have removed this affiliation. Thanks!  MATERIALS AND METHODS: Multi-shell diffusion and multi-echo gradient echo acquisitions were used to derive mean kurtosis and iron measures (R₂* and magnetic susceptibility), respectively, in subcortical grey matter nuclei and white matter tracts in a discovery cohort (110 healthy older and 63 younger adults) and replication cohort (72 healthy older adults).Please confirm if the author names are presented accurately and in the correct sequence (Ilana J. Bennett and Xiaoping P. Hu). Also, kindly confirm the details in the metadata are correct.Thanks for asking. We've checked and the names are presented accurately and in the correct sequence. We have corrected some details in the metadata - adding an affiliation to Murphy Shao (Department of Physics) and removing the Materials Science and Engineering affiliation for Xiaoping P. Hu. Is it possible to add an orcid id for Vala Masjedizadeh? His Orcid ID is  0009-0009-3692-2553 Everything else looks okay RESULTS: Iron-rich grey matter regions exhibited higher mean kurtosis, R₂*, and magnetic susceptibility and white matter regions had lower mean kurtosis in the older adult group from the discovery cohort. In both cohorts, mean kurtosis was significantly correlated with R₂* and magnetic susceptibility in iron-rich grey matter nuclei. No association was seen between signal-to-noise ratio and mean kurtosis in any grey matter region, indicating that the increase in mean kurtosis was not due to reduced signal-to-noise. As keywords are mandatory for this journal, please provide 3-6 keywords.I'm not sure where to put the keywords so I'll reply to the query with the keywords. Our keywords are: kurtosis, iron, grey matter, aging CONCLUSION: Our findings indicate that kurtosis is associated with iron-sensitive metrics in iron-rich grey matter structures, suggesting that iron deposits may be contributing to kurtosis.

Cognitive decline, in healthy older adults without cognitive impairment or dementia, has been associated with numerous microstructural alterations in brain tissue using magnetic resonance imaging (MRI). Prior studies have primarily linked age-related cognitive decline to alterations in white matter tissue, but methodological advances in diffusion-weighted imaging (dMRI) data acquisition and modeling now allow for these analyses to be extended to gray matter tissue. Here, using a sample of 152 healthy adults (18-88 years of age), we used a multicompartment dMRI model to assess (1) age-related differences in gray matter microstructure of functionally defined networks and (2) whether microstructural alterations accounted for age-related differences in episodic memory and speed-dependent fluid cognition. We observed significant age-related alterations in gray matter tissue in the form of nonlinear, age-related increases and decreases in intracellular and dispersed diffusion, respectively, and linear increases in free diffusion. Free diffusion exhibited the most pronounced age-related effects, especially for frontoparietal relative to occipital regions. Dispersed diffusion in the dorsal attention network statistically mediated age-related differences in episodic memory performance. Moreover, higher intracellular diffusion in the default mode and ventral attention networks was related to worse fluid cognition performance, but only for adults > 51 years of age. These results suggest that healthy aging is accompanied by distinct profiles of gray matter microstructural alterations that negatively affect memory and speed-dependent cognition, the latter of which is more pronounced after midlife.

Central nervous system development requires parallel but interrelated processes of neural circuit assembly and vascularization. Intersecting between these two processes is the cell-adhesion G-protein coupled receptor Adgrl2. In select neuronal populations, Adgrl2 is localized and control the assembly of specific synaptic sites. In non-neuronal brain cells, Adgrl2 is restricted in expression to endothelial cells. Testing for Adgrl2 function in these cells in mice (of either sex), here we find that endothelial cell specific Adgrl2 deletion results in an impairment in cerebrovascular integrity. To understand how it might be possible for Adgrl2 to function independently in neuronal and endothelial contexts, we surveyed Adgrl2 transcripts within these cell classes. By analyzing single-cell RNA sequencing datasets, we find that Adgrl2 mRNA is subject to robust cell type-specific alternative splicing that results in distinct isoforms being produced in neurons compared to endothelial cells. To probe the functional significance of this alternative splicing, we forced expression of the neuronal isoform of Adgrl2 in endothelial cells. This resulted in altered cerebrovascular properties including the formation of ectopic glutamatergic synaptic contacts onto endothelial cells, indicating alterations in the cell-cell recognition process. Functionally, in direct contrast to endothelial Adgrl2 deletion, this genetic expression switch instead enhances blood-brain barrier integrity. This overly restrictive cerebrovascular function results in dysregulation of blood to cerebrospinal fluid homeostasis, enlargement of brain ventricles, and a higher risk of hydrocephalus. Thus, alternative splicing serves as a cell type specific mechanism that provides isoform specific Adgrl2 for discerning functions controlling neural circuit assembly and cerebrovascular homeostasis.Significance statement The brain's development depends on two key processes: building neural circuits and forming blood vessels. In this study, we examine Adgrl2, a protein involved in neural circuit formation that is also expressed in endothelial cells. Our findings reveal that Adgrl2 functions differently in these cell types because each produces distinct versions of the protein through cell-type-specific alternative splicing. This mechanism allows the brain to repurpose the same gene for dual roles - assembling neural circuits and the cerebrovasculature.

Juvenile hormones (JHs) mediate various biological processes such as development and reproduction in insects. Although pleiotropic functions of JHs are well investigated in the fruit fly Drosophila melanogaster, their biosynthetic mechanisms are less well understood, partly because many JH biosynthetic enzymes still remain unidentified in this important model species. Here we report that two cytochrome P450 (CYP) epoxidases mediate JH biosynthesis in D. melanogaster. In addition to previously reported Cyp6g2, a second epoxidase, Cyp6a13, also functions in the corpus allatum, the major JH biosynthetic endocrine gland. Combined mutations of the genes encoding these enzymes cause developmental and reproductive defects, which can be rescued by JH application. JH biosynthetic functions of these genes were further confirmed by using a heterologous expression system and ex vivo tissue culture. Collectively, our results indicate that these two CYP epoxidases function cooperatively to mediate JH biosynthesis in D. melanogaster.