Background:The molecular mechanisms regulating brain development are unclear. Results: HDAC3 deletion disrupts the organization of certain neuronal cell types and the proportions of some glial cell types in the cortex and cerebellum. Conclusion: HDAC3 regulates brain development, and other HDACs cannot compensate for its function. Significance: Our study identifies a key player in the regulation of brain development.

Cerebrospinal fluid (CSF) flows through the brain, transporting chemical signals and removing waste. CSF production in the brain is balanced by a constant outflow of CSF, the anatomical basis of which is poorly understood. Here, we characterized the anatomy and physiological function of the CSF outflow pathway along the olfactory sensory nerves through the cribriform plate, and into the nasal epithelia. Chemical ablation of olfactory sensory nerves greatly reduced outflow of CSF through the cribriform plate. The reduction in CSF outflow did not cause an increase in intracranial pressure (ICP), consistent with an alteration in the pattern of CSF drainage or production. Our results suggest that damage to olfactory sensory neurons (such as from air pollution) could contribute to altered CSF turnover and flow, providing a potential mechanism for neurological diseases.

Cortical neural activity is coupled to local arterial diameter and blood flow. However, which neurons control the dynamics of cerebral arteries is not well understood. We dissected the cellular mechanisms controlling the basal diameter and evoked dilation in cortical arteries in awake, head-fixed mice. Locomotion drove robust arterial dilation, increases in gamma band power in the local field potential (LFP), and increases calcium signals in pyramidal and neuronal nitric oxide synthase (nNOS)-expressing neurons. Chemogenetic or pharmocological modulation of overall neural activity up or down caused corresponding increases or decreases in basal arterial diameter. Modulation of pyramidal neuron activity alone had little effect on basal or evoked arterial dilation, despite pronounced changes in the LFP. Modulation of the activity of nNOS-expressing neurons drove changes in the basal and evoked arterial diameter without corresponding changes in population neural activity.

Cerebrospinal fluid (CSF) flows through the brain, transporting chemical signals and removing waste. CSF production in the brain is balanced by a constant outflow of CSF, the anatomical basis of which is poorly understood. Here we characterized the anatomy and physiological function of the CSF outflow pathway along the olfactory sensory nerves through the cribriform plate, and into the nasal epithelia. Chemical ablation of olfactory sensory nerves greatly reduced outflow of CSF through the cribriform plate. The reduction in CSF outflow did not cause an increase in intracranial pressure (ICP), consistent with an alteration in the pattern of CSF drainage or production. Our results suggest that damage to olfactory sensory neurons (such as from air pollution) could contribute to altered CSF turnover and flow, providing a potential mechanism for neurological diseases.

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Exposure to air pollution has been linked to the development of neurodegenerative diseases and anosmia, but the underlying mechanism is not known. Additionally, the loss of olfactory function often precedes the onset of neurodegenerative diseases. Chemical ablation of olfactory sensory neurons blocks the drainage of cerebrospinal fluid (CSF) through the cribriform plate and alters normal CSF production and/or circulation. Damage to this drainage pathway could contribute to the development of neurodegenerative diseases and could link olfactory sensory neuron health and neurodegeneration. Here, we investigated the impact of intranasal treatment of combustion products (laboratory-generated soots) and their oxygen functionalized derivatives on mouse olfactory sensory neurons, olfactory nerve cell progenitors, and the behavior of the mouse. We found that after a month of every-other-day intranasal treatment of soots, there was minimal effect on olfactory sensory neuron anatomy or exploratory behavior in the mouse. However, oxygen-functionalized soot caused a large decrease in globose basal cells, which are olfactory progenitor cells. These results suggest that exposure to air pollution damages the olfactory neuron progenitor cells, and could lead to decreases in the number of olfactory neurons, potentially disrupting CSF drainage.

FGFR‐related craniosynostosis syndromes, such as Apert syndrome, are characterized in part by dysmorphology of the anterior cranial vault bones and early closure of the coronal suture. Understanding the cellular processes during early formation of the anterior cranial vault bones and the coronal suture is key to the development of therapies for these syndromes. Runt‐related transcription factor 2 (RUNX2) and Osterix (OSX) play critical roles in the regulation of osteoblast differentiation and function and are first expressed at different stages of osteoblast lineage cell (OLC) development. RUNX2 is known to act upstream of OSX and is expressed during an earlier stage of OLC differentiation, but relatively little is known about the behavior and developmental sequence of OLCs that contribute to the initial formation of cranial dermal bones and the sutures between them. To address this issue, we made the R2Tom transgenic mouse line by introducing the tdTomato reporter gene joined with an enhancer fragment of the human RUNX2 gene and the Hsp68 minimal promoter sequence that labels developmentally early OLCs. Crossing this novel R2Tom mouse line with the Osx‐GFP line produced R2Tom;Osx‐GFP mice, in which expression of RUNX2 and Osx is detected with different fluorescent reporters. The R2Tom;Osx‐GFP mouse line was then crossed with Fgfr2+/P253R;Emx1‐Cre (referred to below as Apert) mice that show phenotypes similar to Apert syndrome patients to produce Apert;R2Tom;Osx‐GFP mice and “unaffected” littermates that carry the fluorescent marker but do not express the mutant Fgfr2 gene. Using large field, high‐resolution fluorescent microscopy (ranging between 12.5x and 112x) and light sheet microscopy, we captured expression of RUNX2 and Osx across the surface of whole mouse embryos and at the cellular level. R2Tom;Osx‐GFP and Apert;R2Tom;Osx‐GFP mice were developmentally staged to provide precise information about the developmental sequence of expression of RUNX2 and Osx and 3D physical organization of early OLCs during the cellular assembly of what will be the frontal and parietal bones and initiation of the coronal suture in mouse embryos between E11.5 to E14.5. Our preliminary data on Apert;R2Tom;Osx‐GFP mice at E12.5 and E13.5 reveal differences in the timing and pattern of the developmental sequence of RUNX2 and Osx expression in the anterior cranial vault of mice carrying the Fgfr2+/P253R mutation relative to their unaffected litter mates. These results provide our first view of OLC differentiation in the anterior cranial vault of Fgfr2+/P253R Apert mice prior to the formation of anterior cranial vault bones and the coronal suture and suggest that differences in the timing of OLC patterning play an import role in dysmorphologies of the anterior cranial vault.