Abstract Life experiences profoundly influence brain function, yet how opposing experiences are encoded remains unclear. Here, we show that opposing experiences, chronic stress (CS) and voluntary running (VR), induce largely distinct molecular programs rather than a simple bidirectional modulation of a shared molecular program in parvalbumin interneurons (PVIs). PVI-specific translational profiling across frontal cortex and dorsal and ventral hippocampus reveals that experience-dependent gene expression is organized into brain region-specific architectures, which are further structured into distinct co-expression modules. We uncovered CS-induced upregulation of histone acetyltransferase KAT6A and H3K23 acetylation specifically in PVIs of the frontal cortex accompanied by altered genome-wide redistribution of acetylated H3K23, including genes implicated in neuropsychiatric disorders. Targeted elevation of KAT6A in PVIs recapitulates CS-induced morphological and behavioral alterations. Together, our findings reveal that opposing experiences engage distinct and region-specific molecular programs in PVIs and identify a stress-responsive epigenetic pathway underlying inhibitory circuit plasticity.

Inherited Retinal Degenerations (IRDs) are a group of diseases where genetic variants lead to retinal photoreceptor dysfunction and subsequent visual impairment. We aimed to compare the characteristics of pediatric versus adult IRD patients at the time of presentation at a tertiary care IRD clinic. A retrospective chart review of 538 patients with IRDs was conducted. Information obtained included age, diagnosis, presenting characteristics, demographics, distance from the clinic, and referring physician. This study found that high hyperopia, congenital syndactyly, high refractive error, high astigmatism, and a history of developmental delay were most predictive of pediatric presentation. In adults, we found reduced central vision, peripheral vision loss, color vision deficits, nyctalopia, flashes/floaters, cataracts, diabetes mellitus, obesity, cardiac conditions, and a family history of cataract were most predictive of presentation. There was a greater proportion of pediatric patients presenting from 20 or more miles away. Additionally, there was no significant difference between the type of healthcare provider referring adult or pediatric patients. This study identifies characteristics predictive of pediatric and adult presentation in IRD patients thus addressing current knowledge gaps. A better understanding of these characteristics may provide for quicker recognition, education of clinicians likely to encounter IRDs, and allow for earlier treatment. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Wisconsin School of Medicine and Public Health gave Institutional Review Board approval under protocol number 2020-1207 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients’ neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD.

The regulation of polymorphonuclear leukocyte (PMN) function by mechanical forces encountered during their migration across restrictive endothelial cell junctions is not well understood. Using genetic, imaging, microfluidic, and in vivo approaches, we demonstrated that the mechanosensor Piezo1 in PMN plasmalemma induced spike-like Ca2+ signals during trans-endothelial migration. Mechanosensing increased the bactericidal function of PMN entering tissue. Mice in which Piezo1 in PMNs was genetically deleted were defective in clearing bacteria, and their lungs were predisposed to severe infection. Adoptive transfer of Piezo1-activated PMNs into the lungs of Pseudomonas aeruginosa-infected mice or exposing PMNs to defined mechanical forces in microfluidic systems improved bacterial clearance phenotype of PMNs. Piezo1 transduced the mechanical signals activated during transmigration to upregulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4, crucial for the increased PMN bactericidal activity. Thus, Piezo1 mechanosensing of increased PMN tension, while traversing the narrow endothelial adherens junctions, is a central mechanism activating the host-defense function of transmigrating PMNs.

Parvalbumin interneurons (PVIs) are affected in many psychiatric disorders including schizophrenia (SCZ), however the mechanism remains unclear. FXR1, a high confident risk gene for SCZ, is indispensable but its role in the brain is largely unknown. We show that deleting FXR1 from PVIs of medial prefrontal cortex (mPFC) leads to reduced PVI excitability, impaired mPFC gamma oscillation, and SCZ-like behaviors. PVI-specific translational profiling reveals that FXR1 regulates the expression of Cacna1h/Cav3.2 a T-type calcium channel implicated in autism and epilepsy. Inhibition of Cav3.2 in PVIs of mPFC phenocopies whereas elevation of Cav3.2 in PVIs of mPFC rescues behavioral deficits resulted from FXR1 deficiency. Stimulation of PVIs using a gamma oscillation-enhancing light flicker rescues behavioral abnormalities caused by FXR1 deficiency in PVIs. This work unveils the function of a newly identified SCZ risk gene in SCZ-relevant neurons and identifies a therapeutic target and a potential noninvasive treatment for psychiatric disorders.