Fadool, D. A. | Search bioRxiv

bioRxiv2025

The superficial tufted and mitral cell output neurons of the mouse olfactory bulb have a dual role in insulin sensing

The olfactory bulb (OB) contains multiple, parallel projection neurons to relay the nature of a stimulus. In a mouse ex vivo slice preparation, we used patch-clamp electrophysiology to measure intrinsic properties, excitability, action potential (AP) shape, voltage-activated conductances, and neuromodulation in the newly-categorized superficial tufted cells (sTCs) compared with those of mitral cells (MCs). We propose that a marked difference in voltage-dependent current represents distinct ion channel populations that affect the kinetics of action potentials, and evokes an increase in sTC firing frequency, albeit both types of projection neurons having similar AP spiking activity. Triple-colored immunofluorescence and RNA scope were used to detect co-localization of the Kv1.3 ion channel and the insulin receptor in sTCs, with [~]73% of sTCs expressing both. The sTCs were modulated by bath application of insulin - increasing AP firing frequency by 97%, attributable to an 8% decrease in the intraburst interval, and a reduction of the latency to first spike by 37%. We conclude that there may be a range of neuromodulators of sTCs that may alter excitability and fine-tune olfactory information processing or metabolic balance. SUMMARY STATEMENTSuperficial tufted cells, as output neurons of the olfactory bulb, were electrophysiologically studied to be insulin sensitive. Brain insulin signaling represents a manner in which olfactory and metabolic circuitry are intertwined.

neuroscience↗

bioRxiv2024

Oral cannabidiol administration in mice during pregnancy and lactation affects early postnatal body weight, fasting glucose, ingestive behavior, anxiety- and obsessive compulsive-like behaviors, and long-term object-memory in adult offspring in a sex-dependent manner

RationaleThe consequences of perinatal cannabidiol (CBD) exposure are severely understudied, but are important, given its widespread use and believed safety as a natural supplement. ObjectiveThe objective of this study was to test the health, metabolic, and behavioral consequences of perinatal CBD exposure on dams and their offspring raised to adult. MethodsPrimiparous female C57BL/6J mice were orally administered 100 mg/kg CBD in strawberry jam to expose offspring during gestation, lactation, or both using a cross-fostering design. Adult offspring were metabolically profiled using indirect calorimetry and intraperitoneal glucose tolerance testing. Adults were behaviorally phenotyped, video recorded, and mouse position tracked using DeepLabCut. ResultsCBD was detected in maternal plasma using LC-MS 10-min post consumption (34.2 {+/-} 1.7 ng/ul) and peaked within 30 min (371.0 {+/-} 34.0 ng/ul). Fetal exposure to CBD significantly decreased survival of the pups, and decreased male postnatal development, but did not alter litter size, maternal body weight or pup birth weight. We observed many sex-dependent effects of perinatal CBD exposure. Exposure to CBD during gestation and lactation increased meal size, caloric intake, and respiratory exchange ratio for adult male offspring, while exposure during lactation decreased fasting glucose, but had no effect on clearance. Adult female offspring exposed to CBD during lactation showed increased drink size. Perinatal CBD exposure increased obsessive compulsive- and decreased anxiety-like behaviors (marble burying, light-dark box, elevated-plus maze) in female mice, decreased long-term object memory in male mice, and had no effect on attention tasks for either sex. ConclusionsWe conclude that orally-administered CBD during pregnancy affects behavior and metabolism in a sex-dependent manner, and mice are differentially sensitive to exposure during gestation vs. lactation, or both. Because long-term changes are observed following perinatal exposure to the drug, and exposure significantly decreases survival to weaning, more research during development is warranted. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/602955v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1a9341dorg.highwire.dtl.DTLVardef@19c7356org.highwire.dtl.DTLVardef@5833baorg.highwire.dtl.DTLVardef@ac153c_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIMice can be trained to orally consume CBD using strawberry jam as the vehicle. C_LIO_LICBD administration to pregnant dams decreases pup survival to weaning age without significantly affecting maternal behavior. C_LIO_LIPerinatal CBD exposure decreases developmental body weight in males. C_LIO_LIGestational or lactational CBD increases the respiratory exchange ratio (RER), increases mean meal and drink size, and reduces fasting glucose in a sex-dependent manner. C_LIO_LICBD increases obsessive-compulsive like behavior in adult offspring, which could be eliminated in females by cross-fostering to a drug-free dam. C_LIO_LIPerinatal CBD selectively decreases anxiety-like behavior in females and decreases long-term object memory in males. C_LI

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