Intrauterine growth restriction (IUGR) and oxygen exposure in isolation and combination adversely affect the developing brain, putting infants at risk for neurodevelopmental disability including cerebral palsy (CP). Rodent models of IUGR and postnatal hyperoxia have demonstrated oligodendroglial (OL) injury with subsequent white matter injury (WMI) and motor dysfunction. Here, we investigate transcriptomic dysregulation in IUGR with and without hyperoxia exposure to account for the abnormal brain structure and function previously documented. We performed RNA sequencing and analysis using a mouse model of IUGR and found that IUGR, hyperoxia, and the combination of IUGR with hyperoxia (IUGR/hyperoxia) produced distinct changes in gene expression. IUGR in isolation demonstrated the fewest differentially expressed genes (DEGs) compared with control. In contrast, we detected several gene alterations in IUGR/hyperoxia; genes involved in myelination were strikingly downregulated. We also identified changes to spe...

The Xenopus laevis experimental system has provided significant insight into the development and plasticity of neural circuits. Xenopus neuroscience research would be enhanced by additional tools to study neural circuit structure and function. Rabies viruses are powerful tools to label and manipulate neural circuits and have been widely used to study mesoscale connectomics. Whether rabies virus can be used to transduce neurons and express transgenes in Xenopus has not been systematically investigated. Glycoprotein-deleted rabies virus transduces neurons at the axon terminal and retrogradely labels their cell bodies. We show that glycoprotein-deleted rabies virus infects local and projection neurons in the Xenopus tadpole when directly injected into brain tissue. Pseudotyping glycoprotein-deleted rabies with EnvA restricts infection to cells with exogenous expression of the EnvA receptor, TVA. EnvA pseudotyped virus specifically infects tadpole neurons with promoter-driven expression of TVA, demonstrating i...

Pyramidal neurons in rodent visual cortex homeostatically maintain their firing rates in vivo within a target range. In young cultured rat cortical neurons, Ca2+/calmodulin-dependent kinase IV (CaMKIV) signaling jointly regulates excitatory synaptic strength and intrinsic excitability to allow neurons to maintain their target firing rate. However, the role of CaMKIV signaling in regulating synaptic strength and intrinsic excitability in vivo has not been tested. Here, we show that in pyramidal neurons in visual cortex of juvenile male and female mice, CaMKIV signaling is not essential for the maintenance of basal synaptic or intrinsic properties. Neither CaMKIV conditional knock-down nor viral expression of dominant negative CaMKIV (dnCaMKIV) in vivo disrupts the intrinsic excitability or synaptic input strength of pyramidal neurons in primary visual cortex (V1), and CaMKIV signaling is not required for the increase in intrinsic excitability seen following monocular deprivation (MD). Viral expression of co...

Gonadotropin-releasing hormone (GnRH) drives pituitary secretion of luteinizing hormone and follicle-stimulating hormone, which in turn regulate gonadal functions including steroidogenesis. The pattern of GnRH release and thus fertility depend on gonadal steroid feedback. Under homeostatic (negative) feedback conditions, removal of the gonads from either females or males increases the amplitude and frequency of GnRH release and alters the long-term firing pattern of these neurons in brain slices. The neurobiological mechanisms intrinsic to GnRH neurons that are altered by homeostatic feedback are not well studied and have not been compared between sexes. During estradiol-positive feedback, which is unique to females, there are correlated changes in voltage-gated potassium currents and neuronal excitability. We thus hypothesized that these same mechanisms would be engaged in homeostatic negative feedback. Voltage-gated potassium channels play a direct role in setting excitability and action potential proper...

Glutamate is the principal excitatory neurotransmitter in the human brain. Following neurotransmission, astrocytes remove excess extracellular glutamate to prevent neurotoxicity. Glutamate neurotoxicity has been reported in multiple neurologic diseases including multiple sclerosis (MS), representing a shared neurodegenerative mechanism. A potential modulator of glutamate neurotoxicity is the bioactive lysophospholipid sphingosine 1-phosphate (S1P) that signals through five cognate G-protein-coupled receptors, S1P1–S1P5; however, a clear link between glutamate homeostasis and S1P signaling has not been established. Here, S1P receptor knock-out mice, primary astrocyte cultures, and receptor-selective chemical tools were used to examine the effects of S1P on glutamate uptake. S1P inhibited astrocytic glutamate uptake in a dose-dependent manner and increased mitochondrial oxygen consumption, primarily through S1P2. Primary cultures of wild-type mouse astrocytes expressed S1P1,2,3 transcripts, and selective del...

The adaptable transcriptional response to changes in food availability not only ensures animal survival, but also lets progressing with embryonic development. Interestingly, the central nervous system is preferentially protected to periods of malnutrition, a phenomenon known as ‘ brain sparing ’. However, the mechanisms that mediates this response remains poorly understood. To get a better understanding of this, we used Drosophila melanogaster as a model, analysing the transcriptional response of neural stem cells (neuroblasts) and glia of the blood-brain barrier (BBB), from larvae of both sexes, during nutrient restriction using targeted DamID. We found differentially expressed genes in both neuroblasts and glia of the BBB, although the effect of nutrient deficiency was primarily observed in the BBB. We characterised the function of a nutritional sensitive gene expressed in the BBB, the serine protease homologue, scarface ( scaf ). Scaf is expressed in subperineurial glia in the BBB in response to nutriti...

Textbook descriptions of primary sensory cortex (PSC) revolve around single neurons’ representation of low-dimensional sensory features, such as visual object orientation in V1, location of somatic touch in S1, and sound frequency in A1. Typically, studies of PSC measure neurons’ responses along few (1 or 2) stimulus and/or behavioral dimensions. However, real-world stimuli usually vary along many feature dimensions and behavioral demands change constantly. In order to illuminate how A1 supports flexible perception in rich acoustic environments, we recorded from A1 neurons while rhesus macaques (one male, one female) performed a feature-selective attention task. We presented sounds that varied along spectral and temporal feature dimensions (carrier bandwidth and temporal envelope, respectively). Within a block, subjects attended to one feature of the sound in a selective change detection task. We found that single neurons tend to be high-dimensional, in that they exhibit substantial mixed selectivity for b...

The orbitofrontal cortex (OFC) and hippocampus share striking cognitive and functional similarities. As a result, both structures have been proposed to encode “cognitive maps” that provide useful scaffolds for planning complex behaviors. However while this function has been exemplified by spatial coding in neurons of hippocampal regions—particularly place and grid cells—spatial representations in the OFC have been investigated far less. Here we sought to address this by recording OFC neurons from male rats engaged in an open-field foraging task like that originally developed to characterize place fields in rodent hippocampal neurons. Single unit activity was recorded as rats searched for food pellets scattered randomly throughout a large enclosure. In some sessions, particular flavors of food occurred more frequently in particular parts of the enclosure; in others, only a single flavor was used. OFC neurons showed spatially-localized firing fields in both conditions, and representations changed between fla...

Human listeners achieve quick and effortless speech comprehension through computations of conditional probability using Bayes rule. However, the neural implementation of Bayesian perceptual inference remains unclear. Competitive-selection accounts (e.g. TRACE) propose that word recognition is achieved through direct inhibitory connections between units representing candidate words that share segments (e.g. hygiene and hijack share/haidʒ/). Manipulations that increase lexical uncertainty should increase neural responses associated with word recognition when words cannot be uniquely identified. In contrast, predictive-selection accounts (e.g. Predictive-Coding) proposes that spoken word recognition involves comparing heard and predicted speech sounds and using prediction error to update lexical representations. Increased lexical uncertainty in words like hygiene and hijack will increase prediction error and hence neural activity only at later time points when different segments are predicted. We collected ME...

Sonic Hedgehog (Shh) signaling from the primary cilium drives cerebellar granule cell precursor (GCP) proliferation. Mutations of hedgehog (Hh) pathway repressors commonly cause medulloblastoma, the most prevalent and malignant childhood brain tumor that arises from aberrant GCP proliferation. We demonstrate that Nestin Cre-driven conditional knockout of a Shh pathway repressor- Rab23 in the mouse brain of both genders caused mis-patterning of cerebellar folia and elevated GCP proliferation during early development, but with no prevalent occurrence of medulloblastoma at adult stage. Strikingly, Rab23- depleted GCPs exhibited up-regulated basal level of Shh pathway activities despite showing an abnormal ciliogenesis of primary cilia. In line with the compromised ciliation, Rab23- depleted GCPs were desensitized against Hh pathway activity stimulations by Shh ligand and Smoothened (Smo) agonist-SAG, and exhibited attenuated stimulation of Smo-localization on the primary cilium in response to SAG. These resul...