Retinal ganglion cells (RGCs) project topographically to the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). Spontaneous activity plays a critical role in retinotopic mapping in both regions; however, the molecular mechanisms underlying activity-dependent refinement remain unclear. Previous pharmacologic studies implicate NMDA receptors (NMDARs) in the establishment of retinotopy. In other brain regions, NMDARs are expressed on both the presynaptic and postsynaptic side of the synapse, and recent work suggests that presynaptic and postsynaptic NMDARs play distinct roles in retinotectal developmental dynamics. To directly test the role of NMDARs expressed by RGCs in retinofugal map formation, we took a conditional genetic knock-out approach to delete the obligate GluN1 subunit of NMDARs in RGCs. Here, we demonstrate reduced GluN1 expression in the retina of Chrnb3-Cre;GluN1flox/flox (pre-cKO) mice without altered expression in the SC. Anatomical tracing experiments revealed no signifi...

Nitrous oxide (N2O) is a hypnotic gas with antidepressant and psychedelic properties at subanesthetic concentrations. Despite long-standing clinical use, there is insufficient understanding of its effect on neural dynamics and cortical processing, which is important for mechanistic understanding of its therapeutic effects. We administered subanesthetic (70%), inhaled N2O and studied the dynamic changes of spiking rate, spectral content, and somatosensory information representation in primary motor cortex (M1) in two male rhesus macaques implanted with Utah microelectrode arrays in the hand area of M1. The average sorted multiunit spiking rate in M1 increased from 8.1 ± 0.99 to 10.6 ± 1.3 Hz in Monkey W ( p  <   0.001) and from 5.6 ± 0.87 to 7.0 ± 1.1 Hz in Monkey N ( p  =   0.003). Power spectral densities increased in beta- and gamma-band power. To evaluate somatosensory content in M1 as a surrogate of information transfer, fingers were lightly brushed and classified using a naive Bayes classifier. In bot...

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...

Brain microinfarcts are prevalent in humans, however because of the inherent difficulty of identifying and localizing individual microinfarcts, brain-wide quantification is impractical. In mice, microinfarcts have been created by surgically introducing microemboli into the brain, but a major limitation of this model is the absence of automated methods to identify and localize individual occlusions. We present a novel and semi-automated workflow to identify the anatomic location of fluorescent emboli (microspheres) within the mouse brain through histologic processing and atlas registration. By incorporating vibratome block-face imaging with the QuickNII brain registration tool, we show that the anatomic location of microspheres can be accurately registered to brain structures within the Allen mouse brain (AMB) atlas (e. g ., somatomotor areas, hippocampal region, visual areas, etc.). Compared with registering images of slide mounted sections to the AMB atlas, microsphere location was more accurately determi...

The enteric nervous system (ENS) consists of an interconnected meshwork of neurons and glia residing within the wall of the gastrointestinal (GI) tract. While healthy GI function is associated with healthy ENS structure, defined by the normal distribution of neurons within ganglia of the ENS, a comprehensive understanding of normal neuronal distribution and ganglionic organization in the ENS is lacking. Current methodologies for manual enumeration of neurons parse only limited tissue regions and are prone to error, subjective bias, and peer-to-peer discordance. There is accordingly a need for robust, and objective tools that can capture and quantify enteric neurons within multiple ganglia over large areas of tissue. Here, we report on the development of an AI-driven tool, COUNTEN (COUNTing Enteric Neurons), which is capable of accurately identifying and enumerating immunolabeled enteric neurons, and objectively clustering them into ganglia. We tested and found that COUNTEN matches trained humans in its acc...

In the article “Cellular and Network Mechanisms May Generate Sparse Coding of Sequential Object Encounters in Hippocampal-Like Circuits,” by Anh-Tuan Trinh, Stephen E. Clarke, Erik Harvey-Girard, and Leonard Maler, which published online on July 19, 2019, the legend for Extended Data Figure 8-1 was duplicated from the legend for Extended Data Figure 5-1 because of a production error. The legend should instead read: "Current-evoked …

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...

In macaque monkeys, dorsal intraparietal areas are involved in several daily visuomotor actions. However, their border and sources of cortical afferents remain loosely defined. Combining retrograde histologic tracing and MRI diffusion-based tractography, we found a complex hodology of the dorsal bank of the intraparietal sulcus (db-IPS), which can be subdivided into a rostral intraparietal area PEip, projecting to the spinal cord, and a caudal medial intraparietal area MIP lacking such projections. Both include an anterior and a posterior sector, emerging from their ipsilateral, gradient-like connectivity profiles. As tractography estimations, we used the cross-sectional area of the white matter bundles connecting each area with other parietal and frontal regions, after selecting regions of interest (ROIs) corresponding to the injection sites of neural tracers. For most connections, we found a significant correlation between the proportions of cells projecting to all sectors of PEip and MIP along the conti...

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...