Biology subjects

Gibson, J. R.

Publications and source records attributed to Gibson, J. R..

10 recordsLinked to original sources

bioRxiv2026

Molecular and cell type-specific determinants of inferior colliculus development and auditory function

Sound perception requires sensory information processing through brain regions where alterations to cellular composition or function may impact auditory-relevant behaviors. The inferior colliculus (IC) is a central midbrain hub for integrating and transforming auditory information prior to relay to the forebrain. However, the molecular logic that underlies the cell type specification of the IC remains unknown. Here, using a multiomic approach, we define the transcriptional and chromatin landscapes that underlie IC cell type diversity. We identify distinct glutamatergic neuronal subclasses and the gene regulatory programs that drive their specification, maturation, and survival. We show that perturbation to the transcription factor FOXP2, previously implicated in speech and language as well as brain disorders with altered sensory processing, selectively disrupts the specification and survival of three newly defined glutamatergic neuronal subclasses. We link these molecular and cellular disruptions to functional deficits in auditory processing including altered brainstem and forebrain responses and impaired behavioral sensitivity to acoustic stimuli. Together, these results link gene regulatory mechanisms to cell type-specification in the IC, providing insight into how molecular control of neuronal identity in midbrain sensory centers contributes to systems-level processing of sound.

neuroscience↗

bioRxiv2025

Enhanced CB1 receptor function in GABAergic neurons mediates hyperexcitability and impaired sensory-driven synchrony of cortical circuits in Fragile X Syndrome model mice

Electroencephalographic (EEG) recordings in individuals with Fragile X Syndrome (FXS) and the mouse model of FXS (Fmr1 KO) display cortical hyperexcitability at rest, as well as deficits in sensory-driven cortical network synchrony. A form of circuit hyperexcitability is observed in ex vivo cortical slices of Fmr1 KO mice as prolonged persistent activity, or Up, states. It is unknown if the circuit mechanisms that cause prolonged Up states contribute to FXS-relevant EEG phenotypes. Here we examined the role of endocannabinoids (eCB) in prolonged Up states in slices and resting and sensory-driven EEG phenotypes in awake Fmr1 KO mice. Bidirectional changes in eCB function are reported in the Fmr1 KO that depend on synapse type (excitatory or inhibitory). We demonstrate that pharmacological or genetic reduction of Cannabinoid Receptor 1 (CB1R) in GABAergic neurons rescues prolonged cortical Up states and deficits in sensory-driven cortical synchrony in Fmr1 KO mice. In support of these findings, recordings from Fmr1 KO cortical Layer (L) 2/3 pyramidal neurons revealed enhanced CB1R-mediated suppression of inhibitory synaptic currents. In contrast, genetic reduction of Cnr1 in glutamatergic neurons did not affect Up state duration, but deletion of Fmr1 in the same neurons was sufficient to cause long Up states. These findings support a model where loss of Fmr1 in glutamatergic neurons leads to enhanced CB1R-mediated suppression of GABAergic synaptic transmission, prolonged cortical circuit activation and reduced sensory-driven circuit synchronization. Results suggest that antagonism of CB1Rs as a therapeutic strategy to correct sensory processing deficits in FXS.

neuroscience↗

bioRxiv2023

FOXP1 regulates the development of excitatory synaptic inputs onto striatal neurons and induces phenotypic reversal with reinstatement

Long-range glutamatergic inputs from the cortex and thalamus are critical for motor and cognitive processing in the striatum. Transcription factors that orchestrate the development of these inputs are largely unknown. We investigated the role of a transcription factor and high-risk autism-associated gene, FOXP1, in the development of glutamatergic inputs onto spiny projection neurons (SPNs) in the striatum. We find that FOXP1 robustly drives the strengthening and maturation of glutamatergic input onto dopamine receptor 2-expressing SPNs (D2 SPNs) but has a comparatively milder effect on D1 SPNs. This process is cell-autonomous and is likely mediated through postnatal FOXP1 function at the postsynapse. We identified postsynaptic FOXP1-regulated transcripts as potential candidates for mediating these effects. Postnatal reinstatement of FOXP1 rescues electrophysiological deficits, reverses gene expression alterations resulting from embryonic deletion, and mitigates behavioral phenotypes. These results provide support for a possible therapeutic approach for individuals with FOXP1 syndrome.

neuroscience↗

bioRxiv2023

Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-cage Behavior

Lafora Disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD, as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, [~]6-7 months and [~]12 months of age, malin deficient mice ("KO") and wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age dependent LB accumulation, gliosis and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. Using an in vitro assay of neocortical function, paroxysmal increases in network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but were similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced post-ictal suppression of movement, feeding and drinking behavior. Together, these results highlight a stark clinicopathologic dissociation in a mouse model of LD, where LBs accrue substantially without clinically meaningful changes in overall wellbeing. Our findings allude to a delay between LB accumulation and neurobehavioral decline: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.

neuroscience↗

bioRxiv2023

Female specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and Estrogen Receptor α

Autism manifests differently in males and females and the brain mechanisms that mediate these sex-dependent differences are unknown. Here, we demonstrate that deletion of the ASD-risk gene, Pten, in neocortical pyramidal neurons (NSEPten KO) results in robust hyperexcitability of local neocortical circuits in female, but not male, mice, observed as prolonged, spontaneous persistent activity states (UP states). Circuit hyperexcitability in NSEPten KO mice is mediated by enhanced and/or altered signaling of metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor (ER) to ERK and protein synthesis selectively in Pten deleted female neurons. In support of this idea, Pten deleted Layer 5 cortical neurons have female-specific increases in mGluR5 and mGluR5-driven protein synthesis. In addition, mGluR5-ER complexes are elevated in female cortex and genetic reduction of ER in Pten KO cortical neurons rescues circuit excitability, protein synthesis and enlarged neurons selectively in females. Abnormal timing and hyperexcitability of neocortical circuits in female NSEPten KO mice are associated with deficits in temporal processing of sensory stimuli and social behaviors as well as mGluR5-dependent seizures. Female-specific cortical hyperexcitability and mGluR5-dependent seizures are also observed in a human disease relevant mouse model, germline Pten+/- mice. Our results reveal molecular mechanisms by which sex and a high impact ASD-risk gene interact to affect brain function and behavior.

neuroscience↗

bioRxiv2023

Excitatory neuron-specific suppression of the integrated stress response pathway contributes to autism-related phenotypes in a mouse model of fragile X syndrome

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2 phosphorylation (p-eIF2), is suppressed in excitatory but not inhibitory neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2 is mediated via activation of the mTORC1. Genetic reduction of p-eIF2 only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, genetic restoration of p-eIF2 solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis and core phenotypes reminiscent of autism in a mouse model of FXS.

neuroscience↗

bioRxiv2023

An extra-circadian function for human CLOCK in the neocortex

Core circadian-related proteins such as the transcription factor CLOCK are ubiquitously expressed and important for regulating molecular pathways underlying circadian rhythms. Previous work has suggested that CLOCK has evolved human neocortex-specific gene regulation and therefore may have extra-circadian functions. To test this in vivo, we generated a mouse model that recapitulates human cortical expression of CLOCK. The CLOCK humanized (HU) mice show enhanced cognitive flexibility, which is associated with the alteration in spatiotemporal expression of CLOCK. Cell type specific genomic profiling of HU mice identified upregulated genes related to dendritic growth and spine formation in excitatory neurons. Consistent with this result, we found that excitatory neurons in HU mice have increased complexity of dendritic branching and spine density, as well as a greater frequency of excitatory postsynaptic currents, suggesting an increase in neural connectivity. In contrast, CLOCK knockout in human induced pluripotent stem cell-induced neurons showed reduced complexity of dendrites and lower density of presynaptic puncta. Together, our data demonstrate that CLOCK evolved extra-circadian gains of function via altered spatiotemporal gene expression and these functions may underlie human brain specializations.

neuroscience↗

bioRxiv2021

FMRP regulates experience-dependent maturation of callosal synaptic connections and bilateral cortical synchrony

Reduced structural and functional interhemispheric connectivity correlates with the severity of Autism Spectrum Disorder (ASD) behaviors in humans. Little is known of how ASD-risk genes regulate callosal connectivity. Here we show that Fmr1, whose loss-of-function leads to Fragile X Syndrome (FXS), cell autonomously promotes maturation of callosal excitatory synapses between somatosensory barrel cortices in mice. Postnatal, cell-autonomous deletion of Fmr1 in postsynaptic Layer (L) 2/3 or L5 neurons results in a selective weakening of AMPA receptor- (R), but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. In contrast to callosal inputs, synapses originating from local L4 and L2/3 circuits are normal, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. These results suggest direct cell autonomous and postnatal roles for FMRP in development of specific cortical circuits and suggest a synaptic basis for long-range functional underconnectivity observed in FXS patients.

neuroscience↗

bioRxiv2020

FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents

Heterozygous loss-of-function mutations in the transcription factor FOXP1 are strongly associated with autism. Dopamine receptor 2 expressing (D2) striatal projection neurons (SPNs) in heterozygous Foxp1 (Foxp1+/-) mice have higher intrinsic excitability. To understand the mechanisms underlying this alteration, we examined SPNs with cell-type specific homozygous Foxp1 deletion to study cell-autonomous regulation by Foxp1. As in Foxp1+/- mice, D2 SPNs had increased intrinsic excitability with homozygous Foxp1 deletion. This effect involved postnatal mechanisms. The hyperexcitability was mainly due to down-regulation of two classes of potassium currents: inwardly rectifying (KIR) and leak (KLeak). Single-cell RNA sequencing data from D2 SPNs with Foxp1 deletion indicated the down-regulation of transcripts of candidate ion channels that may underlie these currents: Kcnj2 and Kcnj4 for KIR and Kcnk2 for KLeak. This Foxp1-dependent regulation was neuron-type specific since these same currents and transcripts were either unchanged, or very little changed, in D1 SPNs with cell-specific Foxp1 deletion. Our data are consistent with a model where FOXP1 negatively regulates the excitability of D2 SPNs through KIR and KLeak by transcriptionally activating their corresponding transcripts. This, in turn, provides a novel example of how a transcription factor may regulate multiple genes to impact neuronal electrophysiological function that depends on the integration of multiple current types - and do this in a cell-specific fashion. Our findings provide initial clues to altered neuronal function and possible therapeutic strategies not only for FOXP1-associated autism but also for other autism forms associated with transcription factor dysfunction.

neuroscience↗

bioRxiv2020

Abundance and Distribution of Heterelmis cf. glabra (Coleoptera: Elmidae) within Dolan Falls Preserve and the Devils River State Natural Area, Texas, USA

The Devils River watershed in south-central Texas has baseflows entirely attributable to groundwater primarily sourced from the Edwards-Trinity and Edwards Aquifers. The largest known populations of a species of riffle beetle, Heterelmis cf. glabra, are located in springs associated with the upper Devils River. The focus of this study was to 1) determine site-level abundances of H. cf. glabra using open system N-mixture models, 2) test mesohabitat associations of members in the riffle beetle family Elmidae and, 3) measure and examine abiotic and habitat associations for adult and larval beetles within the study area. We sampled 32 spring sources to determine occupancy and abundance of adult and larval riffle beetles (Elmidae) within the study area. Spring sources were mapped and categorized by type (orifice, upwelling, group of springs, or seep). Basic water chemistry and flow rate categorization were also performed at each site. Model results suggest that rainfall, flow and site are important for detection of H. cf. glabra. Based on our results, regular monitoring of these 32 sites using these methods, is recommended to conduct hypotheses tests on covariates influencing abundance. Such baseline information will be important in measuring impacts to this and other spring-associated species as the habitats of this region are impacted by natural or anthropogenic phenomena.

ecology↗