Biology subjects

Jones, K. S.

Publications and source records attributed to Jones, K. S..

8 recordsLinked to original sources

bioRxiv2025

Population genetics of the endangered narrowly endemic Island Marble butterfly (Euchloe ausonides insulanus)

The Island Marble butterfly (Euchloe ausonides insulanus) is an endangered species endemic to the San Juan Islands off the coast of Washington State, United States, and British Columbia, Canada. The species was thought to be extinct for [~]90 years before it was rediscovered at American Camp, San Juan Island National Historical Park in 1998. Here, we report the results of the first population genetic analyses for insulanus, using DNA collected non-invasively from individuals in the last known stronghold for the species. We used DNA extracted from meconium, larval exuviae, and natural mortalities to generate and test thirteen new microsatellite markers to estimate genetic diversity, population structure, and kinship. We assembled and annotated mitochondrial genomes, which were used alongside museum specimens of insulanus collected [~]100 years ago from Vancouver Island, and other members of the E. ausonides species complex, to infer the evolutionary history of the species. The results indicated that insulanus experiences low heterozygosity, a small effective population size (Ne), and low allelic diversity. High levels of inbreeding were found in some individuals, but inbreeding was uneven across the population. No population structure or partitioning of genetic variation by host plant was detected. The mitogenomes of extant insulanus were all identical and modern samples showed a loss of allelic diversity compared to insulanus from museums. Extant insulanus formed a clade with museum specimens and we identified multiple putatively diagnostic alleles to differentiate insulanus from other subspecies. Based on these results, we outline considerations for species management and genetic monitoring.

genetics↗

bioRxiv2025

Grin2a Dysfunction Impairs Cognitive Flexibility by Disrupting LC Modulation of mPFC Circuits

Cognitive flexibility, a key executive function, is impaired in psychiatric disorders involving prefrontal cortical dysfunction. The medial prefrontal cortex (mPFC) regulates cognitive flexibility and receives noradrenergic input from the locus coeruleus (LC). Mutations in GRIN2A, encoding GluN2A-containing NMDA receptors, impair cognitive flexibility and psychiatric resilience, yet the circuit mechanisms remain unclear. Optogenetic LC[->]mPFC activation improved reversal learning in wild-type and Grin2a heterozygous (HET) mice but not in knockouts (KO), indicating a loss of noradrenergic modulation. Grin2a mutants displayed disrupted gamma and high-frequency oscillations (HFOs) in the mPFC. Exogenous norepinephrine failed to restore oscillatory activity, implicating 2-adrenoceptors in NE-driven cortical dynamics. Increased LC innervation and norepinephrine transporter (NET) expression in Grin2a mutants suggest excessive noradrenergic input and impaired NE clearance. These findings identify GluN2A as essential for LC-driven prefrontal network synchronization and cognitive flexibility, offering insights into NE dysfunction in psychiatric disorders.

neuroscience↗

bioRxiv2024

Grin2a Ablation Distinctly Reshapes PV+ and SST+ Interneuron circuits in the Medial Prefrontal Cortex to Amplify Gamma Oscillations

Schizophrenia (SCZ) is a debilitating mental health disorder marked by cognitive deficits, especially in executive functions, which are often resistant to treatment. The GRIN2A gene encodes the GluN2A subunit of N-methyl-D-aspartate (NMDA) receptor. Rare coding mutations in GRIN2A, such as protein-truncating variants, increase susceptibility to SCZ by [~]20-fold. However, the effects on network dynamics and the function of GABAergic interneurons (INs) in the medial prefrontal cortex (mPFC) remain unclear. In this study, we use brain slices from Grin2a mutant mice to investigate inhibitory synaptic and oscillatory activity driven by parvalbumin-positive (PV+) and somatostatin-positive (SST+) INs. Our findings reveal significant alterations in synaptic currents and inhibitory modulation arise from GluN2A deficiency. Specifically, both heterozygous and knockout Grin2a mutants exhibit impaired synaptic transmission and release properties of INs inputs, including changes in release probability and evoked quantal events to layer V pyramidal neurons. Genotype-dependent alterations were observed in the frequency, kinetics, and amplitude of excitatory and inhibitory postsynaptic currents. Immunohistochemical analysis showed an increased density of PV+ and SST+ INs in the Grin2a mutants, consistent with an overall increase in inhibitory tone. Additionally, optogenetic stimulation revealed a dynamic shift for inducing gamma-band oscillations through PV+ INs. Overall, our study highlights the essential role of GluN2A-containing NMDA receptors in modulating inhibitory tone and maintaining network stability in the mPFC of adult mice and elucidates a pathophysiological mechanism that might contribute to cognitive deficits often observed in SCZ patients.

neuroscience↗

bioRxiv2024

Grin2a Hypofunction Disrupts Hippocampal Network Oscillations and E/I Balance Contributing to Cognitive Deficits

BackgroundN-methyl-D-aspartate (NMDA) receptors, particularly those containing the GluN2A subunit, play a critical role in hippocampal-dependent learning and memory. The GluN2A subunit, encoded by the Grin2a gene, is essential for maintaining cognitive function, including working memory. In this study, we explore how Grin2a mutations impair working memory and disrupt hippocampal network oscillations and E/I balance. MethodsGrin2a mutant mice were assessed for spatial working memory deficits using the 8-arm radial maze. We utilized multi-electrode arrays and whole-cell patch-clamp electrophysiology to evaluate network oscillation and synaptic inputs to pyramidal cells in ex vivo hippocampal slices. We performed an immunohistochemical analysis of hippocampal slices to evaluate changes in the abundance of GABAergic neurons. ResultsOur results demonstrate that Grin2a deficiency impairs spatial working memory and disrupts coupling of theta-gamma oscillations in the hippocampus. Moreover, Grin2a mutants express an overabundance of parvalbumin-expressing (PV+) interneurons that integrate into hippocampal circuits and destabilize excitatory/inhibitory (E/I) input to CA1 pyramidal neurons. ConclusionThis study highlights the critical role of GluN2A-containing NMDA receptors in maintaining hippocampal network synchrony. Impairments in network synchrony and E/I balance within the hippocampus may drive the cognitive deficits observed in Grin2a-related disorders such as schizophrenia, epilepsy, and intellectual disability.

neuroscience↗

bioRxiv2022

Molecular diversity and connectivity of accessory olfactory system neurons

Olfaction is the primary sensory modality by which most vertebrate species interpret environmental cues for appropriate behavioral outputs. The olfactory system is subdivided into main (MOS) and accessory (AOS) components which process volatile and non-volatile cues. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the AOS which is largely comprised of the peripheral vomeronasal organ (VNO), the accessory olfactory bulb (AOB) and the medial subnucleus of the amygdala (MeA), we studied the molecular diversity and neuronal subtype connectivity of this interconnected circuit. We show that populations of neurons of the AOS can be molecularly subdivided based on their current or prior expression of the transcription factors Foxp2 or Dbx1. We show that the majority of AOB neurons that project directly to the MeA are of the Foxp2-lineage. Using single cell patch clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the relative contributions of excitatory and inhibitory inputs to MeA Foxp2-lineage neurons differ between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons and lineage- and sex-differences in patterns of connectivity.

neuroscience↗

bioRxiv2021

Placental uptake and metabolism as determinants of pregnancy vitamin D status

Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.

physiology↗

bioRxiv2021

A Novel Approach to Study Gamma-Band Coherence in Ex Vivo Hippocampal Slices from a Mouse Model of Bipolar Disorder.

Oscillations play crucial roles in many cognitive processes such as memory formation and attention. GABAergic interneurons can synchronize neuronal activity leading to gamma oscillations (30-60 Hz). Abnormalities in oscillatory activity in the hippocampus have been implicated in the pathology of some mental health disorders including schizophrenia and bipolar disorder, however the neurobiological mechanism underlying these abnormal oscillations are not yet fully understood. We set out to develop a reliable approach to study gamma oscillations in ex vivo hippocampal preparations using perforated microelectrode arrays. Perforated microelectrode arrays allow for the simultaneous measurement of electrical activity at multiple sites while allowing solutions to pass through the brain section. We obtained extracellular electrophysiological recordings from acute sections of mouse hippocampus situated on a 60-channel, perforated microelectrode arrays (pMEAs). Bath application of kainate rapidly induced and maintained oscillatory activity in the CA1 and CA3 regions of the hippocampus. Kainate-induced oscillations were quickly abolished by the GABAA receptor antagonist, bicuculline. Furthermore, we employed this approach on a mouse model of bipolar disorder. Sections prepared from mutant mice exhibited an increase in the coherence of gamma power within CA1 despite a reduction in gamma band power.

neuroscience↗

bioRxiv2018

Ankyrin-G Regulates Forebrain Connectivity and Network Synchronization via Interaction with GABARAP

GABAergic circuits are critical for the synchronization and higher order function of brain networks, and defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons where it interacts directly with the GABAO_SCPCAPAC_SCPCAP receptor associated protein (GABARAP) to stabilize cell surface GABAO_SCPCAPAC_SCPCAP receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

neuroscience↗