Biology subjects

Oram, C.

Publications and source records attributed to Oram, C..

3 recordsLinked to original sources

bioRxiv2025

Transient Early Postnatal Neuronal Hyperexcitation Results in Lasting Social Preference Deficits

Perturbations during critical periods of neurodevelopment are implicated in the etiology of autism spectrum disorder (ASD), a condition marked by considerable heterogeneity and prevalent comorbidities. One such comorbidity is epilepsy, with approximately 30% of children with ASD experiencing seizures and a similar proportion of children with epilepsy displaying ASD-like symptoms. Both conditions have been associated with disruptions in the brains excitation-to-inhibition (E/I) balance. Although early-life seizures in rodents have been linked to social impairments, direct causal evidence connecting E/I imbalance, interneuron development, and social behavior remains limited. To address this gap, we induced transient, brain-wide hyperexcitation in neonatal mice using pentylenetetrazol (PTZ), a GABA_A receptor antagonist. We administered both convulsive and subconvulsive doses and assessed long-term effects on social behavior, cortical E/I balance, and parvalbumin (PV) interneuron development. PTZ-treated groups displayed impaired social preference as measured in the 3-chamber test and increased PV interneuron density within the medial prefrontal cortex. These findings highlight a critical developmental window during which E/I imbalance leads to social deficits characteristic of ASD and epilepsy. They also reveal dose-dependent neurobiological changes, underscoring the importance of early-life neural activity in shaping social circuitry.

neuroscience↗

bioRxiv2025

Calbindin Stratifies Midbrain Dopaminergic Neurons Governing Distinct Aspects of Locomotion

Despite advances in delineating the molecular diversity and projection patterns of midbrain dopaminergic (DA) neurons, their specific contributions to locomotion and motor learning remain poorly defined. Here, we applied intersectional ablation and chemogenetic approaches to dissect the distinct roles of calbindin-expressing (CALB1+) and non-expressing (CALB1-) DA neurons in locomotion. Using newly engineered intersectional constructs, we ablated CALB1+ or CALB1- DA neurons in the mouse midbrain. Loss of either subtype led to pronounced deficits in the initiation and vigor of voluntary movements, as demonstrated by a reduction in peak speed, acceleration and deceleration of locomotor bouts. Notably, only CALB1- ablation disrupted locomotor learning. Beyond these functional effects, we observed that selective ablation of CALB1 DA neurons induced local microglial activation and was followed by a non-cell-autonomous loss of CALB1- DA neurons, suggesting that CALB1- neurons are more vulnerable to inflammation triggered by CALB1 neuron loss. We then confirmed these findings by performing acute inhibition of either population using inhibitory DREADD hM4Di. CALB1- DA neurons inhibition impaired the initial acquisition of locomotor learning, whereas inhibition of CALB1+ DA neurons disrupted the retention of acquired motor skills from previous days. Moreover, inhibition of CALB1+ DA neurons further impaired the initiation and amplitude of voluntary movements, as well as the velocity and acceleration/deceleration of locomotor bouts. Together, these findings provide causal evidence for functional specialization among molecularly distinct midbrain DA subtypes and reveal new aspects of mesostriatal circuit organization underlying locomotion and motor memory.

neuroscience↗

bioRxiv2024

Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson's disease

Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using single cell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown that molecularly defined DA subtypes within the substantia nigra (SNc) display distinctive anatomic and functional properties, and differential vulnerability in Parkinsons disease (PD). Based on these provocative results, a granular understanding of these putative subtypes and their alterations in PD models, is imperative. We developed an optimized pipeline for single-nuclear RNA sequencing (snRNA-seq) and generated a high-resolution hierarchically organized map revealing 20 molecularly distinct DA neuron subtypes belonging to three main families. We integrated this data with spatial MERFISH technology to map, with high definition, the location of these subtypes in the mouse midbrain, revealing heterogeneity even within neuroanatomical sub-structures. Finally, we demonstrate that in the preclinical LRRK2G2019S knock-in mouse model of PD, subtype organization and proportions are preserved. Transcriptional alterations occur in many subtypes including those localized to the ventral tier SNc, where differential expression is observed in synaptic pathways, which might account for previously described DA release deficits in this model. Our work provides an advancement of current taxonomic schemes of the mouse midbrain DA neuron subtypes, a high-resolution view of their spatial locations, and their alterations in a prodromal mouse model of PD. Teaser: Using snRNASeq and MERFISH we identified midbrain DA subtypes, mapped their spatial location, and identified alterations in a LRRK2 model

neuroscience↗