Search bioRxiv⌕ Search

Biology subjects

Burke, S.

Publications and source records attributed to Burke, S..

7 recordsLinked to original sources

A biophysical corticostriatal model predicts learning-dependent 7T fMRI dynamics and individual reward bias in humans

Circuit-level computational models can do more than explain existing data; they can generate novel hypotheses and capture individual differences in human populations. We demonstrate this using a biophysical corticostriatal model, transforming simulated neuronal activity from local field potential (LFP) into functional magnetic resonance imaging (fMRI) signals via the balloon model, and finally generating behavioral outcomes. We then validate the results against those obtained from human subjects. The model generates a counterintuitive yet testable prediction. Although prefrontal-striatal coherence demonstrates an increase at the neural LFP scale during learning, the same circuit-- passed through the hemodynamic transform---predicts a decrease in prefrontal-striatal BOLD correlation, driven by category-selective representations that emerge in cortex but not striatum. This prediction is confirmed in fMRI data optimized for single-subject-level detection sensitivity. The model further enables single-subject fitting of a behavioral outcome, classifying individuals into those differentially responding to positive versus negative reward bias. Established biomarkers, including activation measured by the amplitude of low-frequency fluctuations and dopaminergic effects on hemodynamic latency, are also conserved across LFP and fMRI scales. These findings reposition circuit models as generative tools for human neuroscience, capable of producing mechanistically grounded hypotheses and parsing individual variation in ways inaccessible to data-driven approaches alone.

neuroscience↗

Decades of Parkinson's disease neuropathology yield a sparse and underpowered map of neuronal vulnerability: a systematic review and meta-analysis

Selective vulnerability is widely assumed in Parkinson's disease (PD), but whether dopaminergic neurons of the substantia nigra are uniquely vulnerable has not been established. Explanations of neuronal degeneration in Parkinson's disease often centre on the distinctive properties of substantia nigra dopaminergic neurons. Whether these properties are necessary for substantial neuronal loss remains unclear. We preregistered a systematic review of 166 post-mortem case-control studies published between 1963 and 2025 and synthesised neuronal counts and densities from 152 studies using a multilevel meta-analysis. After six decades, only 18% of countable brain atlas labels had been examined, and most populations were represented by a single study. Substantial loss beyond dopaminergic and classically pigmented populations shows that neither dopaminergic identity nor neuromelanin is necessary for marked degeneration, challenging key tenets of selective vulnerability in PD. Comparisons across other anatomical and physiological features remain limited by sparse sampling and uncertainty. We identify less-studied populations with substantial estimated loss and estimate the additional sampling needed to improve precision under specified assumptions. These findings direct replication and comparative counting towards uncertainties that limit explanations of neuronal loss across affected and potentially spared populations.

neuroscience↗

Loss of neurexins disrupts inhibitory connectivity and increases vulnerability of dopamine neurons in culture

Midbrain dopamine (DA) neurons are essential regulators of basal ganglia function. Their axonal structure is intricate, with numerous non-synaptic release sites and fewer synaptic terminals that notably release glutamate or GABA. Despite their significance, the molecular mechanisms governing DA neuron connectivity and neurochemical identity remain poorly understood. We hypothesize that trans-synaptic cell adhesion molecules such as neurexins (Nrxns) regulate the interactions of DA neuron axons with target cells and thereby influence axonal branching and synapse formation by DA neurons. We therefore examined neuronal survival, axonal growth and synapse formation in cultured DA neurons lacking all neurexins (DAT::NrxnsKO). Conditional deletion of all Nrxns in DA neurons revealed that loss of Nrxns does not disrupt the basic development of these neurons or the structure of their axonal terminals, including normal expression of the vesicular monoamine transporter (VMAT2) and the calcium sensor synaptotagmin 1 (Syt1). However, loss of Nrxns affects the survival of DA neurons and their formation of inhibitory synapses, suggesting that Nrxns regulate the axonal connectivity of these neurons.

neuroscience↗

Long-Term Effects of Early Adolescent Second-Generation Antipsychotic Exposure on Body Weight, Caloric Intake, and Metabolism-Associated Gene Expression

The use of second-generation antipsychotic (SGA) medications in pediatric patients raises concerns about potential long-term adverse outcomes. The current study evaluated the long-term effects of treatment with risperidone or olanzapine on body weight, caloric intake, serum insulin, blood glucose, and metabolism-associated gene expression in C57Bl/6J female mice. Compared to mice treated with vehicle, female mice treated with risperidone or olanzapine gained weight at higher rates during treatment and maintained higher body weights for months following treatment cessation. During high-fat diet feeding, some groups of treated mice gained weight at higher rates than their respective control groups, but the finding was not consistent across experiments. Finally, female mice previously treated with olanzapine also exhibited increased expression of genes associated with inflammation and lipogenesis. These findings suggest that pediatric use of SGA medications that induce excess weight gain during treatment may exert persistent effects on body weight and gene expression and such outcomes may form an important aspect of assessing risk-to-benefit ratios in prescribing decisions.

pharmacology and toxicology↗

Keywords to success: a practical guide to maximise the visibility and impact of academic papers

In a growing digital landscape, enhancing the discoverability and resonance of scientific articles is essential. Here, we offer ten recommendations to amplify the discoverability of studies in scientific databases. Particularly, we argue that the strategic use and placement of key terms in the title, abstract, and keyword sections can boost indexing and appeal. By surveying 237 journals in ecology and evolutionary biology, we found that current author guidelines may unintentionally limit article discoverability. Our survey of 5842 studies revealed that authors frequently exhaust abstract word limits -- particularly those capped under 250 words. This suggests that current guidelines may be overly restrictive and not optimised to increase the dissemination and discoverability of digital publications. Additionally, 91.9% of studies used redundant keywords in the title or abstract, undermining optimal indexing in databases. We encourage adopting structured abstracts to maximise the incorporation of key terms in titles, abstracts, and keywords. In addition, we encourage the relaxation of abstract and keyword limitations in journals with strict guidelines, and the inclusion of multilingual abstracts to broaden global accessibility. These evidence-based recommendations to editors are designed to improve article engagement and facilitate evidence synthesis, thereby aligning scientific publishing with the modern needs of academic research.

scientific communication and education↗

Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism

Initiating drug use during adolescence increases the risk of developing addiction and psychiatric disorders later in life, with long-term outcomes varying according to sex and exact timing of use. Even though most individuals begin experimenting with drugs of abuse in adolescence, to date, the cellular and molecular underpinnings explaining differential sensitivity to detrimental drug effects remain unknown. The Netrin-1/DCC guidance cue system plays a critical role in the adolescent development of mesocorticolimbic dopamine circuitry, segregating the cortical and limbic pathways. Adolescent experiences, including exposure to drugs of abuse, can regulate Dcc expression in male mice, placing Netrin-1/DCC signaling as a potential molecular link between experience and enduring changes to circuitry and behavior. Here we show that exposure to a recreational-like regimen of amphetamine (AMPH) in adolescence induces sex- and age-specific alterations in Dcc expression in the ventral tegmental area. Female mice are protected against the deleterious long-term effects of AMPH-induced Dcc regulation by compensatory changes in the expression of its binding partner, Netrin-1. AMPH induces targeting errors in mesolimbic dopamine axons and triggers their ectopic growth to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to its enduring cognitive effects. Upregulating DCC receptor expression in dopamine neurons in adolescent males using a neuron-optimized CRISPR/dCas9 Activation System induces female-like protection against the persistent effects of AMPH in early adolescence on inhibitory control. Netrin-1/DCC signaling is therefore a molecular switch which can be differentially regulated in response to the same experience as function of age and sex of the individual, leading to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

neuroscience↗

Neurexins Regulate GABA Co-release by Dopamine Neurons

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) showed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression, and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings suggest that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions. HighlightsO_LIThe study provides the first direct evidence of the role of neurexins in dopaminergic neurons. C_LIO_LIThe synaptic adhesion molecules, neurexins, are not required for maintaining the structure of dopamine neuron terminals. C_LIO_LINeurexins regulate dopaminergic neurotransmission through regulation of dopamine reuptake, impacting amphetamine-induced locomotion. C_LIO_LIDeletion of Nrxns in DA neurons causes a region-specific increase of GABA release by DA neurons. C_LI

neuroscience↗