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Using fast-scan cyclic voltammetry to investigate somatodendritic dopamine release
Midbrain dopamine (DA) neurons of the substantia nigra (SN, “A9”) and adjacent ventral tegmental area (VTA, “A10”) are critical to a range of CNS functions, including motor facilitation by the basal ganglia and the regulation of motivation by natural rewards as well as by drugs of addiction. A characteristic shared by DA cells in the SN and VTA is that they release DA locally from somatodendritic regions1-4 as well as from their axonal projections. There is evidence for release from soma5 as well as from dendrites.2,6 Somatodendritic release of neurotransmitter is not restricted to DA neurons; rather, neurons found throughout the brain can signal via the somatodendritic release of neurotransmitters, including GABA and glutamate as well as neuropeptides.7,8 Somatodendritic neurotransmission operates both at a synaptic level and by more paracrine/autocrine- like modes to offer neuronal cross-talk as well as self- or auto-feedback control.7,8 This chapter will focus specifically on the somatodendritic release of DA within the midbrain and how voltammetric methods, particularly fast-scan cyclic voltammetry (FCV), have been used to explore its characteristics.
Sleep pressure accumulates in a voltage-gated lipid peroxidation memory.
Voltage-gated potassium (KV) channels contain cytoplasmically exposed β-subunits1-5 whose aldo-keto reductase activity6-8 is required for the homeostatic regulation of sleep9. Here we show that Hyperkinetic, the β-subunit of the KV1 channel Shaker in Drosophila7, forms a dynamic lipid peroxidation memory. Information is stored in the oxidation state of Hyperkinetic's nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, which changes when lipid-derived carbonyls10-13, such as 4-oxo-2-nonenal or an endogenous analogue generated by illuminating a membrane-bound photosensitizer9,14, abstract an electron pair. NADP+ remains locked in the active site of KVβ until membrane depolarization permits its release and replacement with NADPH. Sleep-inducing neurons15-17 use this voltage-gated oxidoreductase cycle to encode their recent lipid peroxidation history in the collective binary states of their KVβ subunits; this biochemical memory influences-and is erased by-spike discharges driving sleep. The presence of a lipid peroxidation sensor at the core of homeostatic sleep control16,17 suggests that sleep protects neuronal membranes against oxidative damage. Indeed, brain phospholipids are depleted of vulnerable polyunsaturated fatty acyl chains after enforced waking, and slowing the removal of their carbonylic breakdown products increases the demand for sleep.
Transient photocurrents in a subthreshold evidence accumulator accelerate perceptual decisions.
Perceptual decisions are complete when a continuously updated score of sensory evidence reaches a threshold. In Drosophila, αβ core Kenyon cells (αβc KCs) of the mushroom bodies integrate odor-evoked synaptic inputs to spike threshold at rates that parallel the speed of olfactory choices. Here we perform a causal test of the idea that the biophysical process of synaptic integration underlies the psychophysical process of bounded evidence accumulation in this system. Injections of single brief, EPSP-like depolarizations into the dendrites of αβc KCs during odor discrimination, using closed-loop control of a targeted opsin, accelerate decision times at a marginal cost of accuracy. Model comparisons favor a mechanism of temporal integration over extrema detection and suggest that the optogenetically evoked quanta are added to a growing total of sensory evidence, effectively lowering the decision bound. The subthreshold voltage dynamics of αβc KCs thus form an accumulator memory for sequential samples of information.
CaV2.1 mediates presynaptic dysfunction induced by amyloid β oligomers.
Synaptic dysfunction is an early pathological phenotype of Alzheimer's disease (AD) that is initiated by oligomers of amyloid β peptide (Aβos). Treatments aimed at correcting synaptic dysfunction could be beneficial in preventing disease progression, but mechanisms underlying Aβo-induced synaptic defects remain incompletely understood. Here, we uncover an epithelial sodium channel (ENaC) - CaV2.3 - protein kinase C (PKC) - glycogen synthase kinase-3β (GSK-3β) signal transduction pathway that is engaged by Aβos to enhance presynaptic CaV2.1 voltage-gated Ca2+ channel activity, resulting in pathological potentiation of action-potential-evoked synaptic vesicle exocytosis. We present evidence that the pathway is active in human APP transgenic mice in vivo and in human AD brains, and we show that either pharmacological CaV2.1 inhibition or genetic CaV2.1 haploinsufficiency is sufficient to restore normal neurotransmitter release. These findings reveal a previously unrecognized mechanism driving synaptic dysfunction in AD and identify multiple potentially tractable therapeutic targets.
Brain aging shows nonlinear transitions, suggesting a midlife "critical window" for metabolic intervention.
Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain's regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons' energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife "critical window" for early metabolic intervention.
Characterising human disparity tuning properties using population receptive field mapping.
Our visual percept of small differences in depth is largely informed by binocular stereopsis, the ability to decode depth from the horizontal offset between the retinal images in each eye. While multiple cortical areas are associated with stereoscopic processing, it is unclear how tuning to specific binocular disparities is organised across human visual cortex. We used 3T functional magnetic resonance imaging to generate population receptive fields in response to modulation of binocular disparity to characterise the neural tuning to disparity. We also used psychophysics to measure stereoacuity thresholds compared to backgrounds at different depths (pedestal disparity). Ten human participants (7 female) observed correlated or anticorrelated random-dot stereograms with disparity ranging from -0.3° to 0.3°, and responses were modelled as 1-dimensional tuning curves along the depth dimension. First, we demonstrate that lateral and dorsal visual areas show the greatest proportion of vertices selective for binocular disparity. Second, with binocularly correlated stimuli, we show a polynomial relationship between preferred disparity and tuning curve width, with sharply tuned disparity responses at near-zero disparities, and broader disparity tuning profiles at near or far disparities. This relationship held across visual areas and was not present for anticorrelated stimuli. Finally, the individual thresholds for psychophysical stereoacuity at the 3 different pedestal disparities were broadly related to population receptive field tuning width in area V1, suggesting a possible limit for fine stereopsis at the earliest level of cortical processing. Together, these findings point to heterogeneity of disparity processing across human visual areas, comparable to non-human primates.Significance Statement Binocular disparity arises from the horizonal separation of the two eyes and provides information for determining depth and 3D structure. We used functional magnetic resonance imaging and population receptive field mapping to measure tuning of multiple visual areas to binocular disparity in the human visual cortex. We additionally measured psychophysical thresholds for detecting binocular disparity and correlated these with the neural measures. The width of the disparity tuning was related to the preferred disparity across all visual areas. Disparity tuning widths in V1 were also related to psychophysical thresholds. These findings in the human are broadly comparable to non-human primates.
Cyclic nucleotide phosphodiesterases as drug targets.
Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.
Recent developments in gene therapy for Parkinson's disease.
Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no cure. Gene therapy has emerged as a novel approach offering renewed hope for the development of treatments that meaningfully alter the course of the disease. In this review we explore various gene therapy strategies currently being developed targeting key aspects of PD pathogenesis: the restoration of the dopamine system by delivering genes involved in dopamine biosynthesis; reinforcing the inhibitory signalling pathways through glutamic acid decarboxylase (GAD) delivery to increase GABA production; enhancing neuronal survival and development by introducing various neurotrophic factors; delivery of genes to complement recessive familial PD mutations to correct mitochondrial dysfunction; restoring lysosomal function through delivery of GBA1 to increase glucocerebrosidase (GCase) activity; and reducing alpha-synuclein levels by reducing or silencing SNCA expression. Despite promising early work, challenges remain in developing safe, effective, and long-lasting gene therapies. Key considerations include optimizing viral vectors for targeted delivery, achieving controlled and sustained gene expression using different promoters, minimizing immune responses and increasing transgene delivery capacity. Future prospects may involve combinatory strategies targeting multiple pathways, such as multi-gene constructs delivered via high-capacity viral systems.
Addressing the speed-accuracy simulation trade-off for adaptive spiking neurons
The adaptive leaky integrate-and-fire (ALIF) model is fundamental within computational neuroscience and has been instrumental in studying our brains in silico. Due to the sequential nature of simulating these neural models, a commonly faced issue is the speed-accuracy trade-off: either accurately simulate a neuron using a small discretisation time-step (DT), which is slow, or more quickly simulate a neuron using a larger DT and incur a loss in simulation accuracy. Here we provide a solution to this dilemma, by algorithmically reinterpreting the ALIF model, reducing the sequential simulation complexity and permitting a more efficient parallelisation on GPUs. We computationally validate our implementation to obtain over a 50× training speedup using small DTs on synthetic benchmarks. We also obtained a comparable performance to the standard ALIF implementation on different supervised classification tasks - yet in a fraction of the training time. Lastly, we showcase how our model makes it possible to quickly and accurately fit real electrophysiological recordings of cortical neurons, where very fine sub-millisecond DTs are crucial for capturing exact spike timing.
Abstract Or122: Noncoding regulation of epicardial gene expression and epithelial-to-mesenchymal transition during heart development
During organogenesis, epicardial cells undergo epithelial-to-mesenchymal transition (EMT), contributing essential cell types and paracrine signalling to the growing heart. The epicardium is integral to heart regeneration in lower vertebrates and neonatal mammalian injured hearts. That said, prospects to harness the epicardium for therapeutic applications to effect adult heart repair, heavily depend on improved insight into its intrinsic properties in development. Cell fate decisions underpinning EMT are directed by transcription factors such as Wilms’ tumour 1 (WT1). Whilst a requirement for Wt1 in heart development is established, the mechanisms underpinning its activation remain elusive. We identified two e volutionary c onserved r egions (ECRs) shared in mouse and human, located within intron 1 of Wt1 locus. We hypothesised these regulatory sequences direct locus activation and EMT to support normal heart development. Here, we used CRISPR/Cas9 gene-editing technology to generate mice carrying a sequence deletion containing one ECR or a deletion comprising both ECRs. Extensive survival analysis, high-resolution episcopic microscopy (HREM), qPCR, immunostaining, confocal microscopy and epicardial explants were used to characterise heart formation. Mendelian ratios indicated an overall underrepresentation of Wt1 ΔECR/ΔECR mutants in adulthood. HREM revealed smaller hearts, incidence of myocardial non-compaction and spongy interventricular septum with muscular and membranous defects, tricuspid hypoplasia and enlarged aortic valves, as well as abnormal patterning of coronary artery stems in mutant hearts. Expression of Wt1 was markedly reduced in Wt1 ΔECR/ΔECR hearts but not kidneys, suggesting intronic enhancers are cardiac-specific. Whole-mount and tissue immunostaining revealed abnormal coronary vessel and innervation patterning in the subepicardium, as well as reduced EMT and myocardial non-compaction/hyper-trabeculation in Wt1 ΔECR/ΔECR . Collectively, we demonstrated a requirement for novel Wt1 intronic enhancers regulating locus activity and essential epicardial EMT-associated biological processes in normal heart development. Importantly, observation of septum and semilunar valve defects in Δ ECR hearts suggests an hitherto unrecognised role for WT1-driven EMT, opening new avenues of research to improve our understanding of congenital heart disease affecting at least 1:150 live births, with remarkably two thirds of cases having unknown aetiology.