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Midbrain dopamine neurons signal phasic and ramping reward prediction error during goal-directed navigation.
Goal-directed navigation requires learning to accurately estimate location and select optimal actions in each location. Midbrain dopamine neurons are involved in reward value learning and have been linked to reward location learning. They are therefore ideally placed to provide teaching signals for goal-directed navigation. By imaging dopamine neural activity as mice learned to actively navigate a closed-loop virtual reality corridor to obtain reward, we observe phasic and pre-reward ramping dopamine activity, which are modulated by learning stage and task engagement. A Q-learning model incorporating position inference recapitulates our results, displaying prediction errors resembling phasic and ramping dopamine neural activity. The model predicts that ramping is followed by improved task performance, which we confirm in our experimental data, indicating that the dopamine ramp may have a teaching effect. Our results suggest that midbrain dopamine neurons encode phasic and ramping reward prediction error signals to improve goal-directed navigation.
KATP channel mutation disrupts hippocampal network activity and nocturnal gamma shifts.
ATP-sensitive potassium (KATP) channels couple cell metabolism to cellular electrical activity. Humans affected by severe activating mutations in KATP channels suffer from developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). While the aetiology of diabetes in DEND syndrome is well understood, the pathophysiology of the neurological symptoms remains unclear. We hypothesised that impaired activity of parvalbumin-positive interneurons (PV-INs) may result in seizures and cognitive problems. We found, by performing electrophysiological experiments, that expressing the DEND mutation Kir6.2-V59M selectively in mouse PV-INs reduced intrinsic gamma frequency preference and short-term depression as well as disturbed cognition-associated gamma oscillations and hippocampal sharp waves. Furthermore, the risk of seizures was increased and the day-night shift in gamma activity disrupted. Blocking KATP channels with tolbutamide partially rescued the network oscillations. The non-reversible part may, to some extent, result from observed altered PV-IN dendritic branching and PV-IN arrangement within CA1. In summary, PV-INs play a key role in DEND syndrome, and this provides a framework for establishing treatment options.
Neurocardiology: translational advancements and potential.
In our original white paper published in the The Journal of Physiology in 2016, we set out our knowledge of the structural and functional organization of cardiac autonomic control, how it remodels during disease, and approaches to exploit such knowledge for autonomic regulation therapy. The aim of this update is to build on this original blueprint, highlighting the significant progress which has been made in the field since and major challenges and opportunities that exist with regard to translation. Imbalances in autonomic responses, while beneficial in the short term, ultimately contribute to the evolution of cardiac pathology. As our understanding emerges of where and how to target in terms of actuators (including the heart and intracardiac nervous system (ICNS), stellate ganglia, dorsal root ganglia (DRG), vagus nerve, brainstem, and even higher centres), there is also a need to develop sensor technology to respond to appropriate biomarkers (electrophysiological, mechanical, and molecular) such that closed-loop autonomic regulation therapies can evolve. The goal is to work with endogenous control systems, rather than in opposition to them, to improve outcomes.
Feto-placental and coronary endothelial genes implicated in miscarriage, congenital heart disease and stillbirth, a systematic review and meta-analysis.
The first trimester placenta is very rarely investigated for placental vascular formation in developmental or diseased contexts. Defects in placental formation can cause heart defects in the fetus, and vice versa. Determining the causality is therefore difficult as both organs develop concurrently and express many of the same genes. Here, we performed a systematic review to determine feto-placental and coronary endothelial genes implicated in miscarriages, stillbirth and congenital heart defects (CHD) from human genome wide screening studies. 4 single cell RNAseq datasets from human first/early second trimester cardiac and placental samples were queried to generate a list of 1187 endothelial genes. This broad list was cross-referenced with genes implicated in the pregnancy disorders above. 39 papers reported feto-placental and cardiac coronary endothelial genes, totalling 612 variants. Vascular gene variants were attributed to the incidence of miscarriage (8 %), CHD (4 %) and stillbirth (3 %). The most common genes for CHD (NOTCH, DST, FBN1, JAG1, CHD4), miscarriage (COL1A1, HERC1), and stillbirth (AKAP9, MYLK), were involved in blood vessel and cardiac valve formation, with roles in endothelial differentiation, angiogenesis, extracellular matrix signaling, growth factor binding and cell adhesion. NOTCH1, AKAP12, CHD4, LAMC1 and SOS1 showed greater relative risk ratios with CHD. Many of the vascular genes identified were expressed highly in both placental and heart EC populations. Both feto-placental and cardiac vascular genes are likely to result in poor endothelial cell development and function during human pregnancy that leads to higher risk of miscarriage, congenital heart disease and stillbirth.
Evaluation of Cerebrospinal Fluid α-Synuclein Seed Amplification Assay in Progressive Supranuclear Palsy and Corticobasal Syndrome.
BACKGROUND: Seed amplification assay (SAA) testing has been developed as a biomarker for the diagnosis of α-synuclein-related neurodegenerative disorders. OBJECTIVE: The objective of this study was to assess the rate of α-synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) and to analyze clinical and pathological features of SAA-positive and -negative cases. METHODS: A total of 96 cerebrospinal fluid samples from clinically diagnosed PSP (n = 59) and CBS (n = 37) cases were analyzed using α-synuclein SAA. RESULTS: Six of 59 (10.2%) PSP cases were α-synuclein SAA positive, including one case who was MSA-type positive. An exploratory analysis showed that PSP cases who were Parkinson's disease-type positive were older and had a shorter disease duration compared with SAA-negative cases. In contrast, 11 of 37 (29.7%) CBS cases were α-synuclein SAA positive, including two cases who were MSA-type positive. CONCLUSIONS: Our results suggest that α-synuclein seeds can be detected in PSP and CBS using a cerebrospinal fluid α-synuclein SAA, and in PSP this may impact on clinical course. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes.
Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion1. In healthy people, a fall in plasma glucose stimulates glucagon release and thereby increases counter-regulatory hepatic glucose production. This response is absent in many patients with type-1 diabetes (T1D)2, which predisposes to severe hypoglycaemia that may be fatal and accounts for up to 10% of the mortality in patients with T1D3. In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists4-7 but both the underlying cellular mechanism and whether it can be extended to humans remain unestablished. Here, we show that glucagon secretion is not stimulated by low glucose in isolated human islets from donors with T1D, a defect recapitulated in non-obese diabetic mice with T1D. This occurs because of hypersecretion of somatostatin, leading to aberrant paracrine inhibition of glucagon secretion. Normally, KATP channel-dependent hyperpolarization of β-cells at low glucose extends into the δ-cells through gap junctions, culminating in suppression of action potential firing and inhibition of somatostatin secretion. This 'electric brake' is lost following autoimmune destruction of the β-cells, resulting in impaired counter-regulation. This scenario accounts for the clinical observation that residual β-cell function correlates with reduced hypoglycaemia risk8.
Optogenetic Determination of Dynamic and Cell-Type-Specific Inhibitory Reversal Potentials.
The reversal potential refers to the membrane potential at which the net current flow through a channel reverses direction. The reversal potential is determined by transmembrane ion gradients and, in turn, determines how the channel's activity will affect the membrane potential. Traditional investigation into the reversal potential of inhibitory ligand-gated ion channels (EInh) has relied upon the activation of endogenous receptors, such as the GABA-A receptor (GABAAR). There are, however, challenges associated with activating endogenous receptors, including agonist delivery, isolating channel responses, and the effects of receptor saturation and desensitization. Here, we demonstrate the utility of using a light-gated anion channel, stGtACR2, to probe EInh in the rodent brain. Using mice of both sexes, we demonstrate that the properties of this optically activated channel make it a suitable proxy for studying GABAAR receptor-mediated inhibition. We validate this agonist-independent optogenetic strategy in vitro and in vivo and further show how it can accurately capture differences in EInh dynamics following manipulations of endogenous ion fluxes. This allows us to explore distinct resting EInh differences across genetically defined neuronal subpopulations. Using this approach to challenge ion homeostasis mechanisms in neurons, we uncover cell-specific EInh dynamics that are supported by the differential expression of endogenous ion handling mechanisms. Our findings therefore establish an effective optical strategy for revealing novel aspects of inhibitory reversal potentials and thereby expand the repertoire of optogenetics.
A Facile Method to Quantify Synthetic Peptide Concentrations on Biomaterials.
While it is well understood that peptides can greatly improve cell-material interactions, it is often challenging to determine the concentration of the peptide which decorates a material. Herein, we describe a straightforward method using readily, synthetically accessible Fmoc peptides and commercially available reagents to measure the concentration of peptides on nanoparticles, surfaces, and hydrogels. To achieve this, the Fmoc protecting group from immobilized peptides is removed under optimized basic conditions. The dibenzofulvene released can be quantified by HPLC or UV-vis spectroscopy, enabling a direct experimental measurement of the concentration of the peptide. We show that we can measure the concentration of a BMP-2 peptide mimic on a hydrogel to determine the concentration required to stimulate osteogenesis of human mesenchymal stem cells. We envision that this methodology will enable a more thorough understanding of the concentration of synthetic peptides decorated on many biomaterials (e.g., nanoparticles, surfaces, hydrogels) to improve deconvolution of the interactions at the cell-material interface.