Recordings Of Neurons Research Articles

Error Function Optimization to Compare Neural Activity and Train Blended Rhythmic Networks.

We present a novel set of quantitative measures for "likeness" (error function) designed to alleviate the time-consuming and subjective nature of manually comparing biological recordings from electrophysiological experiments with the outcomes of their mathematical models. Our innovative "blended" system approach offers an objective, high-throughput, and computationally efficient method for comparing biological and mathematical models. This approach involves using voltage recordings of biological neurons to drive and train mathematical models, facilitating the derivation of the error function for further parameter optimization. Our calibration process incorporates measurements such as action potential (AP) frequency, voltage moving average, voltage envelopes, and the probability of post-synaptic channels. To assess the effectiveness of our method, we utilized the sea slug Melibe leonina swim central pattern generator (CPG) as our model circuit and conducted electrophysiological experiments with TTX to isolate CPG interneurons. During the comparison of biological recordings and mathematically simulated neurons, we performed a grid search of inhibitory and excitatory synapse conductance. Our findings indicate that a weighted sum of simple functions is essential for comprehensively capturing a neuron's rhythmic activity. Overall, our study suggests that our blended system approach holds promise for enabling objective and high-throughput comparisons between biological and mathematical models, offering significant potential for advancing research in neural circuitry and related fields.

Examining The Effects Of Gallein On Opioid Induced GIRK Currents

Opioids are powerful analgesics, but carry a risk of overdose that has become a pressing issue to public health in the United States. Overdose deaths are caused by the opioid-induced shutdown of neuronal circuits that operate unconscious breathing cycles, leading to respiratory depression. Respiratory depression, alongside antinociception, is mediated by the activation of μ-opioid receptors, which are coupled to inhibitory heterotrimeric G proteins. Recent studies have shown that gallein, a Gβγ subunit inhibitor, amplifies the antinociceptive effects of opioids through Gq-phospholipase C (PLC) mediated mechanisms, while either attenuating or having no effect on respiratory depression. The molecular mechanisms of gallein effects on respiratory depression are unclear. Based on the binding interface, gallein is predicted to inhibit Gβγ binding to phospholipase C, but not G protein inwardly rectifying potassium channels (GIRK). The goal of this study is to examine the effects of gallein on opioid-induced GIRK currents, with or without Gq subunit activation, in mouse locus coeruleus (LC) neurons. The LC is an area of particular interest due its involvement in respiratory circuits, and activation of Gq-coupled pathways decreases the amplitude of opioid-mediated GIRK currents in LC neurons. We hypothesized that gallein would have no effect on opioid mediated GIRK currents without Gq activation, but would prevent Gq-mediated inhibition of GIRK. We tested this hypothesis using whole-cell voltage-clamp recordings of LC neurons contained in brain slices from adult male and female mice. The endogenous opioid agonist Met-enkephalin induced outward GIRK currents that were not significantly altered by gallein. The Gq-coupled receptor agonist oxotremorine-M reduced the amplitude of Met-enkephalin mediated GIRK currents, as expected. Preliminary data suggests no effect of gallein on GIRK currents in the presence of Gq activation, contrary to our hypothesis. These results will increase our understanding of the role of PLC in Gq-mediated inhibition of GIRK currents at the cellular level and provide insight regarding the potential respiratory related impacts associated with using gallein derived compounds in combination with opioids to increase opioid antinociception and reduce the doses of opioids needed to treat pain. This research is supported by NIH Grant R01DA047978-05 to ESL. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Electroacupuncture Rebalances Autonomic Nervous Activities Decreasing Blood Pressure in Salt-Sensitive Hypertensive Rats

High blood pressure (BP) associated with sympathetic overactivity is observed in hypertensive animals and patients. We have recently reported that electroacupuncture (EA) at two sets of acupoints ST36-37 and SP6-7 attenuates BP in Dahl salt-sensitive hypertensive (DSSH) rats through a positive interaction between sympathetic nerve activity inhibition (sympathoinhibition, SI-EA) and anti-inflammation (AI-EA). Chronic inflammation is not only influenced by sympathetic (SNA) but also by parasympathetic nerve activity (PNA). However, it remains unclear if combined SI-EA + AI-EA (cEA) rebalances autonomic nerve activity by both inhibiting SNA and exciting PNA that alleviate hypertension (HTN). We hypothesized that cEA decreased SNA and increased PNA in DSSH rats. Dahl salt-sensitive (DSS) rats were fed 4% salt diet and randomly allocated into two groups: cEA or Sham-EA (no electrical stimulation). Another group of DSS rats studied as normotensive (NTNive) controls were fed a standard rat chow throughout the experiment. Systolic/diastolic BP (SBP/DBP) were measured with Tail-cuff via CODA system once a week. Once DSSH rats developed moderate HTN (SBP 160±5 mmHg), cEA or Sham-EA was applied twice weekly for five weeks, while the NTNive control groups received five weeks of similar study procedures (restraining) without the intervention. After five weeks of treatments, rats were anesthetized for the neuronal recording of SNA and PNA. Cervical vagal nerve (CVN) or splanchnic sympathetic nerve (SSN) was isolated from surrounding connective tissue under a dissecting microscope. Multiple-unit nerve activities were recorded and analyzed with Spike2 software. We observed that SBP (189.2±3.5 mmHg) and DBP (138.6±2.2 mmHg) in Sham-EA treated DSSH rats were higher than SBP (140.8±1.8 mmHg) by 25.6% and DBP (105.5±1.4 mmHg) by 23.9% in rats treated with repetitive cEA. Throughout the study, SBP (132.7±1.8 to 135.2±2.1 mmHg) and DBP (74.1±1.7 to 82.9±2.6 mmHg) in NTNive rats remained within normal range. Furthermore, activity of SSN was significantly greater in Sham-EA treated DSSH rats (23.1±1.6 imp/s) compared to cEA treated rats (15.2±2.0 imp/s, P=0.043) and NTNive rats (11.5 ±0.8 imp/s, P=0.004). Activity of CVN was higher in DSSH rats treated with cEA (27.8±2.9 imp/s) than Sham-EA (12.5±2.3 imp/s, P=0.016). Relative to Sham-EA, activity of CVN was higher (42.5±2.9 imp/s, P=0.001) in normal rats. In conclusion, cEA treatment effectively alleviates hypertension by restoring the balance of autonomic nervous functions through sympathoinhibition and parasympathoexcitation. Funding: NIH 1RO1AT011306-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease and 5XFAD mice.

Approximately 22% of Alzheimer's disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbates AD pathology and related cognitive deficits, suggesting that seizures may be a targetable component of AD progression. Given that alterations in neuronal excitatory:inhibitory (E:I) balance occur in epilepsy, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients. We similarly hypothesized that in 5XFAD mice, the E:I imbalance would progress from an early stage (prodromal) to later symptomatic stages and be further exacerbated by pentylenetetrazol (PTZ) kindling. Post-mortem AD temporal cortical tissues from patients with or without seizure history were examined for changes in several markers of E:I balance, including levels of the inhibitory GABAA receptor, the sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2) and the excitatory NMDA and AMPA type glutamate receptors. We performed patch-clamp electrophysiological recordings from CA1 neurons in hippocampal slices and examined the same markers of E:I balance in prodromal 5XFAD mice. We next examined 5XFAD mice at chronic stages, after PTZ or control protocols, and in response to chronic mTORC1 inhibitor rapamycin, administered following kindled seizures, for markers of E:I balance. We found that AD patients with comorbid seizures had worsened cognitive and functional scores and decreased GABAA receptor subunit expression, as well as increased NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. Patch clamp recordings of prodromal 5XFAD CA1 neurons showed increased intrinsic excitability, along with decreased GABAergic inhibitory transmission and altered glutamatergic neurotransmission, indicating that E:I imbalance may occur in early disease stages. Furthermore, seizure induction in prodromal 5XFAD mice led to later dysregulation of NKCC1/KCC2 and a reduction in GluA2 AMPA glutamate receptor subunit expression, indicative of depolarizing GABA receptors and calcium permeable AMPA receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced amyloid-β pathology and cognitive deficits, could also reverse elevations of the NKCC1/KCC2 ratio in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that targeting E:I balance, potentially with US Food and Drug Administration-approved mTOR inhibitors, hold therapeutic promise for AD patients with a seizure history.

Injectable Fluorescent Neural Interfaces for Cell-Specific Stimulating and Imaging.

Building on current explorations in chronic optical neural interfaces, it is essential to address the risk of photothermal damage in traditional optogenetics. By focusing on calcium fluorescence for imaging rather than stimulation, injectable fluorescent neural interfaces significantly minimize photothermal damage and improve the accuracy of neuronal imaging. Key advancements including the use of injectable microelectronics for targeted electrical stimulation and their integration with cell-specific genetically encoded calcium indicators have been discussed. These injectable electronics that allow for post-treatment retrieval offer a minimally invasive solution, enhancing both usability and reliability. Furthermore, the integration of genetically encoded fluorescent calcium indicators with injectable bioelectronics enables precise neuronal recording and imaging of individual neurons. This shift not only minimizes risks such as photothermal conversion but also boosts safety, specificity, and effectiveness of neural imaging. Embracing these advancements represents a significant leap forward in biomedical engineering and neuroscience, paving the way for advanced brain-machine interfaces.

Actions of remimazolam on inhibitory transmission of rat spinal dorsal horn neurons

Remimazolam is an ultra-short benzodiazepine that acts on the benzodiazepine site of γ-aminobutyric acid (GABA) receptors in the brain and induces sedation. Although GABA receptors are found localized in the spinal dorsal horn, no previous studies have reported the analgesic effects or investigated the cellular mechanisms of remimazolam on the spinal dorsal horn. Behavioral measures, immunohistochemistry, and in vitro whole-cell patch-clamp recordings of dorsal horn neurons were used to assess synaptic transmission. Intrathecal injection of remimazolam induced behavioral analgesia in inflammatory pain-induced mechanical allodynia (six rats/dose; p < 0.05). Immunohistochemical staining revealed that remimazolam suppressed spinal phosphorylated extracellular signal-regulated kinase activation (five rats/group, p < 0.05). In vitro whole-cell patch-clamp analysis demonstrated that remimazolam increased the frequency of GABAergic miniature inhibitory post-synaptic currents, prolonged the decay time (six rats; p < 0.05), and enhanced GABA currents induced by exogenous GABA (seven rats; p < 0.01). However, remimazolam did not affect miniature excitatory post-synaptic currents or amplitude of monosynaptic excitatory post-synaptic currents evoked by Aδ- and C-fiber stimulation (seven rats; p > 0.05). This study suggests that remimazolam induces analgesia by enhancing GABAergic inhibitory transmission in the spinal dorsal horn, suggesting its potential utility as a spinal analgesic for inflammatory pain.

From Finite Element Simulations to Equivalent Circuit Models of Extracellular Neuronal Recording Systems Based on Planar and Mushroom Electrodes.

define a new methodology to build multi-compartment lumped-elements equivalent circuit models for neuron/electrode systems. the equivalent circuit topology is derived by careful scrutiny of accurate and validated multiphysics finite-elements method (FEM) simulations that couple ion transport in the intra- and extracellular fluids, activation of the neuron membrane ion channels, and signal acquisition by the electronic readout. robust and accurate circuit models are systematically derived, suited to represent the dynamics of the sensed extracellular signals over a wide range of geometrical/physical parameters (neuron and electrode sizes, electrolytic cleft thicknesses, readout input impedance, non-uniform ion channel distributions). FEM simulations point out phenomena that escape an accurate description by equivalent circuits; notably: steric effects in the thin electrolytic cleft and the impact of extracellular ion transport on the reversal potentials of the Hodgkin-Huxley neuron model. our multi-compartment equivalent circuits match accurately the FEM simulations. They unveil the existence of an optimum number of compartments for accurate circuit simulation. FEM simulations suggest that while steric effects are in most instances negligible, the extracellular ion transport affects the reversal potentials and consequently the recorded signal if the electrolytic cleft becomes thinner than approximately 100 nm. the proposed methodology and circuit models improve upon the existing area and point contact models. The coupling between the extracellular concentrations and reversal potential highlighted by FEM simulations emerges as a challenge for future developments in lumped-element modeling of the neuron/sensor interface.

Linking fast and slow: The case for generative models.

A pervasive challenge in neuroscience is testing whether neuronal connectivity changes over time due to specific causes, such as stimuli, events, or clinical interventions. Recent hardware innovations and falling data storage costs enable longer, more naturalistic neuronal recordings. The implicit opportunity for understanding the self-organised brain calls for new analysis methods that link temporal scales: from the order of milliseconds over which neuronal dynamics evolve, to the order of minutes, days, or even years over which experimental observations unfold. This review article demonstrates how hierarchical generative models and Bayesian inference help to characterise neuronal activity across different time scales. Crucially, these methods go beyond describing statistical associations among observations and enable inference about underlying mechanisms. We offer an overview of fundamental concepts in state-space modeling and suggest a taxonomy for these methods. Additionally, we introduce key mathematical principles that underscore a separation of temporal scales, such as the slaving principle, and review Bayesian methods that are being used to test hypotheses about the brain with multiscale data. We hope that this review will serve as a useful primer for experimental and computational neuroscientists on the state of the art and current directions of travel in the complex systems modelling literature.

Engineering luminopsins with improved coupling efficiencies.

Luminopsins (LMOs) are bioluminescent-optogenetic tools with a luciferase fused to an opsin that allow bimodal control of neurons by providing both optogenetic and chemogenetic access. Determining which design features contribute to the efficacy of LMOs will be beneficial for further improving LMOs for use in research. We investigated the relative impact of luciferase brightness, opsin sensitivity, pairing of emission and absorption wavelength, and arrangement of moieties on the function of LMOs. We quantified efficacy of LMOs through whole cell patch clamp recordings in HEK293 cells by determining coupling efficiency, the percentage of maximum LED induced photocurrent achieved with bioluminescent activation of an opsin. We confirmed key results by multielectrode array recordings in primary neurons. Luciferase brightness and opsin sensitivity had the most impact on the efficacy of LMOs, and N-terminal fusions of luciferases to opsins performed better than C-terminal and multi-terminal fusions. Precise paring of luciferase emission and opsin absorption spectra appeared to be less critical. Whole cell patch clamp recordings allowed us to quantify the impact of different characteristics of LMOs on their function. Our results suggest that coupling brighter bioluminescent sources to more sensitive opsins will improve LMO function. As bioluminescent activation of opsins is most likely based on Förster resonance energy transfer, the most effective strategy for improving LMOs further will be molecular evolution of luciferase-fluorescent protein-opsin fusions.

Nav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia.

Vincristine-induced peripheral neuropathy is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine-induced pain. Our previous studies have shown that the tetrodotoxin-sensitive voltage-gated sodium channel Nav1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of vincristine-induced allodynia. In this study, we investigated the effects of vincristine administration on excitability in small-diameter DRG neurons and whether the tetrodotoxin-resistant (TTX-R) Nav1.8 channels contribute to mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons, we now show an increase in TTX-R current density and a -7.3 mV hyperpolarizing shift in the half-maximal potential (V1/2) of activation of Nav1.8 channels in vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably, vincristine treatment did not enhance excitability of small DRG neurons from Nav1.8 knockout mice, and the development of mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that sodium channel Nav1.8 in small DRG neurons contributes to the development of vincristine-induced mechanical allodynia.

Changes in intrinsic excitability of hippocampal pyramidal cells in Parkinsons disease model

Parkinsons disease (PD) is the second most common fatal neurodegenerative disease in the world, and it reduces patients quality of life by causing movement disorders (e.g., tremors, muscle stiffness, and impaired balance) and non-motor disorders (e.g., depression, anxiety, and dementia). Previous research has mostly concentrated on dopamine-producing neurons in the substantia nigra compacta (SNc) that are dying off, which restricts therapeutic options and renders the search for disease-modifying therapies fruitless. In order to make a breakthrough, pathological changes in other brain areas deserve more attention. Previous PD studies reported atrophy in the hippocampus, an indispensable part of spatial and temporal memory formation. To answer the question of the cellular mechanism of hippocampus atrophy, this paper intends to research previously uncharted hippocampal intrinsic plasticity alterations. After analysing intercellular recordings of pyramidal neurons gathered from normal mice and genetically engineered PD mice, this paper demonstrates disparities in the intrinsic factors not noted in the previous research, such as peaks and afterhyperpolarization. These findings represent a progressive advancement in our comprehension of hippocampal pyramidal neurons, indicating potential therapeutic targets for Parkinsons disease treatment via SK channels, BK channels, and sodium channels.

Cocaine diminishes functional network robustness and destabilizes the energy landscape of neuronal activity in the medial prefrontal cortex.

We present analysis of neuronal activity recordings from a subset of neurons in the medial prefrontal cortex of rats before and after the administration of cocaine. Using an underlying modern Hopfield model as a description for the neuronal network, combined with a machine learning approach, we compute the underlying functional connectivity of the neuronal network. We find that the functional connectivity changes after the administration of cocaine with both functional-excitatory and functional-inhibitory neurons being affected. Using conventional network analysis, we find that the diameter of the graph, or the shortest length between the two most distant nodes, increases with cocaine, suggesting that the neuronal network is less robust. We also find that the betweenness centrality scores for several of the functional-excitatory and functional-inhibitory neurons decrease significantly, while other scores remain essentially unchanged, to also suggest that the neuronal network is less robust. Finally, we study the distribution of neuronal activity and relate it to energy to find that cocaine drives the neuronal network towards destabilization in the energy landscape of neuronal activation. While this destabilization is presumably temporary given one administration of cocaine, perhaps this initial destabilization indicates a transition towards a new stable state with repeated cocaine administration. However, such analyses are useful more generally to understand how neuronal networks respond to perturbations.

Encoding of Predictive Associations in Human Prefrontal and Medial Temporal Neurons During Pavlovian Appetitive Conditioning.

Pavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here, we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus, and amygdala while patients of both sexes performed an appetitive Pavlovian conditioning task probing both stimulus-value and stimulus-stimulus associations. Ventromedial prefrontal cortex encoded predictive value along with the amygdala, and also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial frontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning.

Toluene alters the intrinsic excitability and excitatory synaptic transmission of basolateral amygdala neurons.

Inhalant abuse is an important health issue especially among children and adolescents who often encounter these agents in the home. Research into the neurobiological targets of inhalants has lagged behind that of other drugs such as alcohol and psychostimulants. However, studies from our lab and others have begun to reveal how inhalants such as the organic solvent toluene affect neurons in key addiction related areas of the brain including the ventral tegmental area, nucleus accumbens and medial prefrontal cortex. In the present study, we extend these findings and examine the effect of toluene on electrophysiological responses of pyramidal neurons in the basolateral amygdala BLA, a region important for generating emotional and reward based information needed to guide future behavior. Whole-cell patch-clamp electrophysiology recordings of BLA pyramidal neurons in rat brain slices were used to assess toluene effects on intrinsic excitability and excitatory glutamatergic synaptic transmission. Acute application of 3 mM but not 0.3 mM toluene produced a small but significant (~20%) increase in current-evoked action potential (AP) firing that reversed following washout of the toluene containing solution. The change in firing during exposure to 3 mM toluene was accompanied by selective changes in AP parameters including reduced latency to first spike, increased AP rise time and decay and a reduction in the fast after-hyperpolization. To examine whether toluene also affects excitatory synaptic signaling, we expressed channelrhodopsin-2 in medial prefrontal cortex neurons and elicited synaptic currents in BLA neurons via light pulses. Toluene (3 mM) reduced light-evoked AMPA-mediated synaptic currents while a lower concentration (0.3 mM) had no effect. The toluene-induced reduction in AMPA-mediated BLA synaptic currents was prevented by the cannabinoid receptor-1 antagonist AM281. These findings are the first to demonstrate effects of acute toluene on BLA pyramidal neurons and add to existing findings showing that abused inhalants such as toluene have significant effects on neurons in brain regions involved in natural and drug induced reward.

Voltage tunes mGlu5 receptor function, impacting synaptic transmission.

Voltage sensitivity is a common feature of many membrane proteins, including some G-protein coupled receptors (GPCRs). However, the functional consequences of voltage sensitivity in GPCRs are not well understood. In this study, we investigated the voltage sensitivity of the post-synaptic metabotropic glutamate receptor mGlu5 and its impact on synaptic transmission. Using biosensors and electrophysiological recordings in non-excitable HEK293T cells or neurons. We found that mGlu5 receptor function is optimal at resting membrane potentials. We observed that membrane depolarization significantly reduced mGlu5 receptor activation, Gq-PLC/PKC stimulation, Ca2+ release and mGlu5 receptor-gated currents through transient receptor potential canonical, TRPC6, channels or glutamate ionotropic NMDA receptors. Notably, we report a previously unknown activity of the NMDA receptor at the resting potential of neurons, enabled by mGlu5. Our findings suggest that mGlu5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions.

Membrane-coated glass electrodes for stable, low-noise electrophysiology recordings in Drosophila central neurons

BackgroundElectrophysiological recording with glass electrodes is one of the best techniques to measure membrane potential dynamics and ionic currents of voltage-gated channels in neurons. However, artifactual variability of the biophysical state variables that determine recording quality can be caused by insufficient affinity between the electrode and cell membrane during the recording. New methodWe introduce a phospholipid membrane coating on glass electrodes to improve intracellular electrophysiology recording quality. Membrane-coated electrodes were prepared with a tip-dip protocol for perforated-patch, sharp-electrode current-clamp, and cell-attached patch-clamp recordings from specific circadian clock neurons in Drosophila. We perform quantitative comparisons based on the variability of functional biophysical parameters used in various electrophysiological methods, and advanced statistical comparisons based on the degree of stationariness and signal-to-noise ratio. ResultsResults indicate a dramatic reduction in artifactual variabilities of functional parameters from enhanced stability. We also identify significant exclusions of a statistically estimated noise component in a time series of membrane voltage signals, improving signal-to-noise ratio. Comparison with existing methodsCompared to standard glass electrodes, using membrane-coated glass electrodes achieves improved recording quality in intracellular electrophysiology. ConclusionsElectrophysiological recordings from Drosophila central neurons can be technically challenging, however, membrane-coated electrodes will possibly be beneficial for reliable data acquisition and improving the technical feasibility of axonal intracellular activities measurements and single-channel recordings. The improved electrical stability of the recordings should also contribute to increased mechanical stability, thus facilitating long-term stable measurements of neural activity. Therefore, it is possible that membrane-coated electrodes will be useful for any model system.

A distinct cortical code for socially learned threat.

Animals can learn about sources of danger while minimizing their own risk by observing how others respond to threats. However, the distinct neural mechanisms by which threats are learned through social observation (known as observational fear learning1-4 (OFL)) to generate behavioural responses specific to such threats remain poorly understood. The dorsomedial prefrontal cortex (dmPFC) performs several key functions that may underlie OFL, including processing of social information and disambiguation of threat cues5-11. Here we show that dmPFC is recruited and required for OFL in mice. Using cellular-resolution microendoscopic calcium imaging, we demonstrate that dmPFC neurons code for observational fear and do so in a manner that is distinct from direct experience. We find that dmPFC neuronal activity predicts upcoming switches between freezing and moving state elicited by threat. By combining neuronal circuit mapping, calcium imaging, electrophysiological recordings and optogenetics, we show that dmPFC projections to the midbrain periaqueductal grey (PAG)constrain observer freezing, and that amygdalar and hippocampal inputs to dmPFC opposingly modulate observer freezing. Together our findings reveal that dmPFC neurons compute a distinct code for observational fear and coordinate long-range neural circuits to select behavioural responses.

Dynamic Gain Decomposition Reveals Functional Effects of Dendrites, Ion Channels, and Input Statistics in Population Coding.

Modern, high-density neuronal recordings reveal at ever higher precision how information is represented by neural populations. Still, we lack the tools to understand these processes bottom-up, emerging from the biophysical properties of neurons, synapses, and network structure. The concept of the dynamic gain function, a spectrally resolved approximation of a population's coding capability, has the potential to link cell-level properties to network-level performance. However, the concept is not only useful but also very complex because the dynamic gain's shape is co-determined by axonal and somato-dendritic parameters and the population's operating regime. Previously, this complexity precluded an understanding of any individual parameter's impact. Here, we decomposed the dynamic gain function into three components corresponding to separate signal transformations. This allowed attribution of network-level encoding features to specific cell-level parameters. Applying the method to data from real neurons and biophysically plausible models, we found: (1) The encoding bandwidth of real neurons, approximately 400 Hz, is constrained by the voltage dependence of axonal currents during early action potential initiation. (2) State-of-the-art models only achieve encoding bandwidths around 100 Hz and are limited mainly by subthreshold processes instead. (3) Large dendrites and low-threshold potassium currents modulate the bandwidth by shaping the subthreshold stimulus-to-voltage transformation. Our decomposition provides physiological interpretations when the dynamic gain curve changes, for instance during spectrinopathies and neurodegeneration. By pinpointing shortcomings of current models, it also guides inference of neuron models best suited for large-scale network simulations.

Cognitive impairment in Alzheimer's disease FAD4T mouse model: Synaptic loss facilitated by activated microglia via C1qA

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by cognitive dysfunction. The connection between neuroinflammation and abnormal synaptic function in AD is recognized, but the underlying mechanisms remain unclear. In this study, we utilized a mouse model of AD, FAD4T mice aged 6–7 months, to investigate the molecular changes affecting cognitive impairment. Behavior tests showed that FAD4T mice exhibited impaired spatial memory compared with their wild-type littermates. Immunofluorescence staining revealed the presence of Aβ plaques and abnormal glial cell activation as well as changes in microglial morphology in the cortex and hippocampus of FAD4T mice. Synaptic function was impaired in FAD4T mice. Patch clamp recordings of hippocampal neurons revealed reduced amplitude of miniature excitatory postsynaptic currents. Additionally, Golgi staining showed decreased dendritic spine density in the cortex and hippocampus of FAD4T mice, indicating aberrant synapse morphology. Moreover, hippocampal PSD-95 and NMDAR1 protein levels decreased in FAD4T mice. RNA-seq analysis revealed elevated expression of immune system and proinflammatory genes, including increased C1qA protein and mRNA levels, as well as higher expression of TNF-α and IL-18. Taken together, our findings suggest that excessive microglia activation mediated by complement factor C1qA may contribute to aberrant synaptic pruning, resulting in synapse loss and disrupted synaptic transmission, ultimately leading to AD pathogenesis and behavioral impairments in the FAD4T mouse model. Our study provides valuable insights into the underlying mechanisms of cognitive impairments and preliminarily explores a potentially effective treatment approach targeting on C1qA for AD.

Highly Customizable 3D Microelectrode Arrays for In Vitro and In Vivo Neuronal Tissue Recordings.

Planar microelectrode arrays (MEAs) for - in vitro or in vivo - neuronal signal recordings lack the spatial resolution and sufficient signal-to-noise ratio (SNR) required for a detailed understanding of neural network function and synaptic plasticity. To overcome these limitations, a highly customizable three-dimensional (3D) printing process is used in combination with thin film technology and a self-aligned template-assisted electrochemical deposition process to fabricate 3D-printed-based MEAs on stiff or flexible substrates. Devices with design flexibility and physical robustness are shown for recording neural activity in different in vitro and in vivo applications, achieving high-aspect ratio 3D microelectrodes of up to 33:1. Here, MEAs successfully record neural activity in 3D neuronal cultures, retinal explants, and the cortex of living mice, thereby demonstrating the versatility of the 3D MEA while maintaining high-quality neural recordings. Customizable 3D MEAs provide unique opportunities to study neural activity under regular or various pathological conditions, both in vitro and in vivo, and contribute to the development of drug screening and neuromodulation systems that can accurately monitor the activity of large neural networks over time.