Synaptic Currents Research Articles

Complex nonlinear dynamics of bursting of thalamic neurons related to Parkinson's disease

<abstract><p>Parkinson's disease is associated with bursting of the thalamic (TC) neuron, which receives the inhibitory synaptic current of the basal ganglia composed of multiple nuclei; deep brain stimulation (DBS) applied to the basal ganglia can eliminate the bursting to recover to the normal state. In this paper, the complex nonlinear dynamics for the appearance and disappearance of the bursting are obtained in a widely used theoretical model of a neuronal network. First, through a bifurcation analysis, isolated TC neurons exhibit paradoxical bursting induced from the resting state by enhanced inhibitory effect, which is different from the common view that the enhanced inhibitory effect should suppress the electrical behaviors. Second, the mechanism for the appearance of bursting is obtained by analyzing the electrical activities of the basal ganglia. The inhibitory synaptic current from the external segment of the globus pallidus (GPe) induces a reduced firing rate of the subthalamic nucleus (STN); then, an excitatory synaptic current from the STN induces the bursting behaviors of the GPe. The excitatory current of STN neurons and the inhibitory current of the GPe cause bursting behaviors of the internal segment of the globus pallidus (GPi), thus resulting in an enhanced inhibition from the GPi to the TC, which can induce the paradoxical bursting similar to the isolated TC neurons. Third, the cause for the disappearance of paradoxical bursting is acquired.The high frequency pulses of DBS induces enhanced firing activity of the STN and GPe neurons and enhanced inhibitory synaptic current from the GPe to the GPi, resulting in a reduced inhibitory effect from the GPi to the TC, which can eliminate the paradoxical bursting. Finally, the fast-slow dynamics of the paradoxical bursting of isolated TC neurons are acquired, which is related to the saddle-node and saddle-homoclinic orbit bifurcations of the fast subsystem of the TC neuron model. The results provide theoretical support for understanding the mechanism of Parkinson's disease and treatment methods such as DBS.</p></abstract>

Unraveling Dravet Syndrome: Exploring the complex effects of sodium channel mutations on neuronal networks.

Dravet Syndrome (DS) is a severe developmental epileptic encephalopathy with frequent intractable seizures accompanied by cognitive impairment, often caused by pathogenic variants in SCN1A encoding sodium channel NaV1.1. Recent research utilizing in vitro patient-derived neuronal networks and accompanying in silico models uncovered that not just sodium-but also potassium-and synaptic currents were impaired in DS networks. Here, we explore the implications of these findings for three questions that remain elusive in DS: How do sodium channel impairments result in epilepsy? How can identical variants lead to varying phenotypes? What mechanisms underlie the developmental delay in DS patients? We speculate that impaired potassium currents might be a secondary effect to NaV1.1 mutations and could result in hyperexcitable neurons and epileptic networks. Moreover, we reason that homeostatic plasticity is actively engaged in DS networks, possibly affecting the phenotype and impairing learning and development when driven to extremes.

Nerve Growth Factor/Tyrosine Kinase A Receptor Pathway Enhances Analgesia in an Experimental Mouse Model of Bone Cancer Pain by Increasing Membrane Levels of δ-Opioid Receptors.

The role of nerve growth factor (NGF)/tyrosine kinase A receptor (TrKA) signaling, which is activated in a variety of pain states, in regulating membrane-associated δ-opioid receptor (mDOR) expression is poorly understood. The hypothesis was that elevated NGF in bone cancer tumors could upregulate mDOR expression in spinal cord neurons and that mDOR agonism might alleviate bone cancer pain. Bone cancer pain (BCP) was induced by inoculating Lewis lung carcinoma cells into the femoral marrow cavity of adult C57BL/6J mice of both sexes. Nociceptive behaviors were evaluated by the von Frey and Hargreaves tests. Protein expression in the spinal dorsal horn of animals was measured by biochemical analyses, and excitatory synaptic transmission was recorded in miniature excitatory synaptic currents. The authors found that mDOR expression was increased in BCP mice (BCP vs. sham, mean ± SD: 0.18 ± 0.01 g vs. mean ± SD: 0.13 ± 0.01 g, n = 4, P < 0.001) and that administration of the DOR agonist deltorphin 2 (Del2) increased nociceptive thresholds (Del2 vs. vehicle, median [25th, 75th percentiles]: 1.00 [0.60, 1.40] g vs. median [25th, 75th percentiles]: 0.40 [0.16, 0.45] g, n = 10, P = 0.001) and reduced miniature excitatory synaptic current frequency in lamina II outer neurons (Del2 vs. baseline, mean ± SD: 2.21 ± 0.81 Hz vs. mean ± SD: 2.43 ± 0.90 Hz, n = 12, P < 0.001). Additionally, NGF expression was increased in BCP mice (BCP vs. sham, mean ± SD: 0.36 ± 0.03 vs. mean ± SD: 0.16 ± 0.02, n = 4, P < 0.001), and elevated NGF was associated with enhanced mDOR expression via TrKA signaling. Activation of mDOR produces analgesia that is dependent on the upregulation of the NGF/TrKA pathway by increasing mDOR levels under conditions of BCP in mice.

Effects of optogenetic astroglia activation in modulation of synaptic transmission and rhythmogenesis of the hippocampus

In the field of neuronal signal transduction research, astroglia have become increasingly important. Astrocytes, or astroglial cells, are recognized as the third element in synaptic transmission regulation. This complex is conventionally known as a tripartite synapse. A multitude of mathematical models are being developed to investigate the function of astroglia in the tripartite synapse. Neurobiological experiments were carried out to confirm the dynamics observed in the previously proposed mean field activity mathematical model [1]. The experiments focused on evaluating the effect of optogenetic activation of astrocytes on synaptic transmission in C57BL/6 inbred mouse hippocampal slices. One month prior to the experiments, the AAV GFAP ChR2 eYFP virus was injected into the lateral ventricles of the brains of the experimental mice. This procedure was crucial for the expression of astrocyte-specific photosensitive channels, also known as channel rhodopsin. The patch-clamp method was used to conduct experiments on both the experimental mice and a control group of mice that did not receive virus injections. Spontaneous neuronal activity (local field potentials) and synaptic currents (GABA currents) were simultaneously recorded in the experiments. After activating astrocytes that expressed the photosensitive channel, an increase in GABAergic currents became evident during the transmission of synaptic signals between neurons. This suggests that astrocytes likely modulate synaptic transmission by releasing a gliotransmitter into the synaptic cleft. Thus, the study confirmed the presence of mean field activity patterns in a phenomenological model that describes the dynamics of a population of neurons. This model was developed based on the Tsodyks–Markram model and considers the primary attributes of neuron-glial interaction through a tripartite synapse. The model includes the short-term synaptic plasticity of the Tsodyks–Markram model and the astrocyte potential of synaptic transmission. The activation of astrocytes results in a diverse range of dynamic modes that describe various patterns of network activity under the mean field approach framework. Currently, multiple experimental hypotheses exist regarding astrocytes’ release of a gliotransfer into the synaptic cleft and its specific type. Alternatively, a complex cascade of sequential activation of glutamateergic and GABAergic receptors may occur. Additional experimental work is necessary to assess the pharmacological contribution of channels and transporters involved in modulating synaptic transmission during astrocyte optogenetic activation. The obtained results will refine the mathematical model of mean field neuronal activity to increase its biological plausibility. The methodology used involves identifying sparse nonlinear dynamical systems from data by solving for the system’s equations of motion [2]. These equations are reconstructed from noisy measurement data, allowing for a more accurate representation of the dynamic system. The only assumption regarding the arrangement of a dynamical system is that there exist only a handful of significant factors regulating the dynamics, leading to equations that are sparse within the realm of potential functions. Sparse regression is used to ascertain the minimum number of terms required in dynamic equations for precise data representation. This strategy enables the construction of mathematical models that are both as accurate as feasible, and maximally uncomplicated, eliminating the need for retraining. Notably, this method is suitable for parameterized systems and systems subjected to external influences or changes over time. The two approaches were used to forecast the dynamics of the mean field of a neural population. The accuracy of the forecast was subsequently evaluated.

Phase-locked states in a spiking neural network model with a context-dependent connectivity

The investigation of nonlinear processes in brain systems based on the oscillatory-wave approach is currently one of the most consequential domains of researching signal generation and processing mechanisms in the brain. These investigations may offer insights into various phenomena, such as the mechanism of associative memory, based on network models of biologically relevant neurons. A neural network architecture is proposed in this paper to solve applied problems, such as signal filtering, processing, and recognition of information images. Mechanisms for incomplete fragments were implemented, enabling the extraction and complete restoration of objects from memory. Each neuron in this neural network comprises a Hodgkin–Huxley biophysical model with a Mainen modification, the dynamics of which most plausibly reproduce the processes in the neural cells of the brain. In the research on individual neurons, a constant external current with varying amplitudes was applied. The study determined the average periods of self-oscillations and identified parameter values for the Andronov–Hopf bifurcation. In particular, a stable limit cycle is created and destroyed depending on different scenarios when the bias current is increased or decreased. A stable limit cycle arises via the Andronov–Hopf bifurcation and is terminated via the saddle-node bifurcation on the cycle. The study identified parameter regions whereby two neurons with excitatory and inhibitory synaptic connections synchronize. The neurons were all in self-oscillating mode and exhibited a stable limit cycle in the phase space. A three-layer neural network was constructed, comprising of a reference neuron, sensory, control, and interneurons. The control and intermediate layer connections are arranged based on the Hebbian learning rule. Areas of excitation for various types of neurons were found. Experiments were conducted using the neural network architecture to distinguish binary information patterns encoded through signal phase. Excitatory and inhibitory synaptic connections were employed to encode the images stored in memory. The dynamic patterns are determined through the in-phase or anti-phase mode of phase locking, i.e., phase synchronization relative to the global rhythm. Before reaching the output layer of neurons, the signals are summed on the interneuron layer with the signal of the reference neuron, resulting in the filtering out of a certain information segment (in-phase or anti-phase). The network accurately recognized the patterns after parameter adjustments were made. Areas of neuron phase synchronization were discovered, enabling control of network activity modes. The confirmation of the viability of phase capture and pattern recognition modes using Hodgkin–Huxley–Mainen neurons was achieved. In total, as a result of the implementation of the spike neural network modeling project: 1) two-parameter diagrams of regions of neuronal excitation in various modes are calculated; 2) the effect of excitatory and inhibitory coupling in synaptic currents is used to represent the input signal; 3) an abstract mathematical algorithm for calculating the Hebbian matrix has been transferred to the implementation of synaptic currents between layers of neurons; 4) the effect of phase clusters is used to represent the output pattern; 5) the neurons’ topology in the visual-cerebral department served as a working model for recognizing graphic images through the Hopfield network on a spike neural network, using the Hebbian rule.

GluD1 binds GABA and controls inhibitory plasticity.

Fast synaptic neurotransmission in the vertebrate central nervous system relies primarily on ionotropic glutamate receptors (iGluRs), which drive neuronal excitation, and type A γ-aminobutyric acid receptors (GABAARs), which are responsible for neuronal inhibition. However, the GluD1 receptor, an iGluR family member, is present at both excitatory and inhibitory synapses. Whether and how GluD1 activation may affect inhibitory neurotransmission is unknown. In this work, by using a combination of biochemical, structural, and functional analyses, we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs. GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring. The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticity challenges the classical dichotomy between glutamatergic and GABAergic receptors.

Age- and region-dependent cortical excitability in the zQ175 Huntington disease mouse model.

The neurodegenerative disorder, Huntington disease (HD), manifests as disorders of movement, cognition and mood. Although studies report abnormal corticostriatal synaptic function early in HD mouse models, less is known about cortical-cortical activity across brain regions and disease stages. Recently, we reported enhanced mesoscale spread of cortical responses to sensory stimulation in vivo at early-manifest stages of two HD mouse models. Here, we investigated cortical excitability of zQ175 HD-model mice compared to their wild-type littermates across different cell types, ages and/or cortical regions using ex vivo electrophysiology. Cortical pyramidal neurons (CPNs) in somatosensory cortex of zQ175 mice showed intrinsic hyper-excitability at 3-4months, but hypo-excitability at early-manifest stage (8-9months); reduced frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was seen at both ages. In contrast, motor cortex CPNs in early-manifest zQ175 mice showed increased intrinsic excitability and sEPSC frequency. Large-amplitude excitatory discharges recorded from CPNs in early-manifest zQ175 mice showed increased frequency only in somatosensory cortex, suggesting the intrinsic hypo-excitability of these CPNs may be compensatory against cortical network hyper-excitability. Similarly, in early-manifest zQ175 mice, region-dependent differences were seen in fast-spiking interneurons (FSIs): somatosensory but not motor FSIs from early-manifest zQ175 mice had reduced intrinsic excitability. Moreover, CPNs showed decreased frequency of spontaneous inhibitory postsynaptic currents and increased excitatory-inhibitory (E-I) balance of evoked synaptic currents in somatosensory cortex. Aberrant large-amplitude discharges and reduced inhibitory drive may therefore underlie E-I imbalances that result in circuit changes and synaptic dysfunction in early-manifest HD.

Acute reorganization of postsynaptic GABAA receptors reveals the functional impact of molecular nanoarchitecture at inhibitory synapses

Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABAA receptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABAA receptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABAA receptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.

Altered synaptic currents, mitophagy, mitochondrial dynamics in Alzheimer's disease models and therapeutic potential of Dengzhan Shengmai capsules intervention

Emerging research suggests a potential association of progression of Alzheimer's disease (AD) with alterations in synaptic currents and mitochondrial dynamics. However, the specific associations between these pathological changes remain unclear. In this study, we utilized Aβ42-induced AD rats and primary neural cells as in vivo and in vitro models. The investigations included behavioural tests, brain magnetic resonance imaging (MRI), liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, Nissl staining, thioflavin-S staining, enzyme-linked immunosorbent assay, Golgi-Cox staining, transmission electron microscopy (TEM), immunofluorescence staining, proteomics, adenosine triphosphate (ATP) detection, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) assessment, mitochondrial morphology analysis, electrophysiological studies, Western blotting, and molecular docking. The results revealed changes in synaptic currents, mitophagy, and mitochondrial dynamics in the AD models. Remarkably, intervention with Dengzhan Shengmai (DZSM) capsules emerged as a pivotal element in this investigation. Aβ42-induced synaptic dysfunction was significantly mitigated by DZSM intervention, which notably amplified the frequency and amplitude of synaptic transmission. The cognitive impairment observed in AD rats was ameliorated and accompanied by robust protection against structural damage in key brain regions, including the hippocampal CA3, primary cingular cortex, prelimbic system, and dysgranular insular cortex. DZSM intervention led to increased IDE levels, augmented long-term potential (LTP) amplitude, and enhanced dendritic spine density and length. Moreover, DZSM intervention led to favourable changes in mitochondrial parameters, including ROS expression, MMP and ATP contents, and mitochondrial morphology. In conclusion, our findings delved into the realm of altered synaptic currents, mitophagy, and mitochondrial dynamics in AD, concurrently highlighting the therapeutic potential of DZSM intervention.

The Effects of Aging on Rod Bipolar Cell Ribbon Synapses.

The global health concern posed by age-related visual impairment highlights the need for further research focused on the visual changes that occur during the process of aging. To date, multiple sensory alterations related to aging have been identified, including morphological and functional changes in inner hair cochlear cells, photoreceptors, and retinal ganglion cells. While some age-related morphological changes are known to occur in rod bipolar cells in the retina, their effects on these cells and on their connection to other cells via ribbon synapses remain elusive. To investigate the effects of aging on rod bipolar cells and their ribbon synapses, we compared synaptic calcium currents, calcium dynamics, and exocytosis in zebrafish (Danio rerio) that were middle-aged (MA,18 months) or old-aged (OA, 36 months). The bipolar cell terminal in OA zebrafish exhibited a two-fold reduction in number of synaptic ribbons, an increased ribbon length, and a decrease in local Ca2+ signals at the tested ribbon location, with little change in the overall magnitude of the calcium current or exocytosis in response to brief pulses. Staining of the synaptic ribbons with antibodies specific for PKCa revealed shortening of the inner nuclear and plexiform layers (INL and IPL). These findings shed light on age-related changes in the retina that are related to synaptic ribbons and calcium signals.

Ultra-low power neuromorphic obstacle detection using a two-dimensional materials-based subthreshold transistor

Accurate, timely and selective detection of moving obstacles is crucial for reliable collision avoidance in autonomous robots. The area- and energy-inefficiency of CMOS-based spiking neurons for obstacle detection can be addressed through the reconfigurable, tunable and low-power operation capabilities of emerging two-dimensional (2D) materials-based devices. We present an ultra-low power spiking neuron built using an electrostatically tuned dual-gate transistor with an ultra-thin and generic 2D material channel. The 2D subthreshold transistor (2D-ST) is carefully designed to operate under low-current subthreshold regime. Carrier transport has been modeled via over-the-barrier thermionic and Fowler–Nordheim contact barrier tunneling currents over a wide range of gate and drain biases. Simulation of a neuron circuit designed using the 2D-ST with 45 nm CMOS technology components shows high energy efficiency of ~3.5 pJ per spike and biomimetic class-I as well as oscillatory spiking. It also demonstrates complex neuronal behaviors such as spike-frequency adaptation and post-inhibitory rebound that are crucial for dynamic visual systems. Lobula giant movement detector (LGMD) is a collision-detecting biological neuron found in locusts. Our neuron circuit can generate LGMD-like spiking behavior and detect obstacles at an energy cost of <100 pJ. Further, it can be reconfigured to distinguish between looming and receding objects with high selectivity. We also show that the spiking neuron circuit can function reliably with ±40% variation in the 2D-ST current as well as up to 3 dB signal-to-noise ratio with additive white Gaussian noise in the input synaptic current.

Regulation of NLGN3 and the Synaptic Rho-GEF Signaling Pathway by CDK5.

Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that are involved in synapse assembly and function. The NLGN gene family consists of 5 genes (NLGN1-3, 4X, and 4Y). NLGN3 forms heterodimers with other NLGNs and is expressed at both excitatory and inhibitory synapses, although the distinct role at different synapses is not fully understood. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that targets various neuronal substrates to impact neuronal migration, neurite outgrowth, synaptic transmission, and plasticity. Both NLGNs and their presynaptic binding partners neurexins are highly associated with neurodevelopmental disorders. The NLGN3 gene is on the X chromosome and variants in NLGN3 have been linked to the pathophysiology in neurodevelopmental disorders. To better understand the endogenous modulation of NLGN3, we generated an HA-tagged knock-in mouse. We found that Cdk5 associates with NLGN3 in vivo and phosphorylates NLGN3 on serine 725 (S725) in the knock-in mouse of either sex. The phosphorylation affects the NLGN3 association with Kalirin-7, a postsynaptic guanine nucleotide exchange factors for Rho GTPase family proteins. We further observed that the phosphorylation modulates NLGN3 surface expression and NLGN3-mediated synaptic currents in cultured rat neurons. Thus, we characterized NLGN3 as a novel Cdk5 substrate and revealed the functional consequences of NLGN3 S725 phosphorylation in neurons. Our study provides a novel molecular mechanism underlying Cdk5-mediated regulation of postsynaptic cell adhesion molecules.SIGNIFICANCE STATEMENT NLGN3 is involved in synapse assembly and function at both excitatory and inhibitory synapses and has been associated with the pathophysiology of neurodevelopmental disorders. Cdk5 has brain-specific activity and is involved in neuronal transmission, synapse function, and plasticity. Here, we characterize NLGN3 as a Cdk5 substrate for the first time and show that Cdk5-mediated phosphorylation regulates NLGN3 function. We demonstrate that NLGN3 S725 is a Cdk5 phosphorylation site, and reveal that the site is important for NLGN3 association with Kalirin-7, NLGN3 surface expression, and NLGN3-mediated synaptic transmission.

Cyclin D1—Cdk4 regulates neuronal activity through phosphorylation of GABAA receptors

Nuclear Cyclin D1 (Ccnd1) is a main regulator of cell cycle progression and cell proliferation. Interestingly, Ccnd1 moves to the cytoplasm at the onset of differentiation in neuronal precursors. However, cytoplasmic functions and targets of Ccnd1 in post-mitotic neurons are unknown. Here we identify the α4 subunit of gamma-aminobutyric acid (GABA) type A receptors (GABAARs) as an interactor and target of Ccnd1–Cdk4. Ccnd1 binds to an intracellular loop in α4 and, together with Cdk4, phosphorylates the α4 subunit at threonine 423 and serine 431. These modifications upregulate α4 surface levels, increasing the response of α4-containing GABAARs, measured in whole-cell patch-clamp recordings. In agreement with this role of Ccnd1–Cdk4 in neuronal signalling, inhibition of Cdk4 or expression of the non-phosphorylatable α4 decreases synaptic and extra-synaptic currents in the hippocampus of newborn rats. Moreover, according to α4 functions in synaptic pruning, CCND1 knockout mice display an altered pattern of dendritic spines that is rescued by the phosphomimetic α4. Overall, our findings molecularly link Ccnd1–Cdk4 to GABAARs activity in the central nervous system and highlight a novel role for this G1 cyclin in neuronal signalling.

Piezo1 channel activation facilitates baroreflex afferent neurotransmission with subsequent blood pressure reduction in control and hypertension rats.

Mechanosensitive cation channels such as Piezo1 and Piezo2 are activated by mechanical force like a starched wall of the aorta while blood pressure (BP) rising, which helps to elucidate the underlying mechanism of mechanotransduction of baroreceptor endings. In this study we investigated how Piezo1 channel activation-mediated gender- and afferent-specific BP regulation in rats. We established high-fat diet and fructose drink-induced hypertension model rats (HFD-HTN) and deoxycorticosterone (DOCA)-sensitive hypertension model rats. We showed that the expression levels of Piezo1 and Piezo2 were significantly up-regulated in left ventricle of HFD and DOCA hypertensive rats, whereas the down-regulation of Piezo1 was likely to be compensated by Piezo2 up-regulation in the aorta. Likewise, down-regulated Piezo1 was observed in the nodose ganglion (NG), while up-regulated Piezo2 was found in the nucleus tractus solitarius (NTS), which might synergistically reduce the excitatory neurotransmitter release from the presynaptic membrane. Notably, microinjection of Yoda1 (0.025-2.5 mg/ml) into the NG concentration-dependently reduced BP in both hypertensive rat models as well as in control rats with similar EC50; the effect of Yoda1 was abolished by microinjection of a Piezo1 antagonist GsMTx4 (1.0 μM). Functional analysis in an in vitro aortic arch preparation showed that instantaneous firing frequency of single Ah-fiber of aortic depressor nerve was dramatically increased by Yoda1 (0.03-1.0 μM) and blocked by GsMTx4 (1.0 μM). Moreover, spontaneous synaptic currents recorded from identified 2nd-order Ah-type baroreceptive neurons in the NTS was also facilitated over 100% by Yoda1 (1.0 μM) and completely blocked by GsMTx4 (3.0 μM). These results demonstrate that Piezo1 expressed on Ah-type baroreceptor and baroreceptive neurons in the NG and NTS plays a key role in a sexual-dimorphic BP regulation under physiological and hypertensive condition through facilitation of baroreflex afferent neurotransmission, which is presumably collaborated by Piezo2 expression at different level of baroreflex afferent pathway via compensatory and synergistic mechanisms.

Dirac signal processing of higher-order topological signals

Higher-order networks can sustain topological signals which are variables associated not only to the nodes, but also to the links, to the triangles and in general to the higher dimensional simplices of simplicial complexes. These topological signals can describe a large variety of real systems including currents in the ocean, synaptic currents between neurons and biological transportation networks. In real scenarios topological signal data might be noisy and an important task is to process these signals by improving their signal to noise ratio. So far topological signals are typically processed independently of each other. For instance, node signals are processed independently of link signals, and algorithms that can enforce a consistent processing of topological signals across different dimensions are largely lacking. Here we propose Dirac signal processing, an adaptive, unsupervised signal processing algorithm that learns to jointly filter topological signals supported on nodes, links and triangles of simplicial complexes in a consistent way. The proposed Dirac signal processing algorithm is formulated in terms of the discrete Dirac operator which can be interpreted as ‘square root’ of a higher-order Hodge Laplacian. We discuss in detail the properties of the Dirac operator including its spectrum and the chirality of its eigenvectors and we adopt this operator to formulate Dirac signal processing that can filter noisy signals defined on nodes, links and triangles of simplicial complexes. We test our algorithms on noisy synthetic data and noisy data of drifters in the ocean and find that the algorithm can learn to efficiently reconstruct the true signals outperforming algorithms based exclusively on the Hodge Laplacian.

Ion Migration‐Modulated Flexible MXene Synapse for Biomimetic Multimode Afferent Nervous System: Material and Motion Cognition

The biomimetic afferent nervous system (ANS) is significant for transporting external stimuli into intelligent robots; however, it is still far from bionics due to traditional multisensor and single‐cognition strategies. Herein, a flexible biomimetic ANS with multimode fuzzy perception and brain‐like cognition is developed, by fusing the ion migration‐modulated MXene synapse and machine learning (ML). First of all, the elementary perceptual ability to mimic biological neuroreceptors is demonstrated. Motion artifact in the ionic conductive elastomer (ICE) current is eliminated. Furthermore, the multimode perception and brain‐like cognition are accomplished by synaptic currents (SCs) and nine ML algorithms. Finally, the cognitions of materials, gestures, and motions are conducted by distributing the ANS devices across body joints, and with the optimal ML method, the accuracies can reach 80%, 100%, and 90%, respectively. This synapse‐based ANS may provide a new idea for developing next‐generation neuromorphic intelligent robots.

Rapid, Activity-Dependent Intrinsic Plasticity in the Developing Zebra Finch Auditory Cortex.

The acoustic environment an animal experiences early in life shapes the structure and function of its auditory system. This process of experience-dependent development is thought to be primarily orchestrated by potentiation and depression of synapses, but plasticity of intrinsic voltage dynamics may also contribute. Here, we show that in juvenile male and female zebra finches, neurons in a cortical-level auditory area, the caudal mesopallium (CM), can rapidly change their firing dynamics. This plasticity was only observed in birds that were reared in a complex acoustic and social environment, which also caused increased expression of the low-threshold potassium channel Kv1.1 in the plasma membrane and endoplasmic reticulum (ER). Intrinsic plasticity depended on activity, was reversed by blocking low-threshold potassium currents, and was prevented by blocking intracellular calcium signaling. Taken together, these results suggest that Kv1.1 is rapidly mobilized to the plasma membrane by activity-dependent elevation of intracellular calcium. This produces a shift in the excitability and temporal integration of CM neurons that may be permissive for auditory learning in complex acoustic environments during a crucial period for the development of vocal perception and production.SIGNIFICANCE STATEMENT Neurons can change not only the strength of their connections to other neurons, but also how they integrate synaptic currents to produce patterns of action potentials. In contrast to synaptic plasticity, the mechanisms and functional roles of intrinisic plasticity remain poorly understood. We found that neurons in the zebra finch auditory cortex can rapidly shift their spiking dynamics within a few minutes in response to intracellular stimulation. This plasticity involves increased conductance of a low-threshold potassium current associated with the Kv1.1 channel, but it only occurs in birds reared in a rich acoustic environment. Thus, auditory experience regulates a mechanism of neural plasticity that allows neurons to rapidly adapt their firing dynamics to stimulation.

Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain

Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABAARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAAR subunit composition, there was a redistribution of extrasynaptic GABAARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABAARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca2+/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.

Loss of spines in the prelimbic cortex is detrimental to working memory in mice with early-life adversity

Adverse experiences in early life can shape neuronal structures and synaptic function in multiple brain regions, leading to deficits of distinct cognitive functions later in life. Focusing on the pyramidal cells of the prelimbic cortex (PrL), a main subregion of the medial prefrontal cortex, the impact of early-life adversity (ELA) was investigated in a well-established animal model generated by changing the rearing environment during postnatal days 2 to 9 (P2-P9), a sensitive developmental period. ELA has enduring detrimental impacts on the dendritic spines of PrL pyramidal cells, which is most apparent in a spatially circumscribed region. Specifically, ELA affects both thin and mushroom-type spines, and ELA-provoked loss of spines is observed on selective dendritic segments of PrL pyramidal cells in layers II-III and V-VI. Reduced postsynaptic puncta represented by postsynaptic density protein-95 (PSD-95), but not synaptophysin-labelled presynaptic puncta, in ELA mice supports the selective loss of spines in the PrL. Correlation analysis indicates that loss of spines and postsynaptic puncta in the PrL contributes to the poor spatial working memory of ELA mice, and thin spines may play a major role in working memory performance. To further understand whether loss of spines affects glutamatergic transmission, AMPA- and NMDA-receptor-mediated synaptic currents (EPSCs) were recorded in a group of Thy1-expressing PrL pyramidal cells. ELA mice exhibited a depressed glutamatergic transmission, which is accompanied with a decreased expression of GluR1 and NR1 subunits in the PrL. Finally, upregulating the activation of Thy1-expressing PrL pyramidal cells via excitatory DREADDs can efficiently improve the working memory performance of ELA mice in a T-maze-based task, indicating the potential of a chemogenetic approach in restoring ELA-provoked memory deficits.

A Compact and Low-Power SoC Design for Spiking Neural Network Based on Current Multiplier Charge Injector Synapse.

This paper presents a compact analog system-on-chip (SoC) implementation of a spiking neural network (SNN) for low-power Internet of Things (IoT) applications. The low-power implementation of an SNN SoC requires the optimization of not only the SNN model but also the architecture and circuit designs. In this work, the SNN has been constituted from the analog neuron and synaptic circuits, which are designed to optimize both the chip area and power consumption. The proposed synapse circuit is based on a current multiplier charge injector (CMCI) circuit, which can significantly reduce power consumption and chip area compared with the previous work while allowing for design scalability for higher resolutions. The proposed neuron circuit employs an asynchronous structure, which makes it highly sensitive to input synaptic currents and enables it to achieve higher energy efficiency. To compare the performance of the proposed SoC in its area and power consumption, we implemented a digital SoC for the same SNN model in FPGA. The proposed SNN chip, when trained using the MNIST dataset, achieves a classification accuracy of 96.56%. The presented SNN chip has been implemented using a 65 nm CMOS process for fabrication. The entire chip occupies 0.96 mm2 and consumes an average power of 530 μW, which is 200 times lower than its digital counterpart.