Static Magnetic Field Stimulation Enhances Shunting Inhibition via a SLC26 Family Cl- Channel, Inducing Intrinsic Plasticity.

Magnetic fields are being used for detailed anatomical and functional examination of the human brain. In addition, evidence for their efficacy in treatment of brain dysfunctions is accumulating. Transcranial static magnetic field stimulation (tSMS) is a recently developed technique for noninvasively modifying brain functions. In tSMS, a strong and small magnet when placed over the skull can temporarily suppress brain functions. Its modulatory effects persist beyond the time of stimulation. However, the neurophysiological mechanisms underlying tSMS-induced plasticity remain unclear. Here, using acute motor cortical slice preparation obtained from male C57BL/6N mice, we show that tSMS alters the intrinsic electrical properties of neurons by altering the activity of chloride (Cl-) channels in neurons. Exposure of mouse pyramidal neurons to a static magnetic field (SMF) at a strength similar to human tSMS temporarily decreased their excitability and induced transient neuronal swelling. The effects of SMF were blocked by DIDS and GlyH-101, but not by NPPB, consistent with the pharmacological profile of SLC26A11, a transporter protein with Cl- channel activity. Whole-cell voltage-clamp recordings of the GlyH-101-sensitive Cl- current component showed significant enhancement of the component at both subthreshold and depolarized membrane potentials after SMF application, resulting in shunting inhibition and reduced repetitive action potential (AP) firing at the respective potentials. Thus, this study provides the first neurophysiological evidence for the inhibitory effect of tSMS on neuronal activity and advances our mechanistic understanding of noninvasive human neuromodulation.

Presynaptic coupling by electrical synapses coordinates a rhythmic behavior by synchronizing the activities of a neuron pair.

Electrical synapses are specialized structures that mediate the flow of electrical currents between neurons and have well known roles in synchronizing the activities of neuronal populations, both by mediating the current transfer from more active to less active neurons and by shunting currents from active neurons to their less active neighbors. However, how these positive and negative functions of electrical synapses are coordinated to shape rhythmic synaptic outputs and behavior is not well understood. Here, using a combination of genetics, behavioral analysis, and live calcium imaging in Caenorhabditis elegans, we show that electrical synapses formed by the gap junction protein INX-1/innexin couple the presynaptic terminals of a pair of motor neurons (AVL and DVB) to synchronize their activation in response to a pacemaker signal. Live calcium imaging reveals that inx-1/innexin mutations lead to asynchronous activation of AVL and DVB, due, in part, to loss of AVL-mediated activation of DVB by the pacemaker. In addition, loss of inx-1 leads to the ectopic activation of DVB at inappropriate times during the cycle through the activation of the L-type voltage-gated calcium channel EGL-19. We propose that electrical synapses between AVL and DVB presynaptic terminals function to ensure the precise and robust execution of a specific step in a rhythmic behavior by both synchronizing the activities of presynaptic terminals in response to pacemaker signaling and by inhibiting their activation in between cycles when pacemaker signaling is low.

Contrast gain control occurs independently of both parvalbumin-positive interneuron activity and shunting inhibition in auditory cortex.

Contrast gain control is the systematic adjustment of neuronal gain in response to the contrast of sensory input. It is widely observed in sensory cortical areas and has been proposed to be a canonical neuronal computation. Here, we investigated whether shunting inhibition from parvalbumin-positive interneurons-a mechanism involved in gain control in visual cortex-also underlies contrast gain control in auditory cortex. First, we performed extracellular recordings in the auditory cortex of anesthetized male mice and optogenetically manipulated the activity of parvalbumin-positive interneurons while varying the contrast of the sensory input. We found that both activation and suppression of parvalbumin interneuron activity altered the overall gain of cortical neurons. However, despite these changes in overall gain, we found that manipulating parvalbumin interneuron activity did not alter the strength of contrast gain control in auditory cortex. Furthermore, parvalbumin-positive interneurons did not show increases in activity in response to high-contrast stimulation, which would be expected if they drive contrast gain control. Finally, we performed in vivo whole-cell recordings in auditory cortical neurons during high- and low-contrast stimulation and found that no increase in membrane conductance was observed during high-contrast stimulation. Taken together, these findings indicate that while parvalbumin-positive interneuron activity modulates the overall gain of auditory cortical responses, other mechanisms are primarily responsible for contrast gain control in this cortical area.NEW & NOTEWORTHY We investigated whether contrast gain control is mediated by shunting inhibition from parvalbumin-positive interneurons in auditory cortex. We performed extracellular and intracellular recordings in mouse auditory cortex while presenting sensory stimuli with varying contrasts and manipulated parvalbumin-positive interneuron activity using optogenetics. We show that while parvalbumin-positive interneuron activity modulates the gain of cortical responses, this activity is not the primary mechanism for contrast gain control in auditory cortex.

Inhibition shapes the organization of hippocampal representations.

Hippocampal neurons become tuned to stimuli that predict behaviorally salient outcomes. This plasticity suggests that memory formation depends upon shifts in how different anatomical inputs can drive hippocampal activity. Here, I present evidence that inhibitory neurons can provide such a mechanism for learning-related changes in the tuning of pyramidal cells. Inhibitory currents arriving on the dendrites of pyramidal cells determine whether an excitatory input can drive action potential output. Specificity and plasticity of this dendritic modulation allows for precise, modifiable changes in how afferent inputs are integrated, a process that defines a neuron's receptive field. In addition, feedback inhibition plays a fundamental role in biasing which excitatory neurons may be co-active. By defining the rules of synchrony and the rules of input integration, interneurons likely play an important role in the organization of memory representation within the hippocampus.

Synaptic Conductance Estimates of the Connection Between Local Inhibitor Interneurons and Pyramidal Neurons in Layer 2/3 of a Cortical Column.

Stimulation of a principal whisker yields sparse action potential (AP) spiking in layer 2/3 (L2/3) pyramidal neurons in a cortical column of rat barrel cortex. The low AP rates in pyramidal neurons could be explained by activation of interneurons in L2/3 providing inhibition onto L2/3 pyramidal neurons. L2/3 interneurons classified as local inhibitors based on their axonal projection in the same column were reported to receive strong excitatory input from spiny neurons in L4, which are also the main source of the excitatory input to L2/3 pyramidal neurons. Here, we investigated the remaining synaptic connection in this intracolumnar microcircuit. We found strong and reliable inhibitory synaptic transmission between intracolumnar L2/3 local-inhibitor-to-L2/3 pyramidal neuron pairs [inhibitory postsynaptic potential (IPSP) amplitude -0.88 ± 0.67 mV]. On average, 6.2 ± 2 synaptic contacts were made by L2/3 local inhibitors onto L2/3 pyramidal neurons at 107 ± 64 µm path distance from the pyramidal neuron soma, thus overlapping with the distribution of synaptic contacts from L4 spiny neurons onto L2/3 pyramidal neurons (67 ± 34 µm). Finally, using compartmental simulations, we determined the synaptic conductance per synaptic contact to be 0.77 ± 0.4 nS. We conclude that the synaptic circuit from L4 to L2/3 can provide efficient shunting inhibition that is temporally and spatially aligned with the excitatory input from L4 to L2/3.

Environmental remodelling of GABAergic and glutamatergic neurotransmission: rise of the anoxia-tolerant turtle brain.

Climate cooling over the past one hundred thousand years has resulted in seasonal ice cover at northern and southern latitudes that has selected for hypoxia and anoxia tolerance in some species, such as freshwater turtles. At the northern reaches of their range, North American freshwater turtles spend 4 months or more buried in the mud bottom of ice covered lakes and ponds. From a comparative perspective this gives us the opportunity to understand how an extremely oxygen-sensitive organ, such as the vertebrate brain, can function without oxygen for long periods. Brain function is based on complex excitatory (on) and inhibitory (off) circuits involving the major neurotransmitters glutamate and, γ-aminobutyric acid (GABA) respectively. When a mammalian brain becomes anoxic, glutamate levels rise within minutes resulting in excitotoxic cell death which does not occur in anoxic turtle brain. The response in turtle brain has been remodelled - GABA levels rise rapidly resulting in large inhibitory GABA receptor currents and inhibition of glutamate receptor function that together depress neuronal activity.

InA: Inhibition Adaption on pre-trained language models.

Fine-tuning pre-trained language models (LMs) may not always be the most practical approach for downstream tasks. While adaptation fine-tuning methods have shown promising results, a clearer explanation of their mechanisms and further inhibition of the transmission of information is needed. To address this, we propose an Inhibition Adaptation (InA) fine-tuning method that aims to reduce the number of added tunable weights and appropriately reweight knowledge derived from pre-trained LMs. The InA method involves (1) inserting a small trainable vector into each Transformer attention architecture and (2) setting a threshold to directly eliminate irrelevant knowledge. This approach draws inspiration from the shunting inhibition, which allows the inhibition of specific neurons to gate other functional neurons. With the inhibition mechanism, InA achieves competitive or even superior performance compared to other fine-tuning methods on BERT-large, RoBERTa-large, and DeBERTa-large for text classification and question-answering tasks.

A Conductance-Based Silicon Synapse Circuit.

Neuron, synapse, and learning circuits inspired by the brain comprise the key components of a neuromorphic chip. In this study, we present a conductance-based analog silicon synapse circuit suitable for the implementation of reduced or multi-compartment neuron models. Compartmental models are more bio-realistic. They are implemented in neuromorphic chips aiming to mimic the electrical activities of the neuronal networks in the brain and incorporate biomimetic soma and synapse circuits. Most contemporary low-power analog synapse circuits implement bioinspired "current-based" synaptic models suited for the implementation of single-compartment point neuron models. They emulate the exponential decay profile of the synaptic current, but ignore the effect of the postsynaptic membrane potential on the synaptic current. This dependence is necessary to emulate shunting inhibition, which is thought to play important roles in information processing in the brain. The proposed circuit uses an oscillator-based resistor-type element at its output stage to incorporate this effect. This circuit is used to demonstrate the shunting inhibition phenomenon. Next, to demonstrate that the oscillatory nature of the induced synaptic current has no unforeseen effects, the synapse circuit is employed in a spatiotemporal spike pattern detection task. The task employs the adaptive spike-timing-dependent plasticity (STDP) learning rule, a bio-inspired learning rule introduced in a previous study. The mixed-signal chip is designed in a Taiwan Manufacturing Semiconductor Company 250 nm complementary metal oxide semiconductor technology node. It comprises a biomimetic soma circuit and 256 synapse circuits, along with their learning circuitries.

How auditory selectivity for sound timing arises: The diverse roles of GABAergic inhibition in shaping the excitation to interval-selective midbrain neurons.

Across sensory systems, temporal frequency information is progressively transformed along ascending central pathways. Despite considerable effort to elucidate the mechanistic basis of these transformations, they remain poorly understood. Here we used a novel constellation of approaches, including whole-cell recordings and focal pharmacological manipulation, in vivo, and new computational algorithms that identify conductances resulting from excitation, inhibition and active membrane properties, to elucidate the mechanisms underlying the selectivity of midbrain auditory neurons for long temporal intervals. Surprisingly, we found that stimulus-driven excitation can be increased and its selectivity decreased following attenuation of inhibition with gabazine or intracellular delivery of fluoride. We propose that this nonlinear interaction is due to shunting inhibition. The rate-dependence of this inhibition results in the illusion that excitation to a cell shows greater temporal selectivity than is actually the case. We also show that rate-dependent depression of excitation, an important component of long-interval selectivity, can be decreased after attenuating inhibition. These novel findings indicate that nonlinear shunting inhibition plays a key role in shaping the amplitude and interval selectivity of excitation. Our findings provide a major advance in understanding how the brain decodes intervals and may explain paradoxical temporal selectivity of excitation to midbrain neurons reported previously.

TRESK channel contributes to depolarization-induced shunting inhibition and modulates epileptic seizures.

Glutamatergic and GABAergic synaptic transmission controls excitation and inhibition of postsynaptic neurons, whereas activity of ion channels modulates neuronal intrinsic excitability. However, it is unclear how excessive neuronal excitation affects intrinsic inhibition to regain homeostatic stability under physiological or pathophysiological conditions. Here, we report that a seizure-like sustained depolarization can induce short-term inhibition of hippocampal CA3 neurons via a mechanism of membrane shunting. This depolarization-induced shunting inhibition (DShI) mediates a non-synaptic, but neuronal intrinsic, short-term plasticity that is able to suppress action potential generation and postsynaptic responses by activated ionotropic receptors. We demonstrate that the TRESK channel significantly contributes to DShI. Disruption of DShI by genetic knockout of TRESK exacerbates the sensitivity and severity of epileptic seizures of mice, whereas overexpression of TRESK attenuates seizures. In summary, these results uncover a type of homeostatic intrinsic plasticity and its underlying mechanism. TRESK might represent a therapeutic target for antiepileptic drugs.

Sparsification of AP firing in adult-born hippocampal granule cells via voltage-dependent α5-GABAA receptors.

GABA can depolarize immature neurons close to the action potential (AP) threshold in development and adult neurogenesis. Nevertheless, GABAergic synapses effectively inhibit AP firing in newborn granule cells of the adult hippocampus as early as two weeks post-mitosis. The underlying mechanisms are largely unclear. Here, we analyze GABAergic inputs in newborn hippocampal granule cells mediated by soma-targeting parvalbumin and dendrite-targeting somatostatin interneurons. Surprisingly, both interneuron subtypes activate α5-subunit-containing GABAA receptors (α5-GABAARs) in young neurons, showing a nonlinear voltage dependence with increasing conductance around the AP threshold. By contrast, in mature cells, parvalbumin interneurons mediate linear GABAergic synaptic currents lacking α5-subunits, while somatostatin interneurons continue to target nonlinear α5-GABAARs. Computational modeling shows that the voltage-dependent amplification of α5-GABAAR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potential.

Dentate Granule Cells Recruited in the Home Environment Display Distinctive Properties.

The dentate granule cells (DGCs) play a crucial role in learning and memory. Many studies have described the role and physiological properties of these sparsely active neurons using different behavioral contexts. However, the morpho-functional features of DGCs recruited in mice maintained in their home cage (without training), considered as a baseline condition, have not yet been established. Using fosGFP transgenic mice, we observed ex vivo that DGCs recruited in animals maintained in the home cage condition are mature neurons that display a longer dendritic tree and lower excitability compared with non-activated cells. The higher GABAA receptor-mediated shunting inhibition contributes to the lower excitability of DGCs activated in the home environment by shifting the input resistance towards lower values. Remarkably, that shunting inhibition is neither observed in non-activated DGCs nor in DGCs activated during training in virtual reality. In short, our results suggest that strong shunting inhibition and reduced excitability could constitute a distinctive neural signature of mature DGCs recruited in the context of the home environment.

Modeling Circadian Phototransduction: Retinal Neurophysiology and Neuroanatomy.

The retina is a complex, but well-organized neural structure that converts optical radiation into neural signals that convey photic information to a wide variety of brain structures. The present paper is concerned with the neural circuits underlying phototransduction for the central pacemaker of the human circadian system. The proposed neural framework adheres to orthodox retinal neuroanatomy and neurophysiology. Several postulated mechanisms are also offered to account for the high threshold and for the subadditive response to polychromatic light exhibited by the human circadian phototransduction circuit. A companion paper, modeling circadian phototransduction: Quantitative predictions of psychophysical data, provides a computational model for predicting psychophysical data associated with nocturnal melatonin suppression while staying within the constraints of the neurophysiology and neuroanatomy offered here.

Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome.

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome.

Nonlinear multiplicative dendritic integration in neuron and network models.

Neurons receive inputs from thousands of synapses distributed across dendritic trees of complex morphology. It is known that dendritic integration of excitatory and inhibitory synapses can be highly non-linear in reality and can heavily depend on the exact location and spatial arrangement of inhibitory and excitatory synapses on the dendrite. Despite this known fact, most neuron models used in artificial neural networks today still only describe the voltage potential of a single somatic compartment and assume a simple linear summation of all individual synaptic inputs. We here suggest a new biophysical motivated derivation of a single compartment model that integrates the non-linear effects of shunting inhibition, where an inhibitory input on the route of an excitatory input to the soma cancels or "shunts" the excitatory potential. In particular, our integration of non-linear dendritic processing into the neuron model follows a simple multiplicative rule, suggested recently by experiments, and allows for strict mathematical treatment of network effects. Using our new formulation, we further devised a spiking network model where inhibitory neurons act as global shunting gates, and show that the network exhibits persistent activity in a low firing regime.