Inhibitory Circuits Research Articles

Neural activity responsiveness by maturation of inhibition underlying critical period plasticity

IntroductionNeural circuits develop during critical periods (CPs) and exhibit heightened plasticity to adapt to the surrounding environment. Accumulating evidence indicates that the maturation of inhibitory circuits, such as gamma-aminobutyric acid and parvalbumin-positive interneurons, plays a crucial role in CPs and contributes to generating gamma oscillations. A previous theory of the CP mechanism suggested that the maturation of inhibition suppresses internally driven spontaneous activity and enables synaptic plasticity to respond to external stimuli. However, the neural response to external stimuli and neuronal oscillations at the neural population level during CPs has not yet been fully clarified. In the present study, we aimed to investigate neuronal activity responsiveness with respect to the maturation of inhibition at gamma-band frequencies.MethodWe calculated inter-trial phase coherence (ITPC), which quantifies event-related phase modulations across trials, using a biologically plausible spiking neural network that generates gamma oscillations through interactions between excitatory and inhibitory neurons.ResultsOur results demonstrated that the neuronal response coherence to external periodic inputs exhibits an inverted U-shape with respect to the maturation of inhibition. Additionally, the peak of this profile was consistent with the moderate suppression of the gamma-band spontaneous activity.DiscussionThis finding suggests that the neuronal population's highly reproducible response to increased inhibition may lead to heightened synaptic plasticity. Our computational model can help elucidate the underlying mechanisms that maximize synaptic plasticity at the neuronal population level during CPs.

Virtual Human Retina: Simulating Neural Signalling, Degeneration, and Responses to Electrical Stimulation.

Current brain-based visual prostheses pose significant challenges impeding adoption such as the necessarily complex surgeries and occurrence of more substantial side effects due to the sensitivity of the brain. This has led to much effort toward vision restoration being focused on the more approachable part of the brain - the retina. Here we introduce a novel, parameterized simulation platform that enables study of human retinal degeneration and optimization of stimulation strategies. The platform bears immense potential for patient-specific tailoring and serves to enhance artificial vision solutions for individuals with visual impairments. Our virtual retina is developed using the software package, NEURON. This virtual retina platform supports large-scale simulations of over 10,000 neurons whilst upholding strong biological plausibility with multiple important visual pathways and detailed network properties. The comprehensive three-dimensional model includes photoreceptors, horizontal cells, bipolar cells, amacrine cells, and midget and parasol retinal ganglion cells, with comprehensive network connectivity across various eccentricities (1 mm to 5 mm from the fovea) in the human retina. The model is constructed using electrophysiology, immunohistology, and optical coherence tomography imaging data from healthy and degenerate human retinas. We validated our model by replicating numerous experimental observations from human and primate retina, with a particular focus on retinal degeneration. We simulated interactions between diseased retinas and state-of-the-art retinal implants, shedding light on the limitations of commercial retinal prostheses. Our results suggested that appropriate stimulation settings with intraretinal prototype devices could leverage network-mediated activation to achieve activation mosaics more alike that of the retina's response to natural light, promoting the prospect of more naturalistic vision. Our study additionally highlights the importance of controlling inhibitory circuits in the retinal network to induce functionally relevant retinal activity. This study demonstrates the potential of this software package and highlights its utility as a valuable tool for engineers, scientists, and clinicians in the design and optimisation of retinal stimulation devices for both research and educational applications.

Neurodevelopmental and Neuropsychiatric Perspectives on Respiratory Control: Understanding Congenital and Developmental Disorders

: Breathing is an automatic process generated by the central nervous system, crucial for the homeostasis of several body processes. This vital process is underpinned by an intricate network in which distinct functional and anatomical factors and structures play a role. Transcription factors (i.e., PHOX2B and Pbx proteins), as well as neuromodulators (i.e., serotonin, noradrenaline, GABA, and glycine), have been demonstrated as implicated in the regulation of breathing. Besides, the several intertwined excitatory and inhibitory brainstem neural circuits comprising the so-called central pattern generator (CPG) have recently demonstrated a potential role of cerebellar structures and circuits in coordinating the complex and coordinated respiratory act in eupnea. A disruption affecting one of these components, which may also occur on a genetic basis, may indeed result in complex and heterogeneous disorders, including neurodevelopmental ones (such as Rett and Prader-Willi syndrome), which may also present with neuropsychiatric and breathing manifestations and potentially lead to sudden infant death syndrome (SIDS). Herein, we discuss the main factors and systems involved in respiratory control and modulation, outlining some of the associated neurodevelopmental disorders (NDDs) deriving from an impairment in their expression/ function. Further studies are needed to deepen our knowledge of the complexity underpinning “breathing” and the relation between respiratory implications and congenital and developmental disorders.

Neurofeedback-induced desynchronization of sensorimotor rhythm elicits pre-movement downregulation of intracortical inhibition that shortens simple reaction time in humans: A double-blind, sham-controlled randomized study

Abstract Sensorimotor rhythm event-related desynchronization (SMR-ERD) is associated with the activities of cortical inhibitory circuits in the motor cortex. The self-regulation of SMR-ERD through neurofeedback training has demonstrated that successful SMR-ERD regulation improves motor performance. However, the training-induced changes in neural dynamics in the motor cortex underlying performance improvement remain unclear. Here, we hypothesized that SMR-neurofeedback based on motor imagery reduces cortical inhibitory activities during motor preparation, leading to shortened reaction time due to the repetitive recruitment of neural populations shared with motor imagery and movement preparation. To test this, we conducted a double-blind, sham-controlled study on 24 participants using neurofeedback training and pre- and post-training evaluation for simple reaction time tests and cortical inhibitory activity using short-interval intracortical inhibition (SICI). The results showed that veritable neurofeedback training effectively enhanced SMR-ERD in healthy male and female participants, accompanied by reduced simple reaction times and pre-movement SICI. Furthermore, SMR-ERD changes correlated with changes in pre-movement cortical disinhibition, and the disinhibition magnitude correlated with behavioral changes. These results suggest that SMR-neurofeedback modulates cortical inhibitory circuits during movement preparation, thereby enhancing motor performance.

Sex-specific age-related changes in excitatory and inhibitory intra-cortical circuits in mouse primary auditory cortex.

A common impairment in aging is age-related hearing loss (presbycusis), which manifests as impaired spectrotemporal processing. Presbycusis can be caused by a dysfunction of the peripheral and central auditory system and these dysfunctions might differ between the sexes. To date, the circuit mechanisms in the central nervous system responsible for age-related auditory dysfunction remain mostly unknown. In the auditory cortex (ACtx), aging is accompanied by alteration in normal inhibitory (GABA) neurotransmission and changes in excitatory (NMDA and AMPA) synapses, but which circuits are affected has been unclear. Here we investigated how auditory cortical microcircuits change with age and if sex-dependent differences existed. We performed laser-scanning photostimulation (LSPS) combined with whole-cell patch clamp recordings from Layer (L) 2/3 cells in primary auditory cortex (A1) in young adult (2-3 months) and aged (older than 18 months) male and female CBA/CaJ mice which have normal peripheral hearing. We found that L2/3 cells in aged male animals display functional hypoconnectivity of inhibitory circuits originating from L2/3 and L4. Compared to cells from young adult mice, cells from aged male mice have weaker excitatory connections from L2/3. We also observed an increased diversity of excitatory and inhibitory inputs. These results suggest a sex-specific reduction and diversification in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits contribute to the functional manifestations of age-related hearing loss in both males and females.Significance Statement A common impairment in aging is age-related hearing loss (presbycusis) which can be caused by a dysfunction of the peripheral and central auditory system. Impaired spectrotemporal processing in the auditory cortex is thought to underlie some of these impairments. We compare auditory cortex circuits in vitro in young adult (∼P60) and aged (∼P585) CBA mice. We find a sex-specific reduction in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits underlie the differential functional manifestations of age-related hearing loss in both males and females.

Astrocytic inhibition of lateral septal neurons promotes diverse stress responses

Inhibitory neuronal circuits within the lateral septum (LS) play a key role in regulating mood and stress responses. Even though glial cells can modulate these circuits, the impact of astrocytes on LS neural circuits and their functional interactions remains largely unexplored. Here, we demonstrate that astrocytes exhibit increased intracellular Ca²⁺ levels in response to aversive sensory and social stimuli in both male and female mice. This astrocytic Ca²⁺ elevation inhibits neighboring LS neurons by reducing excitatory synaptic transmissions through A1R-mediated signaling in both the dorsal (LSd) and intermediate LS (LSi) and enhancing inhibitory synaptic transmission via A2AR-mediated signaling in the LSi. At the same time, astrocytes reduce inhibitory tone on distant LS neurons. In the LSd, astrocytes promote social avoidance and anxiety, as well as increased heart rate in socially stressed male mice. In contrast, astrocytes in the LSi contribute to elevated heart rate and heightened blood corticosterone levels in unstressed male mice. These results suggest that the dynamic interactions between astrocytes and neurons within the LS modulate physiological and behavioral responses to stressful experiences.

Lateral entorhinal cortex afferents reconfigure the activity in piriform cortex circuits

Odors are key signals for guiding spatial behaviors such as foraging and navigation in rodents. Recent findings reveal that odor representations in the piriform cortex (PCx) also encode spatial context information. However, the brain origins of this information and its integration into PCx microcircuitry remain unclear. This study investigates the lateral entorhinal cortex (LEC) as a potential source of spatial contextual information affecting the PCx microcircuit and its olfactory responses. Using mice brain slices, we performed patch-clamp recordings on superficial (SP) and deep (DP) pyramidal neurons, as well as parvalbumin (PV) and somatostatin (SOM) inhibitory interneurons. Concurrently, we optogenetically stimulated excitatory LEC projections to observe their impact on PCx activity. Results show that LEC inputs are heterogeneously distributed in the PCx microcircuit, evoking larger excitatory currents in SP and PV neurons due to higher monosynaptic connectivity. LEC inputs also differentially affect inhibitory circuits, activating PV while suppressing SOM interneurons. Studying the interaction between LEC inputs and sensory signals from the lateral olfactory tract (LOT) revealed that simultaneous LEC and LOT activation increases spiking in SP and DP neurons, with DP neurons showing a sharpened response due to LEC-induced inhibition that suppresses delayed LOT-evoked spikes. This suggests a regulatory mechanism where LEC inputs inhibit recurrent activity by activating PV interneurons. Our findings demonstrate that LEC afferents reconfigure PCx activity, aiding the understanding of how odor objects form within the PCx by integrating olfactory and nonolfactory information.

Input-specific properties of excitatory synapses on oxytocin receptor-expressing neurons in the lateral septum.

Oxytocin receptor (OXTR) is expressed in a distinct population of neurons in the lateral septum (LS), among other brain regions, and is responsible for regulating various social and nonsocial behaviors, including reward processing, feeding, social memory, anxiety, and fear. The LS serves as a key link between the cortical and subcortical regions, yet the synaptic inputs that drive the OXTR-expressing LS neurons have not been characterized. Here, we established retrograde and anterograde viral tracing in the mouse brain to map the input connections of the intermediate part of the LS where OXTR neurons are concentrated. Utilizing pathway-specific optogenetic activation, we identified that the strongest cortical inputs to LS OXTR neurons are from the posteromedial amygdala cortex (PMCo) and the ventral hippocampus (vHipp). We further determined that these excitatory inputs exhibit distinct presynaptic and postsynaptic properties, with PMCo synapses displaying a lower release probability and smaller α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-to-N-methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic current (EPSC) ratio compared to vHipp synapses. Our results also demonstrated that both vHipp and PMCo inputs establish a direct excitatory and a disynaptic inhibitory circuit on LS OXTR neurons. These findings deepen our understanding of the synaptic control of LS OXTR neurons by cortical regions, carrying significant implications for the affective behaviors in which these neurons are involved.NEW & NOTEWORTHY This is the first identification and characterization of the cortical synaptic inputs that drive the oxytocin receptor (OXTR)-expressing neurons in the lateral septum (LS), which are involved in diverse affective behavior. The strongest cortical inputs to LS OXTR neurons are from the posteromedial amygdala cortex, an understudied cortical region that is beginning to gain prominence for its role in social behavior. The synapses from these projections show differences in properties compared to inputs from the ventral hippocampus.

Clinical efficacy of low-dose Perampanel correlates with neurophysiological changes in familial adult myoclonus epilepsy 2.

Familial adult myoclonus epilepsy (FAME) management relies on antiseizure medications (ASMs), which inadequately address myoclonus and cortical tremor. This study evaluates Perampanel (PER), an AMPA-receptor antagonist, for treating FAME symptoms. Fifteen FAME2 patients participated in an observational prospective study. They received up to 6 mg daily of PER and underwent Unified-Myoclonus-Rating-Scale (UMRS) before and after treatment. Neurophysiological evaluations, including somatosensory evoked potentials (SEPs) and transcranial magnetic stimulation (TMS), assessed PER's impact on cortical glutamatergic excitatory and GABAergic inhibitory circuits. PER treatment significantly reduced UMRS total scores (p = 0.001) and action-myoclonus subscores (p = 0.002), irrespective of disease duration, age at onset, or testing time (p >0.05). Patients with more severe baseline myoclonus demonstrated significant improvements. Neurophysiological assessments revealed a PER-induced decrease in sensorimotor hyperexcitability, characterized by diminished N33 amplitudes, attenuated glutamatergic facilitation, and enhanced GABAergic inhibition in the motor cortex. In conclusion, low-dose PER is well tolerated and effective in alleviating myoclonus in FAME2 patients, supported by its modulatory effects on glutamatergic and GABAergic neuronal circuits. Plain Language Summary: This study investigated the effects of low-dose perampanel in individuals with Familial Adult Myoclonus Epilepsy2 (FAME2), a hereditary condition characterized by epilepsy and tremors. Perampanel, an antiepileptic drug, blocks AMPA receptors in the brain, reducing excessive neural activity that causes seizures and abnormal movements. The results showed significant symptom improvement, which correlated with changes in brain activity as measured by neurophysiological tests. This study suggests that perampanel helps regulate abnormal brain signals and may help managing FAME2 symptoms.

Transcutaneous spinal cord stimulation neuromodulates pre- and postsynaptic inhibition in the control of spinal spasticity

Aside from enabling voluntary control over paralyzed muscles, a key effect of spinal cord stimulation is the alleviation of spasticity. Dysfunction of spinal inhibitory circuits is considered a major cause of spasticity. These circuits are contacted by Ia muscle spindle afferents, which are also the primary targets of transcutaneous lumbar spinal cord stimulation (TSCS). We hypothesize that TSCS controls spasticity by transiently strengthening spinal inhibitory circuit function through their Ia-mediated activation. We show that 30min of antispasticity TSCS improves activity in post- and presynaptic inhibitory circuits beyond the intervention in ten individuals with traumatic spinal cord injury to normative levels established in 20 neurologically intact individuals. These changes in circuit function correlate with improvements in muscle hypertonia, spasms, and clonus. Our study opens the black box of the carryover effects of antispasticity TSCS and underpins a causal role of deficient post- and presynaptic inhibitory circuits in spinal spasticity.

Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration.

In many neurological conditions, early-stage neural circuit adaption can preserve relatively normal behaviour. In some diseases, spinal motoneurons progressively degenerate yet movement is initially preserved. We therefore investigated whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration. Using a combination of in vitro and in vivo electrophysiology and super-resolution microscopy, we found that, early in the disease, neurotransmission in a key pre-motor circuit, the recurrent inhibition mediated by Renshaw cells, is reduced by half due to impaired quantal size associated with decreased glycine receptor density. This impairment is specific, and not a widespread feature of spinal inhibitory circuits. Furthermore, it recovers at later stages of disease. Additionally, an increased probability of release from proprioceptive afferents leads to increased monosynaptic excitation of motoneurons. We reveal that in motoneuron degenerative conditions, spinal microcircuits undergo specific multiphasic homeostatic compensations that may contribute to preservation of force output.

Decoding Visual Responses: Insights into Chronic Migraine and Medication Overuse Headache with Electrophysiological Analysis.

Background/Objectives: Habituation and sensitization are opposite phenomena that play a role in the pathophysiology of episodic migraine and its progression to chronic migraine (CM). There have been just a few studies that have investigated these phenomena in patients with medication overuse headache (MOH) in comparison to those with chronic migraine (CM) and healthy controls (HCs), and the findings have been inconsistent. Methods: We measured and examined visual evoked potentials (VEPs) in 81 patients with MOH and 24 patients with CM, as well as 24 HCs. The VEPs were used to assess sensitization by analysing the amplitude of the first block (100 sweeps) and to evaluate habituation by measuring the amplitude response decrement after six blocks. We further examined patients diagnosed with MOH based on their acute medication type and after a 3-week acute medication withdrawal program. Results: There were no significant differences between groups in terms of the first N1-P1 VEP amplitude block and its habituation. It was found that patients with MOH had a greater drop in the amplitude of the VEP P1-N2 complex after repeated stimulation than patients with CM or HC. The VEP parameters showed no significant differences based on the specific overused drug and after a 3-week acute medication withdrawal. Conclusions: We propose that the results obtained in patients with MOH indicate an abnormal activation of inhibitory circuits in the parieto-occipital region in response to repeated modulatory stimuli.

Neural Correlates of Reactive Inhibition in Gambling Disorder: An FMRI Study with Transcranial Magnetic Stimulation (TMS)

Gambling Disorder (GD) is a condition characterized by a persistent and recurrent pattern of problematic gambling behavior. Despite significant advances in understanding the neurobiological correlates of Gambling Disorder phenomenological manifestation, there are still several unanswered questions regarding the pathophysiological mechanisms underlying GD. There is substantial evidence from fMRI studies on the role of pre-SMA stimulation in psychiatric conditions with impairments in response inhibition such as behavioral addictions on enhancing the activity of the brain circuitry involving the right inferior (IFG) and middle frontal gyrus (MFG) (two cortical areas are differentially associated with two distinct aspects of control inhibition). In this study we utilized task-related functional Magnetic Resonance Imaging (fMRI) to explore the impact of continuous Theta-Burst Stimulation (cTBS) on the pre-Supplementary Motor Area (pre-SMA) in patients with Gambling Disorder (GD). Four GD patients underwent cTBS on bilateral pre-SMA, administered with the MagVenture MagPro R30 stimulator with add-on theta-burst option (MagVenture INC.) using a Cool D-B80 figure-of-eight coil. cTBS consists of bursts of 3 pulses separated by 20 ms (i.e., 50 Hz) delivered repeatedly at theta frequency on the pre-SMA bilaterally. Changes in Functional Connectivity (FC) were assessed before and after Real or Sham treatment using CONN functional connectivity toolbox and Statistical Parametric Mapping (SPM). The study aimed to determine whether cTBS influences the functional connectivity between pre-SMA and right prefrontal areas, specifically the right Inferior Frontal Gyrus (rIFG) and right Middle Frontal Gyrus (rMFG), and whether these changes correlate with treatment outcomes. Results indicated that real cTBS treatment increased functional connectivity between pre-SMA and both rIFG and rMFG, suggesting enhanced control inhibition. This was associated with a reduction in Gambling Disorder symptom severity, assessed with the Pathological Gambling version of the Yale-Brown Obsessive-Compulsive Scale (PG-YBOCS) and the Gambling Urges Questionnaire (GUQ), indicating a treatment response. Conversely, sham cTBS did not elicit the same positive FC changes in the reactive control inhibition network, aligning with behavioral measures. The study highlighted the potential of cTBS on pre-SMA in modulating inhibitory control circuit. Overall, this preliminary investigation provides a foundation for future investigations into the neurobiological mechanisms underlying GD and the potential efficacy of TMS interventions.

Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia with no known cause and cure. Research suggests that a reduction of GABAergic inhibitory interneurons' activity in the hippocampus by beta-amyloid peptide (Aβ) is a crucial trigger for cognitive impairment in AD via hyperexcitability. Therefore, enhancing hippocampal inhibition is thought to be protective against AD. However, hippocampal inhibitory cells are highly diverse, and these distinct interneuron subtypes differentially regulate hippocampal inhibitory circuits and cognitive processes. Moreover, Aβ unlikely affects all subtypes of inhibitory interneurons in the hippocampus equally. Hence, identifying the affected interneuron subtypes in AD to enhance hippocampal inhibition optimally is conceptually and practically challenging. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in cultured hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation and synaptic dysfunction in excitatory neurons. We have also revealed that co-activation of α7- and α4β2-nAChRs is required to reverse the Aβ-induced adverse effects in hippocampal excitatory neurons. Here, we discover that α7- and α4β2-nAChRs predominantly control the nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. Furthermore, we reveal that co-activation of these receptors is necessary to reverse hippocampal network dysfunction and fear memory loss in the amyloid pathology model mice. We thus suggest that co-activation of PV+ and SST+ cells is a novel strategy to reverse hippocampal dysfunction and cognitive decline in AD.

EphB2 Signaling Is Implicated in Astrocyte-Mediated Parvalbumin Inhibitory Synapse Development.

Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PCs) through whole-cell patch-clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV→PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV→PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore the crucial role of astrocytes in regulating inhibitory circuit development and discover a new role of EphB2 receptors in PV-specific inhibitory synapse development.

Amelioration of Focal Hand Dystonia via Low-Frequency Repetitive Somatosensory Stimulation.

Dystonia presents a growing concern based on evolving prevalence insights. Previous research found that, in cervical dystonia, high-frequency repetitive somatosensory stimulation (RSS; HF-RSS) applied on digital nerves paradoxically diminishes sensorimotor inhibitory mechanisms, whereas low-frequency RSS (LF-RSS) increases them. However, direct testing on affected body parts was not conducted. This study aims to investigate whether RSS applied directly to forearm muscles involved in focal hand dystonia can modulate cortical inhibitory mechanisms and clinical symptoms. We applied HF-RSS and LF-RSS, the latter either synchronously or asynchronously, on forearm muscles involved in dystonia. Outcome measures included paired-pulse somatosensory evoked potentials, spatial lateral inhibition measured by double-pulse somatosensory evoked potentials, short intracortical inhibition tested with transcranial magnetic stimulation, electromyographic activity from dystonic muscles, and behavioral measures of hand function. Both synchronous and asynchronous low-frequency somatosensory stimulation improved cortical inhibitory interactions, indicated by increased short intracortical inhibition and lateral spatial inhibition, as well as decreased amplitude of paired-pulse somatosensory evoked potentials. Opposite effects were observed with high-frequency stimulation. Changes in electrophysiological markers were paralleled by behavioral outcomes: although low-frequency stimulations improved hand function tests and reduced activation of dystonic muscles, high-frequency stimulation operated in an opposite direction. Our findings confirm the presence of abnormal homeostatic plasticity in response to RSS in the sensorimotor system of patients with dystonia, specifically in inhibitory circuits. Importantly, this aberrant response can be harnessed for therapeutic purposes through the application of low-frequency electrical stimulation directly over dystonic muscles. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impaired Hippocampal Long-Term Potentiation and Memory Deficits upon Haploinsufficiency of MDGA1 Can Be Rescued by Acute Administration of D-Cycloserine.

The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory-inhibitory (E/I) balance. Mdga1-/- mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/- mice. As observed in Mdga1-/- mice, Mdga1+/- mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/- mice, while having no such effect on Mdga1-/- mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.

Resting-state functional connectivity involved in tactile orientation processing

BackgroundGrating orientation discrimination (GOD) is commonly used to assess somatosensory spatial processing. It allows discrimination between parallel and orthogonal orientations of tactile stimuli applied to the fingertip. Despite its widespread application, the underlying mechanisms of GOD, particularly the role of cortico-cortical interactions and local brain activity in this process, remain elusive. Therefore, we aimed to investigate how a specific cortico-cortical network and inhibitory circuits within the primary somatosensory cortex (S1) and secondary somatosensory cortex (S2) contribute to GOD. MethodsIn total, 51 healthy young adults were included in our study. We recorded resting-state magnetoencephalography (MEG) and somatosensory-evoked magnetic field (SEF) in participants with open eyes. We converted the data into a source space based on individual structural magnetic resonance imaging. Next, we estimated S1- and S2-seed resting-state functional connectivity (rs-FC) at the alpha and beta bands through resting-state MEG using the amplitude envelope correlation method across the entire brain (i.e., S1/S2-seeds × 15,000 vertices × two frequencies). We assessed the inhibitory response in the S1 and S2 from SEFs using a paired-pulse paradigm. We automatically measured the GOD task in parallel and orthogonal orientations to the index finger, applying various groove widths with a custom-made device. ResultsWe observed a specific association between the GOD threshold (all P < 0.048) and the alpha rs-FC in the S1–superior parietal lobule and S1–adjacent to the parieto-occipital sulcus (i.e., lower rs-FC values corresponded to higher performance). In contrast, no association was observed between the local responses and the threshold. DiscussionThe results of this study underpin the significance of specific cortico-cortical networks in recognizing variations in tactile stimuli.

Short-latency afferent inhibition is reduced with cold-water immersion of a limb and remains reduced after removal from the cold stimulus.

The experience of pain that is induced by extremely cold temperatures can exert a modulatory effect on motor cortex circuitry. Although it is known that immersion of a single limb in very cold water can increase corticomotor excitability it is unknown how afferent input to the cortex shapes excitatory and inhibitory processes. Therefore, the purpose of this study was to examine motor-evoked potentials (MEP), short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI) in response to immersion of a single hand in cold water. Transcranial magnetic stimulation (TMS) was used to assess MEPs, and peripheral nerve stimulation of the median nerve paired with TMS was used to measure SAI and LAI in motor circuits of the ipsilateral hemisphere. Measurements were obtained from electromyography (EMG) of the first dorsal interosseous (FDI) at baseline, during cold-water immersion, and during recovery from cold-water immersion. The intervention caused unconditioned MEPs to increase during exposure to the cold stimulus (P=0.008) which then returned to baseline levels once the hand was removed from the cold water. MEP responses were decoupled from SAI responses, where SAI was reduced during exposure to the cold stimulus (P=0.005) and remained reduced compared to baseline when the hand was removed from the cold water (P=0.002). The intervention had no effect on LAI. The uncoupling of SAI from MEPs during the recovery period suggests that the mechanisms underlying the modulation of corticospinal excitability by sensory input may be distinct from those affecting intracortical inhibitory circuits. HIGHLIGHTS: What is the central question of this study? Does immersion of a limb in very cold water influence corticospinal excitability and the level of afferent inhibition exerted on motor cortical circuits? What is the main finding and its importance? In additional to perception of temperature, immersion in 6°C water also induced perceptions of pain. Motor evoked potential (MEP) amplitude increased during immersion, and short-latency afferent inhibition (SAI) of the motor cortex was reduced during immersion; however, these responses differed after the limb was removed from the cold stimulus, as MEPs returned to normal levels while SAI remained suppressed.

Fast-spiking interneuron detonation drives high-fidelity inhibition in the olfactory bulb.

Inhibitory circuits in the mammalian olfactory bulb (OB) dynamically reformat olfactory information as it propagates from peripheral receptors to downstream cortex. To gain mechanistic insight into how specific OB interneuron types support this sensory processing, we examine unitary synaptic interactions between excitatory mitral and tufted cells (MTCs), the OB projection neurons, and a conserved population of anaxonic external plexiform layer interneurons (EPL-INs) using pair and quartet whole-cell recordings in acute mouse brain slices. Physiological, morphological, neurochemical, and synaptic analyses divide EPL-INs into distinct subtypes and reveal that parvalbumin-expressing fast-spiking EPL-INs (FSIs) perisomatically innervate MTCs with release-competent dendrites and synaptically detonate to mediate fast, short-latency recurrent and lateral inhibition. Sparse MTC synchronization supralinearly increases this high-fidelity inhibition, while sensory afferent activation combined with single-cell silencing reveals that individual FSIs account for a substantial fraction of total network-driven MTC lateral inhibition. OB output is thus powerfully shaped by detonation-driven high-fidelity perisomatic inhibition.