Journal of Neuroscience最新文献

The subiculum represents a crucial brain pivot in regulating seizure generalization in temporal lobe epilepsy (TLE), primarily through a synergy of local GABAergic and long-projecting glutamatergic signaling. However, little is known about how subicular GABAergic interneurons are involved in a cell-type-specific way. Here, employing Ca²⁺ fiber photometry, retrograde monosynaptic viral tracing, and chemogenetics in epilepsy models of both male and female mice, we elucidate circuit reorganization patterns mediated by subicular cell-type-specific interneurons and delineate their functional disparities in seizure modulation in TLE. We reveal distinct functional dynamics of subicular parvalbumin+ and somatostatin+ interneurons during secondary generalized seizure. These interneuron subtypes have their biased circuit organizations in terms of both input and output patterns, which undergo distinct reorganization in chronic epileptic condition. Notably, somatostatin+ interneurons exert more effective feedforward inhibition onto pyramidal neurons compared with parvalbumin+ interneurons, which engenders consistent antiseizure effects in TLE. These findings provide an improved understanding of different subtypes of subicular interneurons in circuit reorganization in TLE and supplement compelling proofs for precise treatment of epilepsy by targeting subicular somatostatin+ interneurons.

The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly, the function of the NMJ is to transduce nerve action potentials into muscle fiber action potentials (MFAPs). Efficient neuromuscular transmission requires both cholinergic signaling, responsible for generation of endplate potentials (EPPs), and excitation, the amplification of the EPP by postsynaptic voltage-gated sodium channels (Nav1.4) to generate the MFAP. In contrast to the cholinergic component, the signaling pathways that organize Nav1.4 and mediate muscle fiber excitability are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as the main organizer of acetylcholine receptors AChRs), also binds BMPs via its Ig3 domain and shapes BMP-induced signaling and transcriptional output. Here, using mice lacking the MuSK Ig3 domain ('ΔIg3-MuSK'), we probed the role of this domain at the NMJ. NMJs formed in ΔIg3-MuSK animals with pre- and post- synaptic specializations aligned at all ages examined. However, the ΔIg3-MuSK postsynaptic apparatus was fragmented from the first weeks of life. Synaptic electrophysiology showed that spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable at WT and ΔIg3-MuSK NMJs. However, single fiber electromyography revealed that nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal as evidenced by jitter and blocking. Further, nerve-evoked compound muscle action potentials and muscle force production were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK NMJs, but not at the sarcolemma broadly, indicating that the observed excitability defects result from impaired synaptic localization of this ion channel. We propose that MuSK plays distinct, domain-specific roles at the NMJ: the Ig1 domain mediates agrin-LRP4 mediated AChR localization, while the Ig3 domain maintains postsynaptic Nav1.4 density, conferring the muscle excitability required to amplify cholinergic signals and trigger action potentials.Significance Statement The neuromuscular junction (NMJ) is required for nerve-evoked muscle contraction and movement, and its function is compromised during aging and disease. Though the mechanisms underlying neurotransmitter release and cholinergic response at this synapse have been studied extensively, the machinery necessary for nerve-evoked muscle excitation are incompletely characterized. We show that the Ig3 domain of MuSK (muscle-specific kinase) regulates NMJ structure and the localization of voltage-gated sodium channels necessary for nerve-evoked muscle fiber excitation and force production. This function of MuSK is structurally and mechanistically distinct from its role in organizing cholinergic machinery. The Ig3 domain of MuSK thus emerges as a target for selectively modulating excitability, which is defective in conditions such as congenital myasthenic syndromes and age-related muscle weakness.

Despite significant strides in gender equity, the Nobel Prizes in STEM fields continue to exhibit glaring disparities in the recognition of women's contributions to science. Thirty years ago, only 3% of Nobel laureates in science were women; today, that number has increased marginally to 4%, raising the critical question: Why "still" so few? This opinion piece examines systemic inequities and structural barriers that hinder the equitable acknowledgment of women's and underrepresented groups’ contributions to science. Data reveal that while women now comprise a significant proportion of degree recipients and workforce entrants in fields such as biomedical research and chemistry, their representation among Nobel laureates remains disproportionately low. Furthermore, racial inequities exacerbate the lack of diversity, with no Black individuals receiving a Nobel Prize in STEM fields to date. The article advocates for transformative changes in academic and research ecosystems to dismantle the power structures and biases that sustain these inequities. It calls for intentional strategies to support, empower, and recognize women and underrepresented scientists, emphasizing the need for inclusive metrics of success. Drawing on personal experiences and the inspirational achievements of past women laureates, the author underscores the urgency of creating equitable pathways to scientific recognition. The piece concludes with a hopeful vision of a future where diversity and inclusion in Nobel recognitions reflect the rich talent and innovation present across all demographics in STEM.

Predictive updating of an object's spatial coordinates from pre-saccade to post-saccade contributes to stable visual perception. Whether object features are predictively remapped remains contested. We set out to characterise the spatiotemporal dynamics of feature processing during stable fixation and active vision. To do so, we applied multivariate decoding methods to electroencephalography (EEG) data collected while human participants (male and female) viewed brief visual stimuli. Stimuli appeared at different locations across the visual field at either high or low spatial frequency (SF). During fixation, classifiers were trained to decode SF presented at one parafoveal location and cross-tested on SF from either the same, adjacent or more peripheral locations. When training and testing on the same location, SF was classified shortly after stimulus onset (∼79 ms). Decoding of SF at locations farther from the trained location emerged later (∼144 - 295 ms), with decoding latency modulated by eccentricity. This analysis provides a detailed time course for the spread of feature information across the visual field. Next, we investigated how active vision impacts the emergence of SF information. In the presence of a saccade, the decoding time of peripheral SF at parafoveal locations was earlier, indicating predictive anticipation of SF due to the saccade. Crucially however, this predictive effect was not limited to the specific remapped location. Rather, peripheral SF was correctly classified, at an accelerated time course, at all parafoveal positions. This indicates spatially coarse, predictive anticipation of stimulus features during active vision, likely enabling a smooth transition on saccade landing.Significance Statement Maintaining a continuous representation of object features across saccades is vital for stable vision. In order to characterise the spatiotemporal dynamics of stimulus feature representation in the brain, we presented stimuli at a high and low spatial frequency at multiple locations across the visual field. Applying EEG-decoding methods we tracked the neural representation of spatial frequency during both stable fixation and active vision. Using this approach, we provide a detailed time course for the spread of feature information across the visual field during fixation. In addition, when a saccade is imminent, we show that peripheral spatial frequency is predictively represented in anticipation of the post-saccadic input.

Gamma rhythm (30-70 Hz), thought to represent the interactions between excitatory and inhibitory populations, can be induced by presenting achromatic gratings in the primary visual cortex (V1) and is sensitive to stimulus properties such as size and contrast. In addition, gamma occurs in short bursts and shows a "frequency falloff" effect where its peak frequency is high after stimulus onset and slowly decreases to a steady state. Recently, these size-contrast properties and temporal characteristics were replicated in a self-oscillating Wilson-Cowan (WC) model operating as an inhibition stabilized network (ISN), stimulated by Ornstein-Uhlenbeck (OU) type inputs. In particular, frequency falloff was explained by delayed and slowly accumulated inputs arriving at local inhibitory populations. We hypothesized that if the stimulus is preceded by another higher contrast stimulus, frequency falloff could be abolished or reversed, since the excessive inhibition will now take more time to dissipate. We presented gratings at different contrasts consecutively to two female monkeys while recording gamma using microelectrode arrays in V1 and confirmed this prediction. Further, this model also replicated a characteristic pattern of gamma frequency modulation to counter-phasing stimuli as reported previously. These phenomena were also replicated by an ISN model subject to slow adaptation in feedforward excitatory input. Thus, ISN model with delayed surround input or adapted feedforward input replicates gamma frequency responses to time-varying contrasts.

Action potentials (spikes) are regenerated at each node of Ranvier during saltatory transmission along a myelinated axon. The high density of voltage-gated sodium channels required by nodes to reliably transmit spikes increases the risk of ectopic spike generation in the axon. Here we show that ectopic spiking is avoided because K_V1 channels prevent nodes from responding to slow depolarization; instead, axons respond selectively to rapid depolarization because K_V1 channels implement a high-pass filter. To characterize this filter, we compared spike initiation properties in the soma and axon of CA1 pyramidal neurons from mice of both sexes, using spatially restricted photoactivation of channelrhodopsin-2 (ChR2) to evoke spikes in either region while simultaneously recording at the soma. Somatic photostimulation evoked repetitive spiking whereas axonal photostimulation evoked transient spiking. Blocking K_V1 channels converted the axon photostimulation response to repetitive spiking and encouraged spontaneous ectopic spike initiation in the axon. According to computational modeling, the high-pass filter implemented by K_V1 channels matches the axial current waveform associated with saltatory conduction, enabling axons to faithfully transmit digital signals by maximizing their signal-to-noise ratio for this task. Specifically, a node generates a single spike only when rapidly depolarized, which is precisely what occurs during saltatory conduction when a pulse of axial current (triggered by a spike occurring at the upstream node) reaches the next node. The soma and axon use distinct spike initiation mechanisms (filters) appropriate for the task required of each region, namely analog-to-digital transduction in the soma vs. digital signal transmission in the axon.Significance statement Neurons use action potentials, or spikes, to transmit information reliably over long distances. Spikes can be initiated through different dynamical mechanisms depending on the types of ion channels involved. The input required to evoke spikes differs depending on spike initiation dynamics. Using targeted optogenetic stimulation to evoke spikes in different subcellular compartments, we show that the soma and axon of pyramidal neurons use distinct spike initiation mechanisms suited to the distinct role of each compartment. Specifically, the soma uses a low-pass filter supporting analog-to-digital transduction whereas the axon uses K_V1 channels to implement a high-pass filter seemingly optimized for transmitting spikes. Importantly, the high-pass filter prevents the axon from generating ectopic spikes if slowly depolarized.

The hippocampus supports a multiplicity of functions, with the dorsal region contributing to spatial representations and memory, and the ventral hippocampus (vH) being primarily involved in emotional processing. While spatial encoding has been extensively investigated, how the vH activity is tuned to emotional states, e.g. to different anxiety levels, is not well understood. We developed an adjustable linear track maze (aLTM) for male mice with which we could induce a scaling of behavioral anxiety levels within the same spatial environment. Using in vivo single-unit recordings, optogenetic manipulations and population-level analysis, we examined the changes and causal effects of vH activity at different anxiety levels. We found that anxiogenic experiences activated the vH and that this activity scaled with increasing anxiety levels. We identified two processes that contributed to this scaling of anxiety-related activity: increased tuning and successive remapping of neurons to the anxiogenic compartment. Moreover, optogenetic inhibition of the vH reduced anxiety across different levels, while anxiety-related activity scaling could be decoded using a linear classifier. Collectively, our findings position the vH as a critical limbic region that functions as an 'anxiometer' by scaling its activity based on perceived anxiety levels. Our discoveries go beyond the traditional theory of cognitive maps in the hippocampus underlying spatial navigation and memory, by identifying hippocampal mechanisms selectively regulating anxiety.Significant statement This study reveals how the ventral hippocampus (vH) functions as an "anxiometer", tuning its activity to different anxiety levels. Using an adjustable linear track maze (aLTM) for mice, we demonstrated that vH activity scales with increased anxiety. By recording single-neuron activity and performing optogenetic manipulation of vH during the aLTM task, we identified key neuronal mechanisms for neuronal scaling during anxiety. Additionally, a linear classifier was used to highlight anxiety-related activity scaling. Our findings advance the understanding of hippocampal function beyond spatial navigation and memory, offering new insights into how the brain regulates anxiety at the neuronal level.

GlyT2-positive interneurons, Golgi and Lugaro cells, reside in the input layer of the cerebellar cortex in a key position to influence information processing. Here, we examine the contribution of GlyT2-positive interneurons to network dynamics in Crus 1 of mouse lateral cerebellar cortex during free whisking. We recorded neuronal population activity using Neuropixels probes before and after chemogenetic downregulation of GlyT2-positive interneurons in male and female mice. Under resting conditions, cerebellar population activity reliably encoded whisker movements. Reductions in the activity of GlyT2-positive cells produced mild increases in neural activity which did not significantly impair these sensorimotor representations. However, reduced Golgi and Lugaro cell inhibition did increase the temporal alignment of local population network activity at the initiation of movement. These network alterations had variable impacts on behavior, producing both increases and decreases in whisking velocity. Our results suggest that inhibition mediated by GlyT2-positive interneurons primarily governs the temporal patterning of population activity, which in turn is required to support downstream cerebellar dynamics and behavioral coordination.