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Applications · Chemistry and Drug Discovery

Nima Shoghi, Yuxuan Liu, Yuning Shen, Rob Brekelmans, Pan Li, Quanquan Gu

Molecular dynamics (MD) simulations remain the gold standard for studying protein dynamics, but their computational cost limits access to biologically relevant timescales. Recent generative models have shown promise in accelerating simulations, yet they struggle with long-horizon generation due to architectural constraints, error accumulation, and inadequate modeling of spatiotemporal dynamics. We present STAR-MD (Spatio-Temporal Autoregressive Rollout for Molecular Dynamics), a scalable SE(3)-equivariant diffusion model that generates physically plausible protein trajectories over microsecond timescales. Our key innovation is a causal diffusion transformer with joint spatiotemporal attention that efficiently captures complex space-time dependencies while avoiding the memory bottlenecks of existing methods. On the standard ATLAS benchmark, STAR-MD achieves state-of-the-art performance across all metrics--substantially improving conformational coverage, structural validity, and dynamic fidelity compared to previous methods. STAR-MD successfully extrapolates to generate stable microsecond-scale trajectories where baseline methods fail catastrophically, maintaining high structural quality throughout the extended rollout. Our comprehensive evaluation reveals severe limitations in current models for long-horizon generation, while demonstrating that STAR-MD's joint spatiotemporal modeling enables robust dynamics simulation at biologically relevant timescales, paving the way for accelerated exploration of protein function. Project page: https://bytedance-seed.github.io/ConfRover/starmd

Applications · Chemistry and Drug Discovery

Jiayu Qin, Zhengquan Luo, Guy Tadmor, Changyou Chen, David Zeevi, Zhiqiang Xu

Predicting molecule-protein interactions (MPIs) is a fundamental task in computational biology, with crucial applications in drug discovery and molecular function annotation. However, existing MPI models face two major challenges. First, the scarcity of labeled molecule-protein pairs significantly limits model performance, as available datasets capture only a small fraction of biological relevant interactions. Second, most methods rely solely on molecular and protein features, ignoring broader biological context—such as genes, metabolic pathways, and functional annotations—that could provide essential complementary information. To address these limitations, our framework first aggregates diverse biological datasets, including molecular, protein, genes and pathway-level interactions, and then develop an optimal transport-based approach to generate high-quality pseudo-labels for unlabeled molecule-protein pairs, leveraging the underlying distribution of known interactions to guide label assignment. By treating pseudo-labeling as a mechanism for bridging disparate biological modalities, our approach enables the effective use of heterogeneous data to enhance MPI prediction. We evaluate our framework on multiple MPI datasets including virtual screening tasks and protein retrieval tasks, demonstrating substantial improvements over state-of-the-art methods in prediction accuracies and zero shot ability across unseen interactions. Beyond MPI prediction, our approach provides a new paradigm for leveraging diverse biological data sources to tackle problems traditionally constrained by single or bi-modal learning, paving the way for future advances in computational biology and drug discovery.

Applications · Genetics, Cell Biology, Health, etc

Yize Zhou, Haorui Li, Shengchao Liu

Chromosomes are the carriers of genetic information. Further understanding their 3D structure can help reveal gene-regulatory mechanisms and cellular functions. However, high-resolution 3D structures are often missing due to the high cost and inherent noise of experimental screening. A standard pipeline for reconstructing the chromosome 3D structure first applies the single-cell Hi-C high-throughput screening method to measure pairwise interactions between DNA fragments at different resolutions; then it adopts computational methods to reconstruct the 3D structures from these contacts. These include traditional numerical methods and deep learning models, which struggle with limited model expressiveness and poor generalization across resolutions. To handle this issue, we propose InertialGenome, a novel transformer-based framework for robust and resolution-agnostic chromosome reconstruction. InertialGenome first adopts the inertial frame for the pose canonicalization. Then, based on such an invariant pose, it proposes a Transformer with geometry-aware positional encoding, leveraging Nyström estimation. To verify the effectiveness of InertialGenome, we conduct experiments on two single-cell 3D reconstruction datasets with four resolutions, reaching superior performance over all four computational baselines. Additionally, we observe that the 3D structure reconstructed by InertialGenome is more in line with the results of real experimental results on two functional verification tasks. Finally, we leverage InertialGenome for cross-resolution transfer learning, yielding up to a 5\% improvement from low to high resolution. The source code is available at https://github.com/yize1203/InertialGenome.

Applications · Neuroscience, Cognitive Science

Chanwoo Chun, Abdulkadir Canatar, SueYeon Chung, Daniel Lee

The global dimensionality of a neural representation manifold provides rich insight into the computational process underlying both artificial and biological neural networks. However, all existing measures of global dimensionality are sensitive to the number of samples, i.e., the number of rows and columns of the sample matrix. We show that, in particular, the participation ratio of eigenvalues, a popular measure of global dimensionality, is highly biased with small sample sizes, and propose a bias-corrected estimator that is more accurate with finite samples and with noise. On synthetic data examples, we demonstrate that our estimator can recover the true known dimensionality. We apply our estimator to neural brain recordings, including calcium imaging, electrophysiological recordings, and fMRI data, and to the neural activations in a large language model, and show that our estimator is invariant to the sample size. Finally, our estimators can additionally be used to measure the local dimensionalities of curved neural manifolds by weighting the finite samples appropriately.

Applications · Chemistry and Drug Discovery

Yingheng Wang, Yingheng Wang

Self-supervised training of language models (LMs) has seen great success for protein sequences in learning meaningful representations and for generative drug design. Most protein LMs are based on the Transformer architecture trained on individual proteins with short context lengths. Such protein LMs cannot extrapolate to longer proteins and protein complexes well. They also fail to account for the underlying biological mechanisms carried out by biomolecular interactions and dynamics i.e., proteins often interact with other proteins, molecules, and pathways in complex biological systems. In this work, we propose LC-PLM based on an alternative protein LM architecture, BiMamba-S, built upon selective structured state-space models, to learn high-quality universal protein representations at the amino acid token level using masked language modeling. We also introduce its graph-contextual variant, LC-PLM, which contextualizes protein-protein interaction (PPI) graphs for a second stage of training. LC-PLM demonstrates favorable neural scaling laws, better length extrapolation capability, and up to 30% and 16% improvements on protein downstream tasks compared to Transformer-based ESM-2 when trained with 100B and 1T tokens, respectively. LC-PLM-G further trained within the context of PPI graphs shows promising results on protein structure and function prediction tasks. Our study demonstrates the benefit of increasing the context size with computationally efficient LM architecture (e.g., structured state space models) in learning universal protein representations and incorporating molecular interaction contexts contained in biological graphs. Model is available at github.com/amazon-science/LC-PLM.

Guobin Shen, Jindong Li, Tenglong Li, Dongcheng Zhao, Yi Zeng

Spiking Neural Networks (SNNs) hold promise for energy-efficient, biologically inspired computing. We identify substantial information loss during spike transmission, linked to temporal dependencies in traditional Leaky Integrate-and-Fire (LIF) neurons--a key factor potentially limiting SNN performance. Existing SNN architectures also underutilize modern GPUs, constrained by single-bit spike storage and isolated weight-spike operations that restrict computational efficiency. We introduce SpikePack, a neuron model designed to reduce transmission loss while preserving essential features like membrane potential reset and leaky integration. SpikePack achieves constant \mathcal O (1) time and space complexity, enabling efficient parallel processing on GPUs and also supporting serial inference on existing SNN hardware accelerators. Compatible with standard Artificial Neural Network (ANN) architectures, SpikePack facilitates near-lossless ANN-to-SNN conversion across various networks. Experimental results on tasks such as image classification, detection, and segmentation show SpikePack achieves significant gains in accuracy and efficiency for both directly trained and converted SNNs over state-of-the-art models. Tests on FPGA-based platforms further confirm cross-platform flexibility, delivering high performance and enhanced sparsity. By enhancing information flow and rethinking SNN-ANN integration, SpikePack advances efficient SNN deployment across diverse hardware platforms.

Lanning Zhang, Ying Zhou, Fei Gao, Ziyun Li, Maoying Qiao, Jinlan Xu, Nannan Wang

Although deep neural networks have achieved remarkable success in various computer vision tasks, they face significant challenges in degraded image understanding due to domain shifts caused by quality variations. Drawing biological inspiration from the human visual system (HVS), which dynamically adjusts perception strategies through contrast gain control and selective attention to salient regions, we propose Quality-Adaptive Normalization (Q-Norm) - a novel normalization method that learns adaptive parameters guided by image quality features. Our approach addresses two critical limitations of conventional normalization techniques: 1) Domain Covariance Shift: Existing methods fail to align feature distributions across different quality domains. Q-Norm implicitly achieves cross-domain alignment through quality-aware parameter adaptation without explicit loss functions. 2) Biological Plausibility: By mimicking HVS's contrast normalization mechanisms and attention-based feature selection, Q-Norm dynamically adjusts the mean and variance parameters using a pre-trained quality assessment model, ensuring robustness to image degradation. Extensive experiments across multiple tasks (image classification, semantic segmentation, object detection) demonstrate that Q-Norm consistently outperforms baseline methods on low-quality images. Code has been released at https://github.com/IIP-Lab-XDU/Q-Norm.

Manahil Raza, Ayesha Azam, Talha Qaiser, Nasir Rajpoot

Current multimodal fusion approaches in computational oncology primarily focus on integrating multi-gigapixel histology whole slide images (WSIs) with genomic or transcriptomic data, demonstrating improved survival prediction. We hypothesize that incorporating pathology reports can further enhance prognostic performance. Pathology reports, as essential components of clinical workflows, offer readily available complementary information by summarizing histopathological findings and integrating expert interpretations and clinical context. However, fusing these modalities poses challenges due to their heterogeneous nature. WSIs are high-dimensional, each containing several billion pixels, whereas pathology reports consist of concise text summaries of varying lengths, leading to potential modality imbalance. To address this, we propose a prototype-based approach to generate balanced representations, which are then integrated using a Transformer-based fusion model for survival prediction that we term PS3 (Predicting Survival from Three Modalities). Specifically, we present: (1) Diagnostic prototypes from pathology reports, leveraging self-attention to extract diagnostically relevant sections and standardize text representation; (2) Histological prototypes to compactly represent key morphological patterns in WSIs; and (3) Biological pathway prototypes to encode transcriptomic expressions, accurately capturing cellular functions. PS3, the three-modal transformer model, processes the resulting prototype-based multimodal tokens and models intra-modal and cross-modal interactions across pathology reports, WSIs and transcriptomic data. The proposed model outperforms state-of-the-art methods when evaluated against clinical, unimodal and multimodal baselines on six datasets from The Cancer Genome Atlas (TCGA). The code will be released upon publication.

Mainak Biswas, Ambedkar Dukkipati, Devarajan Sridharan

Deep learning models deployed in real-world applications (e.g., medicine) face challenges because source models do not generalize well to domain-shifted target data. Many successful domain adaptation (DA) approaches require full access to source data or reliably labeled target data. Yet, such requirements are unrealistic in scenarios where source data cannot be shared either because of privacy concerns or because it is too large and incurs prohibitive storage or computational costs. Moreover, resource constraints may limit the availability of labeled targets. We illustrate this challenge in a neuroscience setting where source data are unavailable, labeled target data are meager, and predictions involve continuous-valued outputs. We build upon Contradistinguisher (CUDA), an efficient framework that learns a shared model across the labeled source and unlabeled target samples, without intermediate representation alignment. Yet, CUDA was designed for unsupervised DA, with full access to source data, and for classification tasks. We develop CRAFT -- a Contradistinguisher-based Regularization Approach for Flexible Training -- for source-free (SF), semi-supervised transfer of pretrained models in regression tasks. We showcase the efficacy of CRAFT in two neuroscience settings: gaze prediction with electroencephalography (EEG) data and "brain age" prediction with structural MRI data. For both datasets, CRAFT yielded up to 9% improvement in root-mean-squared error (RMSE) over fine-tuned models when labeled training examples were scarce. Moreover, CRAFT leveraged unlabeled target data and outperformed four competing state-of-the-art source-free domain adaptation models by more than 3%. Lastly, we demonstrate the efficacy of CRAFT on two other real-world regression benchmarks. We propose CRAFT as an efficient approach for source-free, semi-supervised deep transfer for regression that is ubiquitous in biology and medicine.

Tianfang Zhu, Hongyang Zhou, Anan Li

Capturing the spatial patterns of neurons and generating high-fidelity morphological data remain critical challenges in developing biologically realistic large-scale brain network models. Existing methods fail to reconcile anatomical complexity with diversity and computational scalability. We propose MorphoGen, a hierarchical framework integrating global structure prediction through denoising diffusion probabilistic models (DDPMs) with local neurites optimization. The pipeline initiates with DDPM-generated coarse-grained neuronal point clouds, followed by skeletonization and growth-guided linking to derive plausible tree-like structures, and culminates in natural neural fibers refinement via a pragmatic smoothing network. Comprehensive evaluations across three distinct long-range projection neuron datasets demonstrate that the proposed method improves 1-Nearest Neighbor Accuracy by approximately 12% on average compared to state-of-the-art baseline, reduces average training time by around 55%, and aligns the distributions of several morphometrics with real data. This work establishes a novel global-to-local paradigm for neuronal morphology generation, offering a more direct and efficient approach compared to current branch-sequential modeling methods. Code is available at https://github.com/Brainsmatics/MorphoGen.

Xiang Fang, Wanlong Fang, Wei Ji 0008, Tat-Seng Chua

Video-language models are pivotal for tasks such as moment retrieval and highlight detection, yet they often struggle to capture the dynamic, non-linear interactions between temporal video sequences and textual semantics. Existing approaches, relying on static cross-attention or prompt-tuning mechanisms, fail to adaptively model the evolving relationships between modalities, leading to suboptimal alignment and limited generalization. Inspired by systems biology, we propose Reaction-Diffusion Multimodal Fusion (RDMF), a novel framework that reimagines video-language alignment as a reaction-diffusion (RD) process, drawing on the principles of pattern formation introduced by Alan Turing. In RDMF, video features diffuse across time to capture temporal context, while text-video interactions are modeled as non-linear reactions that amplify relevant features and suppress noise, forming emergent patterns akin to biological systems. Leveraging the Gray-Scott RD model, we design a computationally efficient fusion module that integrates video and text representations, supported by rigorous mathematical analysis of stability and convergence using Turing instability criteria. Our framework is theoretically grounded, employing advanced mathematical tools to ensure stable pattern formation, and is practically viable, incorporating standard components like pretrained encoders and DETR-style heads for moment retrieval and saliency prediction. RDMF represents a pioneering interdisciplinary approach, bridging systems biology and multimedia research to address the limitations of conventional multimodal fusion. Preliminary experiments demonstrate its potential to outperform existing methods in identifying salient video moments, offering a new paradigm for video-language tasks. Beyond its immediate applications, RDMF opens avenues for exploring biologically inspired architectures in multimedia, with implications for real-time video analysis, interactive media systems, and cross-disciplinary collaboration between multimedia and systems biology communities.

Yang Li, Xinyi Zeng, Zhe Xue, Pinxian Zeng, Zikai Zhang, Yan Wang 0015

As the third generation of neural networks, spiking neural networks (SNNs) have recently gained widespread attention for their biological plausibility, energy efficiency, and effectiveness in processing neuromorphic datasets. To better emulate biological neurons, various models such as Integrate-and-Fire (IF) and Leaky Integrate-and-Fire (LIF) have been widely adopted in SNNs. However, these neuron models overlook the refractory period, a fundamental characteristic of biological neurons. Research on excitable neurons reveal that after firing, neurons enter a refractory period during which they are temporarily unresponsive to subsequent stimuli. This mechanism is critical for preventing over-excitation and mitigating interference from aberrant signals. Therefore, we propose a simple yet effective method to incorporate the refractory period into spiking LIF neurons through spike-triggered threshold dynamics, termed RPLIF. Our method ensures that each spike accurately encodes neural information, effectively preventing neuron over-excitation under continuous inputs and interference from anomalous inputs. Incorporating the refractory period into LIF neurons is seamless and computationally efficient, enhancing robustness and efficiency while yielding better performance with negligible overhead. To the best of our knowledge, RPLIF achieves state-of-the-art performance on Cifar10-DVS(82.40%) and N-Caltech101(83.35%) with fewer timesteps and demonstrates superior performance on DVS128 Gesture(97.22%) at low latency.

Changshuo Wang 0001, Shuting He, Xiang Fang, Fangzhe Nan, Prayag Tiwari

The domain gap between pretraining data (e.g., ImageNet, LUPerson) and downstream ReID datasets often leads to suboptimal performance when directly fine-tuning pretrained models. While existing methods attempt to bridge this gap by incorporating additional modalities (e.g., text, 3D data) or visual cues (e.g., pose, body masks), these approaches introduce two key limitations: (1) they may distract the model with irrelevant factors like background clutter or clothing variations, and (2) they inevitably increase computational overhead during inference. To address these issues, we propose the Weak Saliency Feedback Transformer (WSFFormer), inspired by the feedback mechanisms in biological visual systems. Unlike traditional one-way feature propagation, WSFFormer employs an adaptive feedback loop during training to enhance low-response regions, enabling the model to capture richer and more discriminative features. The WSFFormer introduces three key components: (1) The Lateral Feedback Module (LFM) mimics retinal lateral inhibition by adaptively suppressing high-response regions and amplifying weak discriminative features, forcing attention on subtle details; (2) The Progressive Feedback Module (PFM) refines feedback through deep-to-shallow closed-loop propagation, blending high-level semantics with spatial details; (3) The Feedback Sensitive Entropy Loss (FSE Loss) optimizes target-domain adaptation by quantifying divergence between forward and feedback-corrected features. Experiments on holistic/occluded ReID benchmarks show WSFFormer outperforms ViT/Swin-based SOTA methods without extra inference cost.

Zhicheng Lian, Lizhi Wang 0001, Hua Huang 0001

Automatic speech quality assessment aims to quantify subjective human perception of speech through computational models to reduce the need for labor-consuming manual evaluations. While models based on deep learning have achieved progress in predicting mean opinion scores (MOS) to assess synthetic speech, the neglect of fundamental auditory perception mechanisms limits consistency with human judgments. To address this issue, we propose an auditory perception guided-MOS prediction model (APG-MOS) that synergistically integrates auditory modeling with semantic analysis to enhance consistency with human judgments. Specifically, we first design a perceptual module, grounded in biological auditory mechanisms, to simulate cochlear functions, which encodes acoustic signals into biologically aligned electrochemical representations. Secondly, we propose a residual vector quantization (RVQ)-based semantic distortion modeling method to quantify the degradation of speech quality at the semantic level. Finally, we design a residual cross-attention module, coupled with a progressive learning strategy, to enable multimodal fusion of encoded electrochemical signals and semantic representations. Experiments demonstrate that APG-MOS achieves superior performance on two primary benchmarks. The implementation code is available at https://github.com/BNU-ERC-ITEA/APG-MOS.

Ruian He, Zixian Zhang, Ri Cheng, Weimin Tan, Bo Yan 0001

Live-cell imaging is a powerful tool for studying dynamic subcellular processes by capturing the spatiotemporal organization of the biological microenvironment. However, limitations due to phototoxicity and photobleaching prevent microscopes from achieving high frame rates and high-quality images. Although current deep learning methods can enhance both frame rates and image resolution without compromising cell health, they often overlook the continuity of subcellular trajectories, which leads to discontinuous temporal modeling. It also incurs prohibitive computational costs due to exhaustive correlation computation that hinder real-time applications. To address these issues with high efficiency, we propose Trajectory Space-Time Super-Resolution (T-STSR), a method designed to boost frame rates and resolution in fast subcellular imaging while significantly reducing computational overhead. Our approach incorporates Spatial-Temporal Trajectory Modeling (STTM), which learns a state-space model over spatiotemporal slices to reconstruct particle trajectories at low cost. In addition, our novel Trajectory-Aware Loss randomly subsamples trajectory data during training, promoting continuous trajectory representation and mitigating noise with minimal additional computation. We validated T-STSR on both synthesized and real-world datasets with various particle types and noise conditions, demonstrating that our method achieves superior restoration results while saving 75% inference time compared to the previous SOTA model.

Yeongho Kim, Yuyeong Kim, Geon Lee, Kijung Shin

Graphs are widely used to model complex systems across various domains, including social networks and biological systems. A key task in graph analysis is identifying recurring structural patterns, known as graphlets, which capture connectivity among a fixed-size subset of nodes. While graphlets have been extensively applied in tasks such as measuring graph similarity and identifying communities, conventional graphlets focus only on direct connections between nodes. This limitation overlooks potential insights from more distant relationships within the graph structure. In this paper, we introduce (d,s)-graphlets, a generalization of size-s graphlets that incorporates indirect connections between nodes up to distance d. This new formulation provides a more fine-grained and comprehensive understanding of local graph structures. To efficiently count (d,s)-graphlets in a graph, we present EDGE, an exact counting algorithm that employs optimized combinatorial techniques to significantly reduce computational complexity compared to naive enumeration. Our empirical analysis across diverse real-world datasets demonstrates that (d,s)-graphlets provide superior graph characterization, outperforming conventional graphlets in a graph clustering task. Moreover, our case studies show that (d,s)-graphlets uncover non-trivial insights that would remain undiscovered when using conventional graphlets.

Kaiyu Chen, Dong Wen 0001, Hanchen Wang 0001, Zhengyi Yang 0001, Wenjie Zhang 0001, Xuemin Lin 0001

The k-clique structure in graphs has been investigated in various real-world applications, such as community detection in complex networks, functional module discovery in biological networks, and link spam detection in web graphs. Despite extensive research on k-clique enumeration, the large number of k-cliques in many graphs poses a challenge for practical application and computation. To address this, we explore the k-clique τ-cover problem, a generalization of the vertex cover problem. The problem aims to find a small set of vertices that can effectively represent all k-cliques in the graph. We prove the NP-hardness of finding the minimum k-clique cover. We propose a hierarchical solution that computes a small cover without enumerating k-cliques. Extensive experiments on real-world graphs verify the efficiency and effectiveness of our solution.

Tianyi Zhang 0011, Gaurav Gupta, Aditya Desai, Anshumali Shrivastava

Gene sequence search is a fundamental operation in computational genomics with broad applications in medicine, evolutionary biology, metagenomics, and more. Due to the petabyte scale of genome archives, most gene search systems now use hashing-based data structures such as Bloom Filters (BF). The state-of-the-art systems such as Compact bit-slicing signature index (COBS) and Repeated And Merged Bloom filters (RAMBO) use BF with Random Hash (RH) functions for gene representation and identification. The standard recipe is to cast the gene search problem as a sequence of membership problems testing if each subsequent gene substring (called kmer) of Q is present in the set of kmers of the entire gene database D. We observe that RH functions, which are crucial to the memory and the computational advantage of BF, are also detrimental to the system performance of gene-search systems. While subsequent kmers being queried are likely very similar, RH, oblivious to any similarity, uniformly distributes the kmers to different parts of potentially large BF, thus triggering excessive cache misses and causing system slowdown. We propose a novel hash function called the Identity with Locality (IDL) hash family, which co-locates the keys close in input space without causing collisions. This approach ensures both cache locality and key preservation. IDL functions can be a drop-in replacement for RH functions and help improve the performance of information retrieval systems. We give a simple but practical construction of IDL function families and show that replacing the RH with IDL functions reduces cache misses by a factor of 5x, thus improving query and indexing times of SOTA methods such as COBS and RAMBO by factors up to 2x without compromising their quality. We also provide a theoretical analysis of the false positive rate of BF with IDL functions. Our hash function is the first study that bridges Locality Sensitive Hash (LSH) and RH to obtain cache efficiency. Our design and analysis could be of independent theoretical interest.

Conghao Xiong, Hao Chen, Joseph J. Y. Sung

Computational pathology, which involves analyzing whole slide images for automated cancer diagnosis, relies on multiple instance learning, where performance depends heavily on the feature extractor and aggregator. Recent Pathology Foundation Models (PFMs), pretrained on large-scale histopathology data, have significantly enhanced both the extractor and aggregator, but they lack a systematic analysis framework. In this survey, we present a hierarchical taxonomy organizing PFMs through a top-down philosophy applicable to foundation model analysis in any domain: model scope, model pretraining, and model design. Additionally, we systematically categorize PFM evaluation tasks into slide-level, patch-level, multimodal, and biological tasks, providing comprehensive benchmarking criteria. Our analysis identifies critical challenges in both PFM development (pathology-specific methodology, end-to-end pretraining, data-model scalability) and utilization (effective adaptation, model maintenance), paving the way for future directions in this promising field. Resources referenced in this survey are available at https://github.com/BearCleverProud/AwesomeWSI.

Kai Sun, Peibo Duan, Levin Kuhlmann, Beilun Wang, Bin Zhang

The Spiking Neural Network (SNN) has drawn increasing attention for its energy-efficient, event-driven processing and biological plausibility. To train SNNs via backpropagation, surrogate gradients are used to approximate the non-differentiable spike function, but they only maintain nonzero derivatives within a narrow range of membrane potentials near the firing threshold—referred to as the surrogate gradient support width gamma. We identify a major challenge, termed the dilemma of gamma: a relatively large gamma leads to overactivation, characterized by excessive neuron firing, which in turn increases energy consumption, whereas a small gamma causes vanishing gradients and weakens temporal dependencies. To address this, we propose a temporal Inhibitory Leaky Integrate-and-Fire (ILIF) neuron model, inspired by biological inhibitory mechanisms. This model incorporates interconnected inhibitory units for membrane potential and current, effectively mitigating overactivation while preserving gradient propagation. Theoretical analysis demonstrates ILIF’s effectiveness in overcoming the gamma dilemma, and extensive experiments on multiple datasets show that ILIF improves energy efficiency by reducing firing rates, stabilizes training, and enhances accuracy. The code is available at github.com/kaisun1/ILIF.