Integrating approaches: NAMs, 3Rs and traditional methods in neuroscience

Nonclinical research in neuroscience is at a critical juncture. While animal-based studies remain essential, particularly for modeling the complexity of neuropsychiatric and neurodegenerative conditions, challenges such as reproducibility issues, limited translational impact, animal welfare, and ethical constraints highlight the need for new approaches in experimental design.

In this context the integration of New Approach Methodologies (NAMs), aligned with the 3Rs (Replacement, Reduction, and Refinement), can complement traditional models and offer tools to strengthen scientific validity while reducing reliance on animal models where feasible. NAMs include in vitro systems, in chemico and in silico modelling, microphysiological systems (organs‑on‑chips and organoids), non‑mammalian models, and ex vivo approaches, among others. Used alone or in hybrid experimental pipelines, NAMs can help refine hypotheses, improve mechanistic understanding, and contribute to the reduction of animal use.

The integration of NAMs and 3Rs in neuroscience research holds promise for improving methodological rigor and advancing human-relevant research. However, successful implementation requires a clear context of use, rigorous validation, standardization, and attention to challenges such as variability, limited recapitulation of neural complexity, and reproducibility. These considerations call for a shift towards hybrid and complementary approaches that combine the strengths of NAMs and traditional models, to produce replicable, mechanistically informed, ethically sound, and translationally meaningful outputs.

The 3Rs framework remains the guiding legal and ethical foundation for animal research, promoting refinement and responsible animal use where in vivo approaches are methodologically required. In parallel, NAMs provide a technological platform to support scientific progress by offering scalable and human-relevant alternatives that can supplement or reduce animal studies. A synergistic approach integrating NAMs within a 3Rs framework can support a common ground for responsible, high-impact neuroscience, reinforcing scientific robustness, improving reproducibility, and enhancing animal welfare.

This Research Topic proposes a multidisciplinary reference framework integrating traditional neuroscience methodologies with New Approach Methodologies (NAMs). The objective is to enable direct methodological cross-validation, identify limitations, and promote complementary use. This framework is aimed at improving reproducibility, reducing experimental bias, and enhancing the translational relevance of neuroscience research.

We welcome contributions presenting methodological innovation, model refinement or enhanced translational study design, whether through NAMs, improved in vivo methods, or through integrated hybrid approaches to enrich our basic understanding of human neurological disease processes in the context of the 3Rs.

Guiding questions:
i) How are the 3Rs contributing to improved research quality and reproducibility in nonclinical neuroscience?
ii) In what ways have 3Rs shaped traditional neuroscience methods towards more translational outcomes?
iii) What are the current best practices and limitations in the implementation of NAMs in neuroscience?
iv) How can NAMs integrate with or replace conventional in vivo neuroscience approaches
v) How can the integration of 3Rs and NAMs support a unified, ethically and scientifically sound future neuroscience frameworks?

We encourage submission of methods articles, original empirical basic or translational research, reviews, perspectives, and opinion that address, but not limited to:

• Experimental planning for reproducibility and animal welfare within the 3R framework.
• Hybrid pipelines integrating NAM and in vivo models
• iPSC-derived brain organoids and assembloids: Modeling psychiatric and neurodegenerative disorders (e.g. Schizophrenia, Autism Spectrum Disorder and Parkinsons’ Disease).
• Microphysiological co-cultures and brain-on-a-chip systems: Modeling neuroinflammation, neurotoxicity, and neural connectivity.
• Cost-efficient use of NAMs: Compound prioritization, neurotoxicity screening, and hypothesis refinement.
• Limitations of 3D brain models and the continued role of in vivo systems.
• Challenges for reproducibility and standardization in NAMs-based neuroscience
• Advanced in vitro systems for neurodegeneration: Modeling disease progression and therapeutic testing using brain-mimetic platforms.
• Data integration across NAMs and animal models: Aligning functional (neuroimaging, electrophysiology, and neurochemistry) and anatomical proxies.
• Computational and AI-guided study design: What role for 3Rs?
• Ethical, and regulatory enablers for NAMs integration: Standards, preregistration, open methods and policy for responsible and scalable adoption in neuroscience.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review

Keywords: 3Rs, NAMs, preclinical studies, reproducibility, brain-mimetic platform, in vivo, neuroinflammation, neurotoxicity, neurodegeneration, animal welfare, iPSC, brain organoids, brain-on-a-chip, 3D models

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.