From animal models to human individuality: Integrative approaches to the study of brain plasticity

https://doi.org/10.1016/j.neuron.2024.10.006

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Introduction

Definition of plasticity: The capacity of organisms to form lasting but reversible structural and related functional changes of neural connections in response to interactions with the environment

Two forms of plasticity:

1. Experience expectant: Enables organisms to meet species-specific affordances

2. Experience dependent: Enables individuals to respond and adapt to specific challenges

Gap between animal models and research with humans:

• Many sophisticated experimental methods used in animal studies are not applicable to humans

• Mechanistic understanding of human brain plasticity often inferred from animal models

  
  

Three components to bridge the gap between animal models and human research

Component 1: Strengthening the methods interface

Enhance interpretability of macroscopic methods in human research:

• Complement molecular and fine-structural measures in animals with macroscopic methods

• Create macroscopic metrics common to both examined species

• Focus on structural MRI (sMRI), including quantitative parametric mapping and in vivo histology

Advances in imaging methods:

1. Quantitative MRI (qMRI)

2. In vivo MRI histology

3. Positron emission tomography (PET)

4. Magnetic resonance spectroscopy (MRS)

5. Imaging of genetically modified animal models

6. Human genome-wide association studies (GWASs)

Challenges in linking animal models to human research:

1. Defining common brain space mapping

2. Aligning data along an ontogenetic axis

3. Coordinating analysis pipelines

4. Addressing differences in stress levels during studies

5. Overcoming spatial scope and resolution limitations

Limits to causality attribution:

• Difficulty in drawing causal inferences linking behaviorally relevant mechanisms to changes discernible by macroscopic methods

• Need for experimental manipulations and consistency with underlying physiology

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Component 2: Designing analogous experimental paradigms and environments for animals and humans

Two strategies:

1. Devise human analogs of well-researched animal models

2. Develop animal models to uncover mechanisms of brain plasticity as motors of individuality

Example: Studying skill acquisition in mice and humans

• Single-pellet reaching task for mice

• Adapted reaching task using chopsticks for humans

• Comparison of learning curves and plasticity mechanisms in motor cortices

Animal models of lifespan choice architectures and emergent individuality:

• Individuality paradigm using environmental enrichment

• Large-scale cage systems for studying differential effects of enrichment

• Use of IntelliCage for controlled learning opportunities

Relating animal studies to human longitudinal research:

• High-density sampling of neuroimaging data in humans

• Ecological momentary assessment (EMA) and GPS tracking

• Use of wearables and machine learning techniques

Comparing humans to animals in low-constraint settings:

• Investigation of freely behaving animals in naturalistic environments

• Parallel approaches to ecological momentary assessment in humans and animals

• Introduction of species-adequate stressors and observation of responses

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Component 3: Toward theories and models of plastic change that integrate scales of measurement

Need for theories and models that bridge the gap between microscopic and macroscopic observations

Example: EESR (expansion-exploration-selection-refinement) theory of plastic change

• Describes phases of local plastic change during skill acquisition

• Predicts macroscopic indicators of plasticity

Challenges in developing integrative models:

• Mapping microscopic changes onto macroscopic observations

• Validating model predictions with empirical evidence

Outlook

Need for intensified dialogue between researchers studying plasticity in animals and humans

Challenges in coordination and integration:

• Institutional and organizational barriers

• Funding schemes often focused on either animal or human research

Call for institutions and funders to place greater emphasis on coordinating and integrating research on plasticity in animals and humans

Summary

Plasticity allows organisms to form lasting adaptive changes in neural structures in response to interactions with the environment. It serves both species-general functions and individualized skill acquisition. To better understand human plasticity, we need to strengthen the dialogue between human research and animal models. Therefore, we propose to (1) enhance the interpretability of macroscopic methods used in human research by complementing molecular and fine-structural measures used in animals with such macroscopic methods, preferably applied to the same animals, to create macroscopic metrics common to both examined species; (2) launch dedicated cross-species research programs, using either well-controlled experimental paradigms, such as motor skill acquisition, or more naturalistic environments, where individuals of either species are observed in their habitats; and (3) develop conceptual and computational models linking molecular and fine-structural events to phenomena accessible by macroscopic methods. In concert, these three component strategies can foster new insights into the nature of plastic change.

Figure 3. Display of the cage design used in the individuality paradigm9

Multiple standard cages are connected to each other with connector tubes that are equipped with RFID antennas to track mouse movements. The standard cages can be equipped with a large variety of environmental affordances and opportunities. Given that the mice are individually tracked, experiences can be experimentally manipulated at the individual level in the course of development.