Defining Molecular Control of Reversible Neuronal States to Enhance Cognitive Resilience

1. Abstract

Neuronal resilience is not simply the absence of damage, but the ability to remain within a reversible functional state under stress. This project will test the hypothesis that neuronal fate is governed by a regulated signaling system that determines whether cells remain reversible or transition into irreversible dysfunction. Using human iPSC-derived neurons, I will define a measurable “reversibility window” following stress and test whether modulation of LATS signaling extends this window and enhances functional recovery. Experiments will be conducted using established human neuronal systems and genetic/pharmacological perturbations available in my current research environment. The project is designed as a focused 6–12 month pilot study. All data will be shared openly via ResearchHub in accordance with open science guidelines.

Provide a concise abstract (max 200 words) describing (1) scientific rationale, importance and research plan, (2) description of team/facilities/ethics approvals, (3) estimated timeline, and (4) data sharing commitment.

2. Introduction

Cognitive performance and resilience depend on the ability of neurons to adapt to stress. While traditional approaches focus on preventing cell death, emerging evidence suggests that neurons pass through a reversible intermediate state before irreversible dysfunction. However, the mechanisms controlling this transition remain poorly understood.

My prior work identified a stress-responsive MAP4K4–LATS2 signaling pathway that regulates neuronal state transitions. This pathway provides a mechanistic entry point to test whether neuronal fate can be actively modulated.

Summarize theoretical background, key literature, and rationale for the proposal.

Hypotheses

H1 (Primary):
Neurons enter a reversible intermediate state following stress that can be experimentally defined.

H2 (Primary):
Modulation of LATS signaling extends the reversible state and enhances neuronal recovery.

H3 (Secondary):
Extension of the reversible state improves functional neuronal properties linked to cognitive resilience.

3. Methods

Human iPSC-derived neurons will be used as the experimental system. These models provide a controlled and reproducible platform to study neuronal stress responses.Participants/Sample

Materials and Procedures

Neurons will be exposed to controlled stress conditions (e.g., mitochondrial or metabolic stress). Recovery capacity will be assessed over time to define a “reversibility window.” Genetic and pharmacological perturbations targeting LATS signaling will be applied to test their effects on neuronal recovery.

Functional readouts will include:

cell survival
stress response markers
synaptic and neuronal activity markers

Planned Analyses

Time-resolved measurements will be used to define the transition from reversible to irreversible states. Comparisons between control and perturbed conditions will determine whether signaling modulation extends recovery capacity.

Results will be interpreted based on:

presence or absence of extended reversibility
improvement in functional outcomes

Ethics and Data Management

All experiments will be conducted using established iPSC-derived systems with appropriate institutional approvals. Data will be shared openly via ResearchHub in accordance with open science guidelines.

4. Pilot Data (Optional)

Preliminary observations indicate that stress induces a temporally defined delay between signaling activation and neuronal degeneration, suggesting the existence of a reversible intermediate state.

5. Budget

Cell culture reagents: $3,000
Small molecule inhibitors / reagents: $3,000
Assay reagents and consumables: $2,000
Data analysis and computational resources: $2,000

Total: $10,000

6. References

Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
Ling, S. C., Polymenidou, M. & Cleveland, D. W. Converging mechanisms in ALS and frontotemporal dementia: disrupted RNA and protein homeostasis. Neuron 79, 416–438 (2013).
Taylor, J. P., Brown, R. H. & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature 539, 197–206 (2016).
Meng, Z. et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat. Commun. 6, 8357 (2015).
Furth, N. & Aylon, Y. The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. Cell Death Differ. 24, 1488–1501 (2017).

List all references used in the manuscript using Nature style (e.g. numbered in-text citations and alphabetical references at the end of the manuscript).

Defining Molecular Control of Reversible Neuronal States to Enhance Cognitive Resilience

Defining Molecular Control of Reversible Neuronal States to Enhance Cognitive Resilience

Funding Progress

Nonprofit Recipient

Peer Reviews

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DOI