Biology subjects

Fulton, K. A.

Publications and source records attributed to Fulton, K. A..

4 recordsLinked to original sources

bioRxiv2026

Inferring the evolving objectives that organize animal behavior

Understanding how the brain supports flexible, goal-directed behavior is a central aim of neuroscience. Yet such behavior is highly variable and unfolds over long timescales, making it challenging to understand its organization. Advances in behavioral tracking quantify movements but do not reveal the objectives that guide them. Motivated by this, we develop inverse reinforcement learning (IRL) into a general framework for inferring these objectives from naturalistic behavior. Our approach represents an animal's objectives as internal rewards, and infers these rewards as well as the policies they induce from observed behavior. It applies across diverse behavioral settings, from freely moving behaviors to structured tasks. It can infer objectives that switch over time or gradually change with experience. In mice capturing crickets, it identified a small set of objectives that the animals switched between over the course of a trial. In mice learning a cued labyrinth, it inferred how the animals' internal rewards changed as learning progressed. Across both datasets, the models predicted held-out actions and generated extended behavior that reproduced key features of animal performance. By transforming long, variable behavioral sequences into time-resolved estimates of the animal's objectives, our approach provides a quantitative basis for studying how the brain organizes natural behavior.

neuroscience↗

bioRxiv2025

ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program

Mutations in the chromatin reader and tumor suppressor ZMYND11 are the cause of ZMYND11-related syndromic intellectual disability (ZRSID), a disorder characterized by symptoms such as language and motor delay, behavioral disruptions, and seizures. We find that neuronal deletion of ZMYND11 in mice causes aberrant upregulation of non-neuronal gene programs, leading to reduced dendritic branching and spine density, as well as hyperactivity and abnormal motor behavior. We investigated the mechanism by which ZMYND11 regulates gene expression and discovered that ZMYND11 interacts with and inhibits the histone methyltransferase KMT2A (MLL1), a transcriptional co-activator which contributes to oncogenic and developmental gene programs. We find that a ZRSID-associated ZMYND11 point mutation abrogates ZMYND11 interaction with KMT2A, suggesting that this interaction is critical for the function of ZMYND11 in regulating brain development. Using a degron-tagged ZMYND11 mouse model to enable the rapid degradation of ZMYND11 in primary cortical neurons, we show that gene expression changes induced by ZMYND11 loss are attenuated by treatment with the KMT2A inhibitor revumenib, a drug which has recently been approved for the treatment of KMT2A-rearranged leukemia. Our findings shed light on the convergence of chromatin mechanisms regulating neuronal gene expression and raise the possibility that modulation of KMT2A activity may be a useful therapeutic avenue for ZRSID.

neuroscience↗

bioRxiv2023

GAUSS-EM: Guided accumulation of ultrathin serial sections with a static magnetic field for volume electron microscopy

Serial sectioning electron microscopy of millimeter-scale 3D anatomical volumes requires the collection of thousands of ultrathin sections. Here we report a high-throughput automated approach, GAUSS-EM, utilizing a static magnetic field to collect and densely pack thousands of sections onto individual silicon wafers. The method is capable of sectioning hundreds of microns of tissue per day at section thicknesses down to 35 nm. Relative to other automated volume electron microscopy approaches, GAUSS-EM democratizes the ability to collect large 3D EM volumes because it is simple and inexpensive to implement. We present two exemplar EM volumes of a zebrafish eye and mouse olfactory bulb collected with the method.

neuroscience↗

bioRxiv2020

Permeabilization-free en bloc immunohistochemistry for correlative microscopy

A dense reconstruction of neuronal synaptic connectivity typically requires high-resolution 3D electron microscopy (EM) data, but EM data alone lacks functional information about neurons and synapses. One approach to augment structural EM datasets is with the fluorescent immunohistochemical (IHC) localization of functionally relevant proteins. We describe a protocol that obviates the requirement of tissue permeabilization in thick tissue sections, a major impediment for correlative pre-embedding IHC and EM. We demonstrate the permeabilization-free labeling of neuronal cell types, intracellular enzymes, and synaptic proteins in tissue sections hundreds of microns thick in multiple brain regions while simultaneously retaining the ultrastructural integrity of the tissue. Finally, we explore the utility of this protocol by performing proof-of-principle correlative experiments combining two-photon imaging of protein distributions and 3D electron microscopy.

neuroscience↗