Jessica Tollkuhn, PhD

Prize Winner

Position

Associate Professor Neuroscience

Prize

MIND Prize

Cohort

2023

Program

MIND Prize

Institution

Cold Spring Harbor Laboratory

Website

www.tollkuhnlab.org

Project

Sex hormone modulation of neuronal states across the lifespan

Vision

My vision is to understand how the gonadal hormones estrogen, testosterone, and progesterone modulate brain function and dysfunction. This vision requires integration of neuroscience and molecular genomic approaches because hormone receptors are transcription factors that directly regulate gene expression. My lab’s previous work identified the genomic targets of estrogen receptor alpha (ERα) with unprecedented resolution, providing a comprehensive parts list of ion channels, neurotransmitter receptors and signaling molecules that collectively modulate neuronal activity and connectivity in both females and males. This work has established a new framework for the investigation of sex-variable biology. Our overarching hypothesis is that fluctuating hormone levels across the lifespan intersect with other genetic and environmental factors to create the myriad of well-established sex differences in disease susceptibility and resilience. With our MIND Prize funding, we are now investigating hormonal contributions to brain aging with the goal of identifying genes and cell types that underlie sex differences in the etiology and progression of neurodegenerative diseases. We are also exploring the contributions of the hormone-regulated genes we identified to distinct neurophysiological parameters to obtain a mechanistic understanding of the neuroprotective effects of estrogen and testosterone.

About

Dr. Tollkuhn is an Associate Professor at Cold Spring Harbor Laboratory. She has pioneered the study of gene regulation by sex hormone receptors in the brain. A native Californian, Dr. Tollkuhn received her Ph.D. in Biomedical Sciences from the University of California, San Diego, where she defined a novel transcription mechanism for embryonic cell-type specification. Her postdoctoral work on estrogen regulation of brain sexual differentiation at the University of California, San Francisco was supported by a Ruth L. Kirschstein National Research Service Award. Since joining the faculty of CSHL in 2014, Dr. Tollkuhn has pursued her goal of understanding how fluctuations in sex hormone levels across the lifespan lead to sex differences in neurodevelopment, behavior, and disease risk. In addition to the generous support of the MIND Prize, her work is funded by the National Institute of Mental Health (NIMH) and the Simons Foundation Autism Research Initiative (SFARI).

Impactful discoveries change the scientific conversation by revealing new questions to ask.

Neurodegenerative diseases show robust sex differences in their incidence, age-of-onset, symptoms, and progression. Many of these differences are attributed to the gonadal hormones estrogen and testosterone. Age-related decreases in hormone levels are linked with symptom onset in both sexes, and estrogen in particular has been shown to protect against Alzheimer’s Disease by improving cognitive function, mood and neurovascular health. Gonadal hormones act through receptors that directly bind DNA to regulate gene expression. A central challenge in understanding the neuroprotective effects of hormones has been a lack of information on neural genomic targets of these receptors. We recently identified the genomic targets of estrogen receptor in the brain, revealing a diverse repertoire of ion channels and neurotransmitter receptors that can modulate neuronal function. We now propose that the attenuation of hormone-regulated gene programs during aging underlies susceptibility to neurodegeneration. Our vision is to discover how hormone receptors modulate neural activity states in the brains of females and males across the lifespan, and to identify cell types that are vulnerable or resilient to aging in different hormonal contexts. Our long-term goal is to provide a foundation for the development of novel brain-specific hormone therapeutics that provide early-stage protection against disease without increasing risk of cancer or cardiovascular events.

The MIND Prize has allowed my lab to move into two completely new areas of research at a rapid pace. We have the freedom to tackle important problems without hesitation.