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Michael J Higley, MD/PhD

Professor of Neuroscience and Associate Professor of Biomedical Engineering and of Psychiatry
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Additional Titles

Member, Program in Cellular Neuroscience, Neurodegeneration and Repair (CNNR)

Associate Director, MD-PhD Program

About

Titles

Professor of Neuroscience and Associate Professor of Biomedical Engineering and of Psychiatry

Member, Program in Cellular Neuroscience, Neurodegeneration and Repair (CNNR); Associate Director, MD-PhD Program

Biography

Dr. Higley studied behavioral neuroscience at Cornell University. He then completed his MD and PhD in the MSTP Program and the laboratory of Dr. Diego Contreras at the University of Pennsylvania. He continued his scientific training as a postdoctoral fellow with Dr. Bernardo Sabatini at Harvard Medical School. In 2010, Dr. Higley joined the faculty of the Yale Department of Neuroscience and the Program in Cellular Neuroscience, Neurodegeneration, and Repair (CNNR). He was promoted to Associate Professor with tenure in 2020. He has received numerous honors for his research, including a Sloan Research Fellowship, a Klingenstein Fellowship, and most recently the NIH Director's Pioneer Award. Dr. Higley has a secondary appointment in the Department of Biomedical Engineering and is a member of the Wu Tsai Institute. He also serves as an Associate Director for the Yale MD-PhD Program.

Appointments

Education & Training

Postdoctoral Fellow, Sabatini Lab
Harvard Medical School (2010)
MD/PhD
University of Pennsylvania (2007)
BA
Cornell University (1998)

Research

Overview

Development, function, and plasticity of inhibitory GABAergic circuits.

The balance of synaptic excitation and inhibition is thought to be critical for normal brain function and is disrupted in a variety of neuropsychiatric disorders. In the neocortex, this balance is maintained by an intricate dance between excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons. A major challenge to understanding the role of GABAergic inhibition is the incredible diversity of interneurons, with different subtypes defined by molecular, electrophysiological, and anatomical features corresponding to distinct functions in local microcircuits. For example, we have focused on inhibition mediated by somatostatin-expressing interneurons that target pyramidal neuron dendrites, influencing both electrical and biochemical signaling in the postsynaptic cell. Work in acute brain slices using electrophysiology, 2-photon imaging and uncaging, and optogenetics has provided considerable insight into the function and plasticity of these synapses (Science, 2013; Cell Reports, 2015; J. Neuroscience, 2016; Neuron, 2018; Nature Review Neuroscience, 2019). In ongoing studies, we are investigating the role of neuromodulators such as acetylcholine, norepinephrine, and endocannabinoids in the cell type-specific control of cortical inhibition.

Cortical microcircuits underlying visually-guided behavior.

Visual information is encoded by neuronal activity in the primary visual cortex, whose diverse anatomical projections route these signals to various downstream locations that subserve different aspects of perception, learning, and motor output. Outputs from pyramidal neurons in Layer 5 form the major pathway by which cortical information is communicated to subcortical structures, including the basal ganglia, superior colliculus, and brain stem. We have developed novel behavioral assays, such as visually-cued eyeblink conditioning, to investigate how dynamics in these circuits contributes to task acquisition and performance. We are particularly interested in the mechanisms of plasticity that underlie behavioral flexibility across learning or changes in behavioral state (e.g., arousal or locomotion). To accomplish these goals, we utilize a combination of in vivo imaging (both 2-photon and widefield "mesoscopic"), optogenetics, and electrophysiology to probe the causal links between cortical activity, visual perception, and behavior (Cell Reports, 2016; Nature Methods, 2020; Neuron, 2020, Cell Reports, 2020).

Neuromodulation: providing functional flexibility to cortical circuits.

Adaptive behavior over the life of an organism requires a nervous system with sufficiently stable wiring to support long-term memory but plastic enough to adjust to rapid changes in environmental context. Much of this dynamic flexibility is provided by neuromodulators such as norepinephrine and acetylcholine, which influence neuronal excitability and synaptic transmission. We are using a combination of approaches in both brain slices and behaving mice to study the actions of neuromodulation on identified microcircuits in the mouse cortex (Cell Reports, 2015; J. Neuroscience, 2020; Nature Neuroscience, 2022).

Models of neuropsychiatric illness.

A large body of evidence now suggests that disruption of synaptic transmission and subsequent dysfunction of neuronal circuits contributes to the pathophysiology of neuropsychiatric disorders such as schizophrenia and autism. We are actively investigating how genetic mutations of disease-linked genes, including MeCP2 (Rett Syndrome), RAI1 (Smith-Magenis Syndrome), and CDKL5 (CDD) alter the function and plasticity of cortical synapses and produce consequences for behavior. In recent work, we are using viral vector strategies to drive whole-brain expression of CRISPR/Cas9 constructs for the cell type-specific disruption of target genes. In combination with novel optical approaches like simultaneous 2-photon/mesoscopic imaging, we are attempting to identify convergent network-level phenotypes across a variety of genetic disease models (Nature Methods, 2020).

Medical Subject Headings (MeSH)

Autistic Disorder; Behavior; Dendrites; Electrophysiology; Microscopy, Fluorescence, Multiphoton; Neurobiology

Research at a Glance

Yale Co-Authors

Frequent collaborators of Michael J Higley's published research.

Publications

2024

2023

2022

2020

2019

2018

Academic Achievements & Community Involvement

  • honor

    NIH Director's Pioneer Award

  • honor

    Whitman Fellowship

  • honor

    Inaugural Spector Award for Junior Neuroscientists at Yale University

  • honor

    Basil O'Connor Starter Scholar Award

  • honor

    NARSAD Young Investigator Award

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