Michael J Higley, MD/PhD

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).