Autistic Disorder; Behavior; Dendrites; Electrophysiology; Neurobiology; Neurodegenerative Diseases; Microscopy, Fluorescence, Multiphoton
Our laboratory examines the structure and function of synapses in the mammalian neocortex and their contribution to complex circuit activity and behavior. We are particularly interested in applying an array of methodological approaches, including electrophysiology, 2-photon imaging and transmitter photo-uncaging, optogenetics, and viral tracing to both reduced preparations and intact behaving animals. In this way, we hope to bridge the gaps between molecular, cellular, and systems neuroscience.
Specialized Terms: Synaptic Integration; GABAergic Inhibition; Dendrites; Electrophysiology; Multiphoton Imaging
Extensive Research Description
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. In our studies, we use acute brain slice preparations to dissect the organization of GABAergic synapses and their ability to regulate postsynaptic activity. We have focused particularly on inhibition targeting pyramidal neuron dendrites, which influences both electrical and biochemical signaling in the postsynaptic cell. We are also using in vivo approaches to explore the role of different interneuron populations in the control of learning and perception.
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 are using novel viral tracing approaches to understand the organization of these outputs, combined with 2-photon calcium imaging in vivo to track the activity of identified Layer 5 neurons during the performance of visually-guided behaviors.
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 dopamine, norepinephrine, and acetylcholine, which influence neuronal excitability and synaptic transmission. We are using a combination of approaches to study the cellular mechanisms and functional actions of neuromodulation on identified microcircuits in the mouse visual cortex. Studies in both brain slices and intact behaving animals provide us with a rich array of data to understand how neuromodulation influences behavior.
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) and TSC1 (Tuberous Sclerosis) alter the function and plasticity of cortical synapses and produce consequences for behavior.
- Input-specific NMDAR-dependent potentiation of dendritic GABAergic inhibition. Neuron, in press
- Projection-specific feature encoding by layer 5 cortical subnetworks. Cell Reports 14:2538.
- Visual deprivation during the critical period enhances layer 2/3 GABAergic inhibition in mouse V1. J. Neuroscience 36:5914.
- Glutamate receptor modulation is restricted to synaptic microdomains. Cell Reports 12:326.
Compartmentalization of GABAergic inhibition by dendritic spines.
Chiu CQ, Lur G, Morse TM, Carnevale NT, Ellis-Davies GC, Higley MJ. Compartmentalization of GABAergic inhibition by dendritic spines. Science (New York, N.Y.) 2013, 340:759-62.
Full List of PubMed Publications
- Bessaih T, Higley MJ, Contreras D: Millisecond precision temporal encoding of stimulus features during cortically generated gamma oscillations in the rat somatosensory cortex. J Physiol. 2018 Feb 1; 2018 Jan 9. PMID: 29265375
- Chiu CQ, Martenson JS, Yamazaki M, Natsume R, Sakimura K, Tomita S, Tavalin SJ, Higley MJ: Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic Inhibition. Neuron. 2018 Jan 17. PMID: 29346754
- Batista-Brito R, Vinck M, Ferguson KA, Chang JT, Laubender D, Lur G, Mossner JM, Hernandez VG, Ramakrishnan C, Deisseroth K, Higley MJ, Cardin JA: Developmental Dysfunction of VIP Interneurons Impairs Cortical Circuits. Neuron. 2017 Aug 16. PMID: 28817803
- Xiao X, Levy AD, Rosenberg BJ, Higley MJ, Koleske AJ: Disruption of Coordinated Presynaptic and Postsynaptic Maturation Underlies the Defects in Hippocampal Synapse Stability and Plasticity in Abl2/Arg-Deficient Mice. J Neurosci. 2016 Jun 22. PMID: 27335408
- Kannan M, Gross GG, Arnold DB, Higley MJ: Visual Deprivation During the Critical Period Enhances Layer 2/3 GABAergic Inhibition in Mouse V1. J Neurosci. 2016 Jun 1. PMID: 27251614
- Lur G, Vinck MA, Tang L, Cardin JA, Higley MJ: Projection-Specific Visual Feature Encoding by Layer 5 Cortical Subnetworks. Cell Rep. 2016 Mar 22; 2016 Mar 10. PMID: 26972011
- Gamo NJ, Lur G, Higley MJ, Wang M, Paspalas CD, Vijayraghavan S, Yang Y, Ramos BP, Peng K, Kata A, Boven L, Lin F, Roman L, Lee D, Arnsten AF: Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. Biol Psychiatry. 2015 Dec 15; 2015 Feb 4. PMID: 25731884
- Lur G, Higley MJ: Glutamate Receptor Modulation Is Restricted to Synaptic Microdomains. Cell Rep. 2015 Jul 14; 2015 Jul 2. PMID: 26146087
- Higley MJ, Picciotto MR: Neuromodulation by acetylcholine: examples from schizophrenia and depression. Curr Opin Neurobiol. 2014 Dec; 2014 Jun 28. PMID: 24983212
- Higley MJ: Localized GABAergic inhibition of dendritic Ca(2+) signalling. Nat Rev Neurosci. 2014 Sep; 2014 Aug 13. PMID: 25116141
- Chiu CQ, Lur G, Morse TM, Carnevale NT, Ellis-Davies GC, Higley MJ: Compartmentalization of GABAergic inhibition by dendritic spines. Science. 2013 May 10. PMID: 23661763
- Einstein EB, Asaka Y, Yeckel MF, Higley MJ, Picciotto MR: Galanin-induced decreases in nucleus accumbens/striatum excitatory postsynaptic potentials and morphine conditioned place preference require both galanin receptor 1 and galanin receptor 2. Eur J Neurosci. 2013 May; 2013 Feb 7. PMID: 23387435
- Picciotto MR, Higley MJ, Mineur YS: Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012 Oct 4. PMID: 23040810
- Higley MJ, Sabatini BL: Calcium signaling in dendritic spines. Cold Spring Harb Perspect Biol. 2012 Apr 1; 2012 Apr 1. PMID: 22338091
- Higley MJ, Strittmatter SM: Neuroscience. Lynx for braking plasticity. Science. 2010 Nov 26. PMID: 21109660