Faculty

Research Summary

Brain Mechanisms of Movement and Cognition; Functional Brain Biomarkers; Cortical Networks There three major goals of our research: First, to elucidate the neural mechanisms underlying motor control and cognitive processing; second, to develop functional brain biomarkers for various brain diseases; and third, to understand the workings of developing cortical networks. For the first aim, we pursue experimental psychological studies, neurophysiological recordings, functional magnetic resonance imaging (MRI) at high fields (3, 4 and 7 Tesla), magnetoencephalography (MEG), and neural network modeling (using a supercomputer). For the second aim, we use MEG. And for the third aim, we record electrical activity from embryonic cortical cell cultures using multielectrode arrays.Magnetoencephalography of brain function Neural mechanisms of cognitive processes Neurophysiology of motor control and cognition Functional MRI of motor and cognitive processes

Research Summary

Strategies in Visual Cortex The cerebral cortex embodies an interesting dichotomy in the representation of information: on the one hand it must maintain a consistent and reliable representation of important information, and on the other hand it must be able to modify representations to adapt and learn. My broad research interest is how the cortex addresses these two potentially conflicting requirements. In particular I am interested in how strategies based on past experiences are used in the processing and execution of visually guided behavior.Understanding how and why representations change in visual cortex will provide a powerful basis for studying a number of general issues concerning cortical information processing, including the interactions between behavior and sensation, the mechanisms underlying learning and development, and the neural coding of information.

Research Summary

The principal aim of my laboratory is to understand the molecular pathways that drive neuronal death in Huntington´s Disease (HD), an inherited neurodegenerative disorder caused by a CAG triplet repeat expansion within exon-1 of the Huntingtin gene (Htt). Mutant Htt protein aggregates and accumulates in virtually all cell types in the body, but it predominantly affects Medium Spiny Neurons (MSNs), a neuronal type located in the striatum. We focus on studies directed at understanding what makes MSNs so susceptible to mHtt aggregation and death compared to other cell types in the brain. We also examine the role of Heat Shock Factor (HSF1), a transcription factor that regulates protein folding, inflammation, and apoptosis, in a cell type-specific process. To address this question we apply molecular biology, biochemistry, neuroanatomy, and imaging to different HD cellular and mouse models as well as human specimens. Our final goal is to provide new therapeutic strategies to prevent neuronal death and improve the quality of life of thousands of patients with this devastating neurodegenerative disease.

Research Summary

Research in the lab is focused on understanding brain substrates for flexible behavioral control and reinforcement learning (RL). We have extensive experience in behavioral, systems, and computational neuroscience and work in the lab combines multiple interdisciplinary approaches to study: (i) the functional properties of key brain decision-circuits, (ii) link identified circuit mechanisms to specific computational operations within normative theoretical frameworks, (iii) to ultimately understand how these circuit- and computational-specializations become leveraged during various behavioral demands.Our previous scientific contributions have reported novel empirical findings (including dopamine midbrain-forebrain dissociation, and striatal dopamine waves) that have significantly (re)shaped formalizations of dopamine's role in RL. The lab seeks to build on this trajectory to make deep contributions that integrate experimental findings into multilevel neurocomputational models for tandem and cyclical advances in the simulated and empirical understanding of brain mechanisms for valuation, selection, planning, and execution of behavioral goals.

Research Summary

PTSD, resilience, personality, aging

Bio

Madhu Kannan is an Assistant Professor of Neuroscience and a member of the Medical Discovery Team on Optical Imaging and Brain Science.

Dr. Kannan completed her undergraduate studies in Biochemistry in Chennai, India, and acquired a Master’s in Molecular Genetics at the University of Leicester, UK. She then obtained a Ph.D. in Neurophysiology at the Max Planck Institute of Experimental Medicine and George August University, in Germany. During her postdoctoral work, in the lab of Dr. Mike Higley at Yale School of Medicine, CT, she studied the mechanisms of experience-dependent plasticity at cortical inhibitory synapses using slice electrophysiology and optogenetics. She subsequently joined the lab of Dr. Vincent Pieribone, for a second postdoc, where she created a suite of mutually compatible recombinant voltage indicators and used them to perform some of the first recordings, with millisecond resolution, of the correlated dynamics of genetically distinct neuron types in cortical microcircuits in behaving rodents.

1. C Huang†, J Luo, S J Woo, L A Roitman, J Li, V A Pieribone, M Kannan†, G Vasan†, M J Schnitzer†. Dopamine signals integrate innate and learnt valences to regulate memory dynamics. Research-Square; under revision in Nature. †Corresponding authors.

2. M Kannan*†, G Vasan*†, S Haziza*, C Huang, R Chrapkiewicz, J Luo, J A Cardin, M J Schnitzer† and V A Pieribone†. Dual-polarity voltage imaging of the concurrent dynamics of multiple neuron types. Science, 378(6619), 2022. *Equal contribution. †Corresponding authors.

3. M Kannan, G Vasan, and V A Pieribone. Optimizing strategies for developing genetically encoded voltage indicators. Frontiers in Cellular Neuroscience, 13:53, 2019.

4. M Kannan*, G Vasan*, C Huang, S Haziza, J Z Li, H Inan, M J Schnitzer, and V A Pieribone. Fast, in vivo voltage imaging using a red fluorescent indicator. Nature Methods, 15(12):1108–1116, 2018. *Equal contribution. Highlighted in Yale News.

5. M Kannan, G G Gross, D B Arnold, and M J Higley. Visual deprivation during the critical period enhances layer 2/3 GABAergic inhibition in mouse V1. Journal of Neuroscience, 36(22):5914–5919, 2016.

6. A Matz, S Lee, N S Domeyer, D Zanini, A Holubowska, M Kannan, M Farnworth, O Jahn, M C Gopfert, and J Stegmüller. Regulation of neuronal survival and morphology by the E3 ubiquitin ligase RNF157. Cell Death and Differentiation, 22(4):626–642, 2015.

7. C Mukherjee, A Holubowska, N S Domeyer, M Mitkovski, S Lee, M Kannan, A Matz, M Vadhvani, and J Stegmüller. Loss of the neuron-specific f-box protein FBXO41 models an ataxia-like phenotype in mice with neuronal migration defects and degeneration in the cerebellum. Journal of Neuroscience, 35(23):8701–8717, 2015.

8. M Kannan, S Lee, N S Domeyer, and J Stegmüller. The E3 ligase Cdh1-anaphase promoting complex operates upstream of the E3 ligase Smurf1 in the control of axon growth. Development, 139(19):3600– 3612, 2012.

9. M Kannan, S Lee, N S Domeyer, T Nakazawa, and J Stegmüller. p250GAP is a novel player in the Cdh1-APC/Smurf1 pathway of axon growth regulation. PLoS One, 7(11), 2012.

10. M Kannan, J R Steinert, I D Forsythe, A G Smith, and T Chernova. Mevastatin accelerates loss of synaptic proteins and neurite degeneration in aging cortical neurons in a heme independent manner. Neurobiology of Aging, 31(9):1543–1553, 2010.

Research Summary

Animal cognition is a complex dynamic process that is tightly controlled by feed-forward and feed-back mechanisms and involves the concerted action of multiple distinct excitatory and inhibitory neuron types in the brain. Modern genetic and optical tools enable the targeted identification, stimulation, or recording of a single neuron type at a time. However, how the activation dynamics of multiple neuron types converge in real-time and how these time-varying interactions impact network output to influence the cognitive outcome are unknown. Using single-neuron, single-spike resolution, multi-population voltage imaging in mice, during selective attention paradigms adapted from primates, my research program will examine the synergistic dynamics of targeted cortical neurons in behavior and cognitive function. We will further combine this approach with targeted gene perturbation to understand the contribution of risk genes to impaired circuit function, which may in turn contribute to some of the cognitive deficits associated with psychiatric illnesses.

Bio

Prakash Kara received his PhD from the University of Alabama at Birmingham and postdoctoral training at Harvard Medical School. His previous faculty positions were at the Medical University of South Carolina, as Assistant Professor and then Associate Professor. He came to the University of Minnesota as a Full Professor in 2018 as the first hire in a new initiative, the Medical Discovery Team (MDT) in Optical Imaging and Brain Science.

Research Summary

The Kara lab solves puzzles in sensory perception and neurovascular coupling in the mammalian brain. Our long-term goal is to obtain a comprehensive view of how the brain adapts to change in adulthood, development, and disease. The short-term goals of our current projects are to (1) resolve aspects of neural coding of binocular signals in the visual cortex, (2) build microcircuits for neurovascular coupling and (3) determine the underpinnings of functional magnetic resonance imaging (fMRI).We use two-photon and three-photon imaging, optogenetics, and electrophysiological techniques. More specifically, we assay synaptic and spiking activity along with the responses of individual blood vessels to sensory stimuli and optogenetic activation.

Research Summary

As we learn a new skill, how does our brain change to store information about the actions involved? Cortical neurons receive information from the thousands of synaptic inputs onto the dendritic tree. Learning occurs when the efficacy of these inputs change in response to patterns of activity. Within the dendrite, location-dependent learning rules and interactions between inputs sculpt these changes.The Kerlin Lab uses advanced two-photon microscopy techniques to understand how dendritic compartments and individual synapses within the motor cortex are modified as mice learn to perform new tasks. Recent work has identified a distinct loop between cortex and thalamus that maintains motor plans in the absence of overt action. By tracking and manipulating dendritic activity while monitoring the kinematics of action, we are determining the critical subcellular loci for the learning of new motor plans. Clarifying the biophysical events that drive normal plasticity will help us identify ways to shift cortical plasticity into regimes that favor the improvement of cognitive motor disorders or rehabilitation after damage to motor systems. 

Research Summary

Structure and Function of Potassium Channels in Glia

Ion channels in glial cells

A major effort in our laboratory aims to elucidate the role of inwardly rectifying potassium channels for glial cell function. Glial buffering of the extracellular potassium concentration in the retina has been elegantly demonstrated using electrophysiological methods. Inwardly rectifying potassium channels in these glial cells are spatially localized to optimally perform this function. Research in our laboratory has established the essential role of the glial Kir4.1 channel for the buffering of extracellular potassium concentration. More recently we have been investigating the role of accessory proteins for the modulation and subcellular localization of Kir4.1 channels in Müller cells. We have identified a potential macromolecular complex (Aquaporin-4, Kir4.1 and alpha syntrophin) that hold this cluster together. We are now expanding our research to glial cells in the brain and peripheral nervous system.

Non-image-forming vision

Another research program in our lab is to elucidate the structure and function of the non-image-forming vision. In mammals, photic information is exclusively processed by the retina and reaches the brain through the optic nerve. The eyes are equipped with at least two functionally and anatomically distinct light-detecting streams, the classic image-forming stream involving rods and cones and the non-image forming stream. The non–image-forming photoreceptive stream entrains the circadian timing system and regulates pineal melatonin secretion and pupillary constriction. A small subpopulation of ganglion cells in the mammalian retina expresses the opsin-family photopigment melanopsin (Opn4). These ganglion cells are intrinsically photosensitive (ipRGC) and play a crucial role in "non-image forming" visual responses such as circadian photoentrainment. We have identified subpopulations of ipRGCs with distinct anatomical and functional properties using electrophysiological and genetics methods. We are now studying the role of ipRGCs in a variety of light-evoked behaviors that support organismal responses to environmental light.

Bio

Esther Krook-Magnuson is an Associate Professor in the Department of Neuroscience. Her work focuses on brain circuitry, including the different types of neurons in the brain and their responsiveness to drugs like opioids.

Research Summary

Selective Neuromodulation Neuronal networks, diversity, and specificity of function are important to both physiological processes and neurological disorders, including epilepsy. My laboratory seeks to improve our understanding of how cells interact within a network, how networks interact with each other, and the physiological roles of neuronal populations. In this regard, key questions remain in epilepsy research, including what are the principal networks, conditions, and cell types involved in initiating, sustaining, propagating, terminating, and potentially suppressing, seizures. By improving our understanding of these, we improve the prospects of someday reaching the goal of no seizures, no side effects, for all epilepsy patients. My lab uses rodent models of neurological disorders, including temporal lobe epilepsy, and techniques including electrophysiology, optogenetics, immunocytochemistry, transgenic animals, and behavioral experiments to address these fundamental questions

Research Summary

How do sensory circuits extract and represent behaviorally relevant signals from the environment? We investigate this question in the mammalian retina, the thin neural tissue that lines the back of the eye. We use the retina as a model system because its cell types and circuits are well-defined and we can maintain the sensitivity of the retinal circuitry to its natural input (patterns of light) inex-vivopreparations that allow good experimental access to the different elements of the circuit. We use a combination of patch-clamp electrophysiology and two-photon microscopy in transgenic mice to study how the properties of retinal cells and synapses give rise to the visual computations that underlie how we see. A current focus of the lab is to understand how Müller cells, the primary glial cell type of the retina, shape the function of retinal synapses.