All Publications


  • Deep posteromedial cortical rhythm in dissociation. Nature Vesuna, S., Kauvar, I. V., Richman, E., Gore, F., Oskotsky, T., Sava-Segal, C., Luo, L., Malenka, R. C., Henderson, J. M., Nuyujukian, P., Parvizi, J., Deisseroth, K. 2020

    Abstract

    Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states1-12. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use13,14, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1-3-Hz rhythm in layer5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed-including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found thatrhythmic optogenetic activation of retrosplenial cortex layer5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify themolecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.

    View details for DOI 10.1038/s41586-020-2731-9

    View details for PubMedID 32939091

  • Optically sensing neural activity without imaging NATURE PHOTONICS Wetzstein, G., Kauvar, I. 2020; 14 (6): 340–41
  • Cortical Observation by Synchronous Multifocal Optical Sampling Reveals Widespread Population Encoding of Actions. Neuron Kauvar, I. V., Machado, T. A., Yuen, E., Kochalka, J., Choi, M., Allen, W. E., Wetzstein, G., Deisseroth, K. 2020

    Abstract

    To advance the measurement of distributed neuronal population representations of targeted motor actions on single trials, we developed an optical method (COSMOS) for tracking neural activity in a largely uncharacterized spatiotemporal regime. COSMOS allowed simultaneous recording of neural dynamics at ∼30 Hz from over a thousand near-cellular resolution neuronal sources spread across the entire dorsal neocortex of awake, behaving mice during a three-option lick-to-target task. We identified spatially distributed neuronal population representations spanning the dorsal cortex that precisely encoded ongoing motor actions on single trials. Neuronal correlations measured at video rate using unaveraged, whole-session data had localized spatial structure, whereas trial-averaged data exhibited widespread correlations. Separable modes of neural activity encoded history-guided motor plans, with similar population dynamics in individual areas throughout cortex. These initial experiments illustrate how COSMOS enables investigation of large-scale cortical dynamics and that information about motor actions is widely shared between areas, potentially underlying distributed computations.

    View details for DOI 10.1016/j.neuron.2020.04.023

    View details for PubMedID 32433908

  • A Light-Field Metasurface for High-Resolution Single-Particle Tracking. Nano letters Holsteen, A. L., Lin, D., Kauvar, I., Wetzstein, G., Brongersma, M. L. 2019

    Abstract

    Three-dimensional (3D) single-particle tracking (SPT) is a key tool for studying dynamic processes in the life sciences. However, conventional optical elements utilizing light fields impose an inherent trade-off between lateral and axial resolution, preventing SPT with high spatiotemporal resolution across an extended volume. We overcome the typical loss in spatial resolution that accompanies light-field-based approaches to obtain 3D information by placing a standard microscope coverslip patterned with a multifunctional, light-field metasurface on a specimen. This approach enables an otherwise unmodified microscope to gather 3D information at an enhanced spatial resolution. We demonstrate simultaneous tracking of multiple fluorescent particles within a large 0.5 * 0.5 * 0.3 mm3 volume using a standard epi-fluorescent microscope with submicron lateral and micron-level axial resolution.

    View details for PubMedID 30897902

  • Global Representations of Goal-Directed Behavior in Distinct Cell Types of Mouse Neocortex NEURON Allen, W. E., Kauvar, I. V., Chen, M. Z., Richman, E. B., Yang, S. J., Chan, K., Gradinaru, V., Deverman, B. E., Luo, L., Deisseroth, K. 2017; 94 (4): 891-?

    Abstract

    The successful planning and execution of adaptive behaviors in mammals may require long-range coordination of neural networks throughout cerebral cortex. The neuronal implementation of signals that could orchestrate cortex-wide activity remains unclear. Here, we develop and apply methods for cortex-wide Ca(2+) imaging in mice performing decision-making behavior and identify a global cortical representation of task engagement encoded in the activity dynamics of both single cells and superficial neuropil distributed across the majority of dorsal cortex. The activity of multiple molecularly defined cell types was found to reflect this representation with type-specific dynamics. Focal optogenetic inhibition tiled across cortex revealed a crucial role for frontal cortex in triggering this cortex-wide phenomenon; local inhibition of this region blocked both the cortex-wide response to task-initiating cues and the voluntary behavior. These findings reveal cell-type-specific processes in cortex for globally representing goal-directed behavior and identify a major cortical node that gates the global broadcast of task-related information.

    View details for DOI 10.1016/j.neuron.2017.04.017

    View details for PubMedID 28521139

  • Ancestral Circuits for the Coordinated Modulation of Brain State. Cell Lovett-Barron, M., Andalman, A. S., Allen, W. E., Vesuna, S., Kauvar, I., Burns, V. M., Deisseroth, K. 2017; 171 (6): 1411–23.e17

    Abstract

    Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state.

    View details for PubMedID 29103613

  • Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice. Science translational medicine Selimbeyoglu, A., Kim, C. K., Inoue, M., Lee, S. Y., Hong, A. S., Kauvar, I., Ramakrishnan, C., Fenno, L. E., Davidson, T. J., Wright, M., Deisseroth, K. 2017; 9 (401)

    Abstract

    Alterations in the balance between neuronal excitation and inhibition (E:I balance) have been implicated in the neural circuit activity-based processes that contribute to autism phenotypes. We investigated whether acutely reducing E:I balance in mouse brain could correct deficits in social behavior. We used mice lacking the CNTNAP2 gene, which has been implicated in autism, and achieved a temporally precise reduction in E:I balance in the medial prefrontal cortex (mPFC) either by optogenetically increasing the excitability of inhibitory parvalbumin (PV) neurons or decreasing the excitability of excitatory pyramidal neurons. Surprisingly, both of these distinct, real-time, and reversible optogenetic modulations acutely rescued deficits in social behavior and hyperactivity in adult mice lacking CNTNAP2 Using fiber photometry, we discovered that native mPFC PV neuronal activity differed between CNTNAP2 knockout and wild-type mice. During social interactions with other mice, PV neuron activity increased in wild-type mice compared to interactions with a novel object, whereas this difference was not observed in CNTNAP2 knockout mice. Together, these results suggest that real-time modulation of E:I balance in the mouse prefrontal cortex can rescue social behavior deficits reminiscent of autism phenotypes.

    View details for PubMedID 28768803

  • Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain. Nature methods Kim, C. K., Yang, S. J., Pichamoorthy, N., Young, N. P., Kauvar, I., Jennings, J. H., Lerner, T. N., Berndt, A., Lee, S. Y., Ramakrishnan, C., Davidson, T. J., Inoue, M., Bito, H., Deisseroth, K. 2016; 13 (4): 325-328

    Abstract

    Real-time activity measurements from multiple specific cell populations and projections are likely to be important for understanding the brain as a dynamical system. Here we developed frame-projected independent-fiber photometry (FIP), which we used to record fluorescence activity signals from many brain regions simultaneously in freely behaving mice. We explored the versatility of the FIP microscope by quantifying real-time activity relationships among many brain regions during social behavior, simultaneously recording activity along multiple axonal pathways during sensory experience, performing simultaneous two-color activity recording, and applying optical perturbation tuned to elicit dynamics that match naturally occurring patterns observed during behavior.

    View details for DOI 10.1038/nmeth.3770

    View details for PubMedID 26878381

  • SPED Light Sheet Microscopy: Fast Mapping of Biological System Structure and Function CELL Tomer, R., Lovett-Barron, M., Kauvar, I., Andalman, A., Burns, V. M., Sankaran, S., Grosenick, L., Broxton, M., Yang, S., Deisseroth, K. 2015; 163 (7): 1796-1806

    Abstract

    The goal of understanding living nervous systems has driven interest in high-speed and large field-of-view volumetric imaging at cellular resolution. Light sheet microscopy approaches have emerged for cellular-resolution functional brain imaging in small organisms such as larval zebrafish, but remain fundamentally limited in speed. Here, we have developed SPED light sheet microscopy, which combines large volumetric field-of-view via an extended depth of field with the optical sectioning of light sheet microscopy, thereby eliminating the need to physically scan detection objectives for volumetric imaging. SPED enables scanning of thousands of volumes-per-second, limited only by camera acquisition rate, through the harnessing of optical mechanisms that normally result in unwanted spherical aberrations. We demonstrate capabilities of SPED microscopy by performing fast sub-cellular resolution imaging of CLARITY mouse brains and cellular-resolution volumetric Ca(2+) imaging of entire zebrafish nervous systems. Together, SPED light sheet methods enable high-speed cellular-resolution volumetric mapping of biological system structure and function.

    View details for DOI 10.1016/j.cell.2015.11.061

    View details for Web of Science ID 000366854200024

    View details for PubMedID 26687363

  • Extended field-of-view and increased-signal 3D holographic illumination with time-division multiplexing OPTICS EXPRESS Yang, S. J., Allen, W. E., Kauvar, I., Andalman, A. S., Young, N. P., Kim, C. K., Marshel, J. H., Wetzstein, G., Deisseroth, K. 2015; 23 (25): 32573-32581

    Abstract

    Phase spatial light modulators (SLMs) are widely used for generating multifocal three-dimensional (3D) illumination patterns, but these are limited to a field of view constrained by the pixel count or size of the SLM. Further, with two-photon SLM-based excitation, increasing the number of focal spots penalizes the total signal linearly--requiring more laser power than is available or can be tolerated by the sample. Here we analyze and demonstrate a method of using galvanometer mirrors to time-sequentially reposition multiple 3D holograms, both extending the field of view and increasing the total time-averaged two-photon signal. We apply our approach to 3D two-photon in vivo neuronal calcium imaging.

    View details for DOI 10.1364/OE.23.032573

    View details for Web of Science ID 000366687200093

    View details for PubMedID 26699047

    View details for PubMedCentralID PMC4775739

  • Adaptive Color Display via Perceptually-driven Factored Spectral Projection ACM TRANSACTIONS ON GRAPHICS Kauvar, I., Yang, S. J., Shi, L., McDowall, I., Wetzstein, G. 2015; 34 (6)
  • Natural neural projection dynamics underlying social behavior. Cell Gunaydin, L. A., Grosenick, L., Finkelstein, J. C., Kauvar, I. V., Fenno, L. E., Adhikari, A., Lammel, S., Mirzabekov, J. J., Airan, R. D., Zalocusky, K. A., Tye, K. M., Anikeeva, P., Malenka, R. C., Deisseroth, K. 2014; 157 (7): 1535-1551

    Abstract

    Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.

    View details for DOI 10.1016/j.cell.2014.05.017

    View details for PubMedID 24949967

    View details for PubMedCentralID PMC4123133

  • The Role of Electron Affinity in Determining Whether Fullerenes Catalyze or Inhibit Photooxidation of Polymers for Solar Cells ADVANCED ENERGY MATERIALS Hoke, E. T., Sachs-Quintana, I. T., Lloyd, M. T., Kauvar, I., Mateker, W. R., Nardes, A. M., Peters, C. H., Kopidakis, N., McGehee, M. D. 2012; 2 (11): 1351-1357
  • Influence of the hole-transport layer on the initial behavior and lifetime of inverted organic photovoltaics SOLAR ENERGY MATERIALS AND SOLAR CELLS Lloyd, M. T., Peters, C. H., Garcia, A., Kauvar, I. V., Berry, J. J., Reese, M. O., McGehee, M. D., Ginley, D. S., Olson, D. C. 2011; 95 (5): 1382-1388
  • Unconventional Face-On Texture and Exceptional In-Plane Order of a High Mobility n-Type Polymer ADVANCED MATERIALS Rivnay, J., Toney, M. F., Zheng, Y., Kauvar, I. V., Chen, Z., Wagner, V., Facchetti, A., Salleo, A. 2010; 22 (39): 4359-?

    Abstract

    Substantial in-plane crystallinity and dominant face-on stacking are observed in thin films of a high-mobility n-type rylene-thiophene copolymer. Spun films of the polymer, previously thought to have little or no order are found to exhibit an ordered microstructure at both interfaces, and in the bulk. The implications of this type of packing and crystalline morphology are discussed as they relate to thin-film transistors.

    View details for DOI 10.1002/adma.201001202

    View details for Web of Science ID 000284000700005

    View details for PubMedID 20623753