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Catherine A Marcinkiewcz, Christopher M Mazzone, Giuseppe D'Agostino, Lindsay R Halladay, J Andrew Hardaway, Jeffrey F DiBerto, Montserrat Navarro, Nathan Burnham, Claudia Cristiano, Cayce E Dorrier, Gregory J Tipton, Charu Ramakrishnan, Tamas Kozicz, Karl Deisseroth, Todd E Thiele, Zoe A McElligott, Andrew Holmes, Lora K Heisler, Thomas L Kash
Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT(DRN)) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF(BNST)) in mice. Specifically, 5-HT(DRN) projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRF(BNST) inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus...
August 24, 2016: Nature
Heather K Decot, Vijay Mk Namboodiri, Wei Gao, Jenna A McHenry, Joshua H Jennings, Sung-Ho Lee, Pranish A Kantak, Yu-ChiehJill Kao, Manasmita Das, Ilana B Witten, Karl Deisseroth, Yen-YuIan Shih, Garret D Stuber
Several neuropsychiatric conditions, such as addiction and schizophrenia may arise in part from dysregulated activity of ventral tegmental area dopaminergic (TH(VTA)) neurons, as well as from more global maladaptation in neurocircuit function. However, whether TH(VTA) activity affects large-scale brain-wide function remains unknown. Here, we selectively activated TH(VTA) neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging (fMRI)...
August 12, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Sung-Jin Park, Mattia Gazzola, Kyung Soo Park, Shirley Park, Valentina Di Santo, Erin L Blevins, Johan U Lind, Patrick H Campbell, Stephanie Dauth, Andrew K Capulli, Francesco S Pasqualini, Seungkuk Ahn, Alexander Cho, Hongyan Yuan, Ben M Maoz, Ragu Vijaykumar, Jeong-Woo Choi, Karl Deisseroth, George V Lauder, L Mahadevan, Kevin Kit Parker
Inspired by the relatively simple morphological blueprint provided by batoid fish such as stingrays and skates, we created a biohybrid system that enables an artificial animal--a tissue-engineered ray--to swim and phototactically follow a light cue. By patterning dissociated rat cardiomyocytes on an elastomeric body enclosing a microfabricated gold skeleton, we replicated fish morphology at 1/10 scale and captured basic fin deflection patterns of batoid fish. Optogenetics allows for phototactic guidance, steering, and turning maneuvers...
July 8, 2016: Science
Rainbo Hultman, Stephen D Mague, Qiang Li, Brittany M Katz, Nadine Michel, Lizhen Lin, Joyce Wang, Lisa K David, Cameron Blount, Rithi Chandy, David Carlson, Kyle Ulrich, Lawrence Carin, David Dunson, Sunil Kumar, Karl Deisseroth, Scott D Moore, Kafui Dzirasa
Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1 Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social defeat stress...
July 20, 2016: Neuron
Christina M Gremel, Jessica H Chancey, Brady K Atwood, Guoxiang Luo, Rachael Neve, Charu Ramakrishnan, Karl Deisseroth, David M Lovinger, Rui M Costa
Everyday function demands efficient and flexible decision-making that allows for habitual and goal-directed action control. An inability to shift has been implicated in disorders with impaired decision-making, including obsessive-compulsive disorder and addiction. Despite this, our understanding of the specific molecular mechanisms and circuitry involved in shifting action control remains limited. Here we identify an endogenous molecular mechanism in a specific cortical-striatal pathway that mediates the transition between goal-directed and habitual action strategies...
June 15, 2016: Neuron
Christina K Kim, Samuel J Yang, Nandini Pichamoorthy, Noah P Young, Isaac Kauvar, Joshua H Jennings, Talia N Lerner, Andre Berndt, Soo Yeun Lee, Charu Ramakrishnan, Thomas J Davidson, Masatoshi Inoue, Haruhiko Bito, Karl Deisseroth
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...
April 2016: Nature Methods
Samuel J Yang, William E Allen, Isaac Kauvar, Aaron S Andalman, Noah P Young, Christina K Kim, James H Marshel, Gordon Wetzstein, Karl Deisseroth
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...
December 14, 2015: Optics Express
Benjamin C-K Tee, Alex Chortos, Andre Berndt, Amanda Kim Nguyen, Ariane Tom, Allister McGuire, Ziliang Carter Lin, Kevin Tien, Won-Gyu Bae, Huiliang Wang, Ping Mei, Ho-Hsiu Chou, Bianxiao Cui, Karl Deisseroth, Tse Nga Ng, Zhenan Bao
Human skin relies on cutaneous receptors that output digital signals for tactile sensing in which the intensity of stimulation is converted to a series of voltage pulses. We present a power-efficient skin-inspired mechanoreceptor with a flexible organic transistor circuit that transduces pressure into digital frequency signals directly. The output frequency ranges between 0 and 200 hertz, with a sublinear response to increasing force stimuli that mimics slow-adapting skin mechanoreceptors. The output of the sensors was further used to stimulate optogenetically engineered mouse somatosensory neurons of mouse cortex in vitro, achieving stimulated pulses in accordance with pressure levels...
October 16, 2015: Science
Priyamvada Rajasethupathy, Sethuraman Sankaran, James H Marshel, Christina K Kim, Emily Ferenczi, Soo Yeun Lee, Andre Berndt, Charu Ramakrishnan, Anna Jaffe, Maisie Lo, Conor Liston, Karl Deisseroth
Top-down prefrontal cortex inputs to the hippocampus have been hypothesized to be important in memory consolidation, retrieval, and the pathophysiology of major psychiatric diseases; however, no such direct projections have been identified and functionally described. Here we report the discovery of a monosynaptic prefrontal cortex (predominantly anterior cingulate) to hippocampus (CA3 to CA1 region) projection in mice, and find that optogenetic manipulation of this projection (here termed AC-CA) is capable of eliciting contextual memory retrieval...
October 29, 2015: Nature
Donna Przepiorka, Chia-Wen Ko, Albert Deisseroth, Carolyn L Yancey, Reyes Candau-Chacon, Haw-Jyh Chiu, Brenda J Gehrke, Candace Gomez-Broughton, Robert C Kane, Susan Kirshner, Nitin Mehrotra, Tiffany K Ricks, Deborah Schmiel, Pengfei Song, Ping Zhao, Qing Zhou, Ann T Farrell, Richard Pazdur
On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6...
September 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Talia N Lerner, Carrie Shilyansky, Thomas J Davidson, Kathryn E Evans, Kevin T Beier, Kelly A Zalocusky, Ailey K Crow, Robert C Malenka, Liqun Luo, Raju Tomer, Karl Deisseroth
Recent progress in understanding the diversity of midbrain dopamine neurons has highlighted the importance--and the challenges--of defining mammalian neuronal cell types. Although neurons may be best categorized using inclusive criteria spanning biophysical properties, wiring of inputs, wiring of outputs, and activity during behavior, linking all of these measurements to cell types within the intact brains of living mammals has been difficult. Here, using an array of intact-brain circuit interrogation tools, including CLARITY, COLM, optogenetics, viral tracing, and fiber photometry, we explore the diversity of dopamine neurons within the substantia nigra pars compacta (SNc)...
July 30, 2015: Cell
Daniel J Christoffel, Sam A Golden, Jessica J Walsh, Kevin G Guise, Mitra Heshmati, Allyson K Friedman, Aditi Dey, Milo Smith, Nicole Rebusi, Madeline Pfau, Jessica L Ables, Hossein Aleyasin, Lena A Khibnik, Georgia E Hodes, Gabriel A Ben-Dor, Karl Deisseroth, Matthew L Shapiro, Robert C Malenka, Ines Ibanez-Tallon, Ming-Hu Han, Scott J Russo
Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.
July 2015: Nature Neuroscience
Hannah Alfonsa, Edward M Merricks, Neela K Codadu, Mark O Cunningham, Karl Deisseroth, Claudia Racca, Andrew J Trevelyan
Altered inhibitory function is an important facet of epileptic pathology. A key concept is that GABAergic activity can become excitatory if intraneuronal chloride rises. However, it has proved difficult to separate the role of raised chloride from other contributory factors in complex network phenomena, such as epileptic pathology. Therefore, we asked what patterns of activity are associated with chloride dysregulation by making novel use of Halorhodopsin to load clusters of mouse pyramidal cells artificially with Cl(-)...
May 20, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
M M Sidor, S M Spencer, K Dzirasa, P K Parekh, K M Tye, M R Warden, R N Arey, J F Enwright, J P R Jacobsen, S Kumar, E M Remillard, M G Caron, K Deisseroth, C A McClung
No abstract text is available yet for this article.
November 2015: Molecular Psychiatry
Yan Zhuge, Bhagat Patlolla, Charu Ramakrishnan, Ramin E Beygui, Christopher K Zarins, Karl Deisseroth, Ellen Kuhl, Oscar J Abilez
It is likely that arrhythmias should be avoided for therapies based on human pluripotent stem cell (hPSC)-derived cardiomyocytes (CM) to be effective. Towards achieving this goal, we introduced light-activated channelrhodopsin-2 (ChR2), a cation channel activated with 480 nm light, into human embryonic stem cells (hESC). By using in vitro approaches, hESC-CM are able to be activated with light. ChR2 is stably transduced into undifferentiated hESC via a lentiviral vector. Via directed differentiation, hESC(ChR2)-CM are produced and subjected to optical stimulation...
2014: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
M M Sidor, S M Spencer, K Dzirasa, P K Parekh, K M Tye, M R Warden, R N Arey, J F Enwright, J P R Jacobsen, S Kumar, E M Remillard, M G Caron, K Deisseroth, C A McClung
Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night...
November 2015: Molecular Psychiatry
Michelle Y Cheng, Eric H Wang, Wyatt J Woodson, Stephanie Wang, Guohua Sun, Alex G Lee, Ahmet Arac, Lief E Fenno, Karl Deisseroth, Gary K Steinberg
Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery...
September 2, 2014: Proceedings of the National Academy of Sciences of the United States of America
Benjamin B Land, Nandakumar S Narayanan, Rong-Jian Liu, Carol A Gianessi, Catherine E Brayton, David M Grimaldi, Maysa Sarhan, Douglas J Guarnieri, Karl Deisseroth, George K Aghajanian, Ralph J DiLeone
Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents...
February 2014: Nature Neuroscience
Inna Sukhotinsky, Alexander M Chan, Omar J Ahmed, Vikram R Rao, Viviana Gradinaru, Charu Ramakrishnan, Karl Deisseroth, Ania K Majewska, Sydney S Cash
Epilepsy is a devastating disease, currently treated with medications, surgery or electrical stimulation. None of these approaches is totally effective and our ability to control seizures remains limited and complicated by frequent side effects. The emerging revolutionary technique of optogenetics enables manipulation of the activity of specific neuronal populations in vivo with exquisite spatiotemporal resolution using light. We used optogenetic approaches to test the role of hippocampal excitatory neurons in the lithium-pilocarpine model of acute elicited seizures in awake behaving rats...
2013: PloS One
Kwanghun Chung, Jenelle Wallace, Sung-Yon Kim, Sandhiya Kalyanasundaram, Aaron S Andalman, Thomas J Davidson, Julie J Mirzabekov, Kelly A Zalocusky, Joanna Mattis, Aleksandra K Denisin, Sally Pak, Hannah Bernstein, Charu Ramakrishnan, Logan Grosenick, Viviana Gradinaru, Karl Deisseroth
Obtaining high-resolution information from a complex system, while maintaining the global perspective needed to understand system function, represents a key challenge in biology. Here we address this challenge with a method (termed CLARITY) for the transformation of intact tissue into a nanoporous hydrogel-hybridized form (crosslinked to a three-dimensional network of hydrophilic polymers) that is fully assembled but optically transparent and macromolecule-permeable. Using mouse brains, we show intact-tissue imaging of long-range projections, local circuit wiring, cellular relationships, subcellular structures, protein complexes, nucleic acids and neurotransmitters...
May 16, 2013: Nature
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