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Multi-layer cortical calcium imaging in freely moving mice with prism probes and miniaturized fluorescence microscopy

Srishti Gulati, Vania Cao, Stephani Otte
The Journal of Visual Experiments
June 13th, 2017

 In vivo circuit and cellular level functional imaging is a critical tool for understanding the brain in action.

Cell Reports Logo

Dorsal-CA1 Hippocampal Neuronal Ensembles Encode Nicotine-Reward Contextual Associations

Li Xia, Stephanie K. Nygard, Gabe G. Sobczak, Nicholas J. Hourguettes, Michael R. Bruchas
Cell Reports
June 6th, 2017

Natural and drug rewards increase the motivational valence of stimuli in the environment that, through Pavlovian learning mechanisms, become conditioned stimuli that directly motivate behavior in the absence of the original unconditioned stimulus. While the hippocampus has received extensive attention for its role in learning and memory processes, less is known regarding its role in drug-reward associations.

Nature Neuroscience Logo

Identification of a motor-to-auditory pathway important for vocal learning

Todd F Roberts, Erin Hisey, Masashi Tanaka, Matthew G Kearney, Gaurav Chattree, Cindy F Yang, Nirao M Shah, Richard Mooney
Nature Neuroscience
May 15th, 2017

Learning to vocalize depends on the ability to adaptively modify the temporal and spectral features of vocal elements. Neurons that convey motor-related signals to the auditory system are theorized to facilitate vocal learning, but the identity and function of such neurons remain unknown. Here we identify a previously unknown neuron type in the songbird brain that transmits vocal motor signals to the auditory cortex. Genetically ablating these neurons in juveniles disrupted their ability to imitate features of an adult tutor's song.

Nature Neuroscience Logo

Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior

Tsukasa Kamigaki, Yang Dan
Nature Neuroscience
April 24th, 2017

Memory-guided behavior requires maintenance of task-relevant information without sensory input, but the underlying circuit mechanism remains unclear. Calcium imaging in mice performing a delayed Go or No-Go task revealed robust delay activity in dorsomedial prefrontal cortex, with different pyramidal neurons signaling Go and No-Go action plans.

Engrams and circuits crucial for systems consolidation of a memory

Takashi Kitamura, Sachie K. Ogawa, Dheeraj S. Roy, Teruhiro Okuyama, Mark D. Morrissey, Lillian M. Smith, Roger L. Redondo, Susumu Tonegawa
Science
April 7th, 2017

Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation have thus far been unknown.We found that neocortical prefrontal memory engram cells, which are critical for remote contextual fear memory, were rapidly generated during initial learning through inputs from both the hippocampal–entorhinal cortex network and the basolateral amygdala.

The Journal of Neuroscience Logo

Active dentate granule cells encode experience to promote the addition of adult-born hippocampal neurons

Gregory W. Kirschen, Jia Shen, Mu Tian, Bryce Schroeder, Jia Wang, Guoming Man, Song Wu and Shaoyu Ge
The Journal of Neuroscience
April 3rd, 2017

The continuous addition of new dentate granule cells, exquisitely regulated by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to impact the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca2+ imaging to track the real-time activity of individual dentate granule cells in freely-behaving mice.

Neural ensemble dynamics underlying a long-term associative memory

Benjamin F. Grewe, Jan Gründemann, Lacey J. Kitch, Jerome A. Lecoq, Jones G. Parker, Jesse D. Marshall, Margaret C. Larkin, Pablo E. Jercog, Francois Grenier, Jin Zhong Li, Andreas Lüthi, Mark J. Schnitzer
Nature
March 22nd, 2017

The brain’s ability to associate different stimuli is vital for long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli (CS and US, respectively). Using a miniature fluorescence microscope, we tracked the Ca2+dynamics of ensembles of amygdalar neurons during fear learning and extinction over 6 days in behaving mice.

Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval

Chun Xu, Sabine Krabbe, Jan Gründemann, Paolo Botta, Jonathan P. Fadok, Fumitaka Osakada, Dieter Saur, Benjamin F. Grewe, Mark J. Schnitzer, Edward M. Callaway, Andreas Lüthi
Cell
October 20th, 2016

Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways.

Circuit-based interrogation of sleep control

Franz Weber, Yang Dan
Nature
October 5th, 2016

Sleep is a fundamental biological process observed widely in the animal kingdom, but the neural circuits generating sleep remain poorly understood. Understanding the brain mechanisms controlling sleep requires the identification of key neurons in the control circuits and mapping of their synaptic connections. Technical innovations over the past decade have greatly facilitated dissection of the sleep circuits. This has set the stage for understanding how a variety of environmental and physiological factors influence sleep.

Science Journal

Ventral CA1 neurons store social memory

Teruhiro Okuyama, Takashi Kitamura, Dheeraj S. Roy, Shigeyoshi Itohara, Susumu Tonegawa
Science
September 30th, 2016

The medial temporal lobe, including the hippocampus, has been implicated in social memory. However, it remains unknown which parts of these brain regions and their circuits hold social memory. Here, we show that ventral hippocampal CA1 (vCA1) neurons of a mouse and their projections to nucleus accumbens (NAc) shell play a necessary and sufficient role in social memory. Both the proportion of activated vCA1 cells and the strength and stability of the responding cells are greater in response to a familiar mouse than to a previously unencountered mouse.

A new design for a green calcium indicator with a smaller size and a reduced number of calcium-binding sites

Natalia V. Barykina, Oksana M. Subach, Danila A. Doronin, Vladimir P. Sotskov, Marina A. Roshchina, Tatiana A. Kunitsyna, Aleksey Y. Malyshev, Ivan V. Smirnov, Asya M. Azieva, Ilya S. Sokolov, Kiryl D. Piatkevich, Mikhail S. Burtsev, Anna M. Varizhuk, Galina E. Pozmogova, Konstantin V. Anokhin, Fedor V. Subach, Grigori N. Enikolopov
Scientific Reports
September 28th, 2016

Genetically encoded calcium indicators (GECIs) are mainly represented by two- or one-fluorophore-based sensors. One type of two-fluorophore-based sensor, carrying Opsanus troponin C (TnC) as the Ca2+-binding moiety, has two binding sites for calcium ions, providing a linear response to calcium ions. One-fluorophore-based sensors have four Ca2+-binding sites but are better suited for in vivo experiments.

Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action

Fernanda Carvalho Poyraz, Eva Holzner1, Matthew R. Bailey, Jozsef Meszaros, Lindsay Kenney, Mazen A. Kheirbek, Peter D. Balsam, Christoph Kellendonk
The Journal of Neuroscience
June 1st, 2016

Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OEdev mice) are reversed by decreasing function of the striatopallidal “no-go” pathway. To this end, we expressed the Gαi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO).

Frontiers in Neural Circuits

Calcium Imaging of Basal Forebrain Activity during Innate and Learned Behaviors

Thomas C. Harrison, Lucas Pinto, Julien R. Brock, Yang Dan
Frontiers in Neural Circuits
May 9th, 2016

The basal forebrain (BF) plays crucial roles in arousal, attention, and memory, and its impairment is associated with a variety of cognitive deficits. The BF consists of cholinergic, GABAergic, and glutamatergic neurons. Electrical or optogenetic stimulation of BF cholinergic neurons enhances cortical processing and behavioral performance, but the natural activity of these cells during behavior is only beginning to be characterized. Even less is known about GABAergic and glutamatergic neurons.

Cold Spring Harbor Perspectives In Biology

Large-Scale Fluorescence Calcium-Imaging Methods for Studies of Long-Term Memory in Behaving Mammals

Pablo Jercog, Thomas Rogerson, Mark J. Schnitzer
Cold Spring Harbor Perspectives In Biology
April 5th, 2016

During long-term memory formation, cellular and molecular processes reshape how individual neurons respond to specific patterns of synaptic input. It remains poorly understood how such changes impact information processing across networks of mammalian neurons. To observe how networks encode, store, and retrieve information, neuroscientists must track the dynamics of large ensembles of individual cells in behaving animals, over timescales commensurate with long-term memory.

Frontiers in Neuroscience

Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice

Tamara K. Berdyyeva, E. Paxon Frady, Jonathan J. Nassi, Leah Aluisio, Yauheniya Cherkas, Stephani Otte, Ryan M. Wyatt, Christine Dugovic, Kunal K. Ghosh, Mark J. Schnitzer, Timothy Lovenberg, Pascal Bonaventure
Frontiers in Neuroscience
February 29th, 2016

Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). 

Nature Communications

Calcium imaging of sleep–wake related neuronal activity in the dorsal pons

Julia Cox, Lucas Pinto, Yang Dan
Nature Communications
February 25th, 2016

The dorsal pons has long been implicated in the generation of rapid eye movement (REM) sleep, but the underlying circuit mechanisms remain poorly understood. Using cell-type-specific microendoscopic Ca2+ imaging in and near the laterodorsal tegmental nucleus, we found that many glutamatergic neurons are maximally active during REM sleep (REM-max), while the majority of GABAergic neurons are maximally active during wakefulness (wake-max).

Nature Protocols

Visualization of cortical, subcortical and deep brain neural circuit dynamics during naturalistic mammalian behavior with head-mounted microscopes and chronically implanted lenses

Shanna L Resendez, Josh H Jennings, Randall L Ung, Vijay Mohan K Namboodiri, Zhe Charles Zhou, James M Otis, Hiroshi Nomura, Jenna A McHenry, Oksana Kosyk, Garret D Stuber
Nature Protocols
February 25th, 2016

Genetically encoded calcium indicators for visualizing dynamic cellular activity have greatly expanded our understanding of the brain. However, owing to the light-scattering properties of the brain, as well as the size and rigidity of traditional imaging technology, in vivo calcium imaging has been limited to superficial brain structures during head-fixed behavioral tasks.

Hippocampal ensemble dynamics timestamp events in long-term memory

Hippocampal ensemble dynamics timestamp events in long-term memory

Alon Rubin, Nitzan Geva, Liron Sheintuch, Yaniv Ziv
eLife Sciences
December 18th, 2015

The capacity to remember temporal relationships between different events is essential to episodic memory, but little is currently known about its underlying mechanisms. We performed time-lapse imaging of thousands of neurons over weeks in the hippocampal CA1 of mice as they repeatedly visited two distinct environments. Longitudinal analysis exposed ongoing environment-independent evolution of episodic representations, despite stable place field locations and constant remapping between the two environments.

Entorhinal Cortical Ocean Cells Encode Specific Contexts and Drive Context-Specific Fear Memory

Takashi Kitamura, Chen Sun, Jared Martin, Lacey J. Kitch, Mark J. Schnitzer, Susumu Tonegawa
Neuron
September 23rd, 2015

Forming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions, but the role of the entorhinal cortex (EC) is poorly understood.

Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells - PNAS Logo

Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells

Chen Sun, Takashi Kitamura, Jun Yamamoto, Jared Martin, Michele Pignatelli, Lacey J. Kitch, Mark J. Schnitzer, Susumu Tonegawa
PNAS
July 13th, 2015

Entorhinal–hippocampal circuits in the mammalian brain are crucial for an animal’s spatial and episodic experience, but the neural basis for different spatial computations remain unknown. Medial entorhinal cortex layer II contains pyramidal island and stellate ocean cells. Here, we performed cell type-specific Ca2+ imaging in freely exploring mice using cellular markers and a miniature head-mounted fluorescence microscope.

Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells - Neuron Journal  Logo

Cell-Type-Specific Activity in Prefrontal Cortex during Goal-Directed Behavior

Lucas Pinto, Yang Dan
Neuron
July 2nd, 2015

The prefrontal cortex (PFC) plays a key role in controlling goal-directed behavior. Although a variety of task-related signals have been observed in the PFC, whether they are differentially encoded by various cell types remains unclear. Here we performed cellular-resolution microendoscopic Ca2+ imaging from genetically defined cell types in the dorsomedial PFC of mice performing a PFC-dependent sensory discrimination task.

Mesoscopic Patterns of Neural Activity Support Songbird Cortical Sequences - PLOS Biology Logo

Mesoscopic Patterns of Neural Activity Support Songbird Cortical Sequences

Jeffrey E. Markowitz, William A. Liberti III, Grigori Guitchounts, Tarciso Velho, Carlos Lois, Timothy J. Gardner
PLOS Biology
June 3rd, 2015

Time-locked sequences of neural activity can be found throughout the vertebrate forebrain in various species and behavioral contexts. From “time cells” in the hippocampus of rodents to cortical activity controlling movement, temporal sequence generation is integral to many forms of learned behavior. However, the mechanisms underlying sequence generation are not well known. Here, we describe a spatial and temporal organization of the songbird premotor cortical microcircuit that supports sparse sequences of neural activity.

Hunger Logic

Richard Palmiter
Nature Neuroscience
May 26th, 2015

Activation of AgRP-expressing 'hunger' neurons promotes robust feeding. Recent studies reveal the valence, dynamics and neural circuits engaged by AgRP neurons.

Miniature microscopes for large-scale imaging of neuronal activity in freely behaving rodents

Yaniv Ziv, Kunal Ghosh
Current Opinion in Neurobiology
May 16th, 2015

Recording neuronal activity in behaving subjects has been instrumental in studying how information is represented and processed by the brain. Recent advances in optical imaging and bioengineering have converged to enable time-lapse, cell-type specific recordings of neuronal activities from large neuronal populations in deep-brain structures of freely behaving rodents. We will highlight these advancements, with an emphasis on miniaturized integrated microscopy for large-scale imaging in freely behaving mice.

Neurons for hunger and thirst transmit a negative-valence teaching signal

J. Nicholas Betley, Shengjin Xu, Zhen Fang Huang Cao, Rong Gong, Christopher J. Magnus, Yang Yu & Scott M. Sternson
Nature
April 27th, 2015

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice.

Cellular Level Brain Imaging in Behaving Mammals: An Engineering Approach

Elizabeth J.O. Hamel, Benjamin F. Grewe, Jones G. Parker, Mark J. Schnitzer
Neuron
April 8th, 2015

Fluorescence imaging offers expanding capabilities for recording neural dynamics in behaving mammals, including the means to monitor hundreds of cells targeted by genetic type or connectivity, track cells over weeks, densely sample neurons within local microcircuits, study cells too inactive to isolate in extracellular electrical recordings, and visualize activity in dendrites, axons, or dendritic spines.

Visualizing Hypothalamic Network Dynamics for Appetitive and Consummatory Behaviors

J. Jennings, R. L. Ung, S.L. Resendez, A.M. Stamatakis, J.G. Taylor, J. Huang, K. Veleta, P.A. Kantak, M. Aita, K. Shilling-Scrivo, C. Ramakrishnan, K. Deisseroth, S. Otte, G.D. Stuber
Cell
January 29th, 2015

Optimally orchestrating complex behavioral states, such as the pursuit and consumption of food, is critical for an organism's survival. The lateral hypothalamus (LH) is a neuroanatomical region essential for appetitive and consummatory behaviors, but whether individual neurons within the LH differentially contribute to these interconnected processes is unknown.

Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

Tamara Berdyyeva, Stephani Otte, Leah Aluisio, Yaniv Ziv, Laurie D. Burns, Christine Dugovic, Sujin Yun, Kunal K. Ghosh, Mark J. Schnitzer, Timothy Lovenberg, Pascal Bonaventure
PLOS ONE
November 5th, 2014

Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics.

Tools for Resolving Functional Activity and Connectivity within Intact Neural Circuits

Joshua H. Jennings, Garret D. Stuber
Curr Biol. Cell Press
January 6th, 2014

Mammalian neural circuits are sophisticated biological systems that choreograph behavioral processes vital for survival. While the inherent complexity of discrete neural circuits has proven difficult to decipher, many parallel methodological developments promise to help delineate the function and connectivity of molecularly defined neural circuits. Here, we review recent technological advances designed to precisely monitor and manipulate neural circuit activity.

The Journal of Neuroscience

Imaging Neuronal Populations in Behaving Rodents: Paradigms for Studying Neural Circuits Underlying Behavior in the Mammalian Cortex

Chen J., Andermann M., Keck T., Xu N., Ziv Y.
The Journal of Neuroscience
November 6th, 2013

Understanding the neural correlates of behavior in the mammalian cortex requires measurements of activity in awake, behaving animals. Rodents have emerged as a powerful model for dissecting the cortical circuits underlying behavior attributable to the convergence of several methods. Genetically encoded calcium indicators combined with viral-mediated or transgenic tools enable chronic monitoring of calcium signals in neuronal populations and subcellular structures of identified cell types.

Engineering Approaches to Illuminating Brain Structure and Dynamics

Deisseroth K., Schnitzer M.
Neuron
October 30th, 2013

Historical milestones in neuroscience have come in diverse forms, ranging from the resolution of specific biological mysteries via creative experimentation to broad technological advances allowing neuroscientists to ask new kinds of questions. The continuous development of tools is driven with a special necessity by the complexity, fragility, and inaccessibility of intact nervous systems, such that inventive technique development and application drawing upon engineering and the applied sciences has long been essential to neuroscience.

ACS Nano

Nanotools for Neuroscience and Brain Activity Mapping

Alivisatos A.P., Andrews A., Boyden E., Chun M., Church G., Deisseroth K., Donoghue J., Fraser S., Lippincott-Schwartz J., Looger L., Masmanidis S., McEuen P., Nurmikko A., Park H., Peterka D., Reid C., Roukes M., Scherer A., Schnitzer M., Sejnowski T., Shepard K., Tsao D., Turrigiano G., Weiss P., Xu C., Yuste R., Zhuang X.
ACS Nano
March 20th, 2013

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters.

Nature Neuroscience

Long-term dynamics of CA1 hippocampal place codes

Ziv Y., Burns L., Cocker E., Hamel E., Ghosh K., Kitch L., Gamal A., Schnitzer M.
Nature Neuroscience
February 10th, 2013

Using Ca2+ imaging in freely behaving mice that repeatedly explored a familiar environment, we tracked thousands of CA1 pyramidal cells' place fields over weeks. Place coding was dynamic, as each day the ensemble representation of this environment involved a unique subset of cells. However, cells in the ∼15-25% overlap between any two of these subsets retained the same place fields, which sufficed to preserve an accurate spatial representation across weeks.

CSHL

In vivo microendoscopy of the hippocampus

Barretto R., Schnitzer M.
Cold Spring Harbor Protocols
October 1st, 2012

Conventional intravital microscopy has generally been limited to superficial brain areas such as the olfactory bulb, the neocortex, or the cerebellar cortex. In vivo optical microendoscopy uses gradient refractive index (GRIN) microlenses that can be inserted into tissue to image cells in deeper areas. This protocol describes in vivo microendoscopy of the mouse hippocampus. The general methodology can be applied to many deep brain regions and other areas of the body.

Nature Methods

Miniaturized integration of a fluorescence microscope

Ghosh K., Burns L., Cocker E., Nimmerjahn A., Ziv Y., Gamal A., Schnitzer M.
Nature Methods
September 11th, 2011

The light microscope is traditionally an instrument of substantial size and expense. Its miniaturized integration would enable many new applications based on mass-producible, tiny microscopes. Key prospective usages include brain imaging in behaving animals for relating cellular dynamics to animal behavior. Here we introduce a miniature (1.9 g) integrated fluorescence microscope made from mass-producible parts, including a semiconductor light source and sensor. This device enables high-speed cellular imaging across ∼0.5 mm2 areas in active mice.

Nature Neuroscience Logo

Identification of a motor-to-auditory pathway important for vocal learning

Todd F Roberts, Erin Hisey, Masashi Tanaka, Matthew G Kearney, Gaurav Chattree, Cindy F Yang, Nirao M Shah, Richard Mooney
Nature Neuroscience
May 15th, 2017

Learning to vocalize depends on the ability to adaptively modify the temporal and spectral features of vocal elements. Neurons that convey motor-related signals to the auditory system are theorized to facilitate vocal learning, but the identity and function of such neurons remain unknown. Here we identify a previously unknown neuron type in the songbird brain that transmits vocal motor signals to the auditory cortex. Genetically ablating these neurons in juveniles disrupted their ability to imitate features of an adult tutor's song.

Nature Neuroscience Logo

Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior

Tsukasa Kamigaki, Yang Dan
Nature Neuroscience
April 24th, 2017

Memory-guided behavior requires maintenance of task-relevant information without sensory input, but the underlying circuit mechanism remains unclear. Calcium imaging in mice performing a delayed Go or No-Go task revealed robust delay activity in dorsomedial prefrontal cortex, with different pyramidal neurons signaling Go and No-Go action plans.

Engrams and circuits crucial for systems consolidation of a memory

Takashi Kitamura, Sachie K. Ogawa, Dheeraj S. Roy, Teruhiro Okuyama, Mark D. Morrissey, Lillian M. Smith, Roger L. Redondo, Susumu Tonegawa
Science
April 7th, 2017

Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation have thus far been unknown.We found that neocortical prefrontal memory engram cells, which are critical for remote contextual fear memory, were rapidly generated during initial learning through inputs from both the hippocampal–entorhinal cortex network and the basolateral amygdala.

The Journal of Neuroscience Logo

Active dentate granule cells encode experience to promote the addition of adult-born hippocampal neurons

Gregory W. Kirschen, Jia Shen, Mu Tian, Bryce Schroeder, Jia Wang, Guoming Man, Song Wu and Shaoyu Ge
The Journal of Neuroscience
April 3rd, 2017

The continuous addition of new dentate granule cells, exquisitely regulated by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to impact the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca2+ imaging to track the real-time activity of individual dentate granule cells in freely-behaving mice.

Neural ensemble dynamics underlying a long-term associative memory

Benjamin F. Grewe, Jan Gründemann, Lacey J. Kitch, Jerome A. Lecoq, Jones G. Parker, Jesse D. Marshall, Margaret C. Larkin, Pablo E. Jercog, Francois Grenier, Jin Zhong Li, Andreas Lüthi, Mark J. Schnitzer
Nature
March 22nd, 2017

The brain’s ability to associate different stimuli is vital for long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli (CS and US, respectively). Using a miniature fluorescence microscope, we tracked the Ca2+dynamics of ensembles of amygdalar neurons during fear learning and extinction over 6 days in behaving mice.

Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval

Chun Xu, Sabine Krabbe, Jan Gründemann, Paolo Botta, Jonathan P. Fadok, Fumitaka Osakada, Dieter Saur, Benjamin F. Grewe, Mark J. Schnitzer, Edward M. Callaway, Andreas Lüthi
Cell
October 20th, 2016

Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways.

Science Journal

Ventral CA1 neurons store social memory

Teruhiro Okuyama, Takashi Kitamura, Dheeraj S. Roy, Shigeyoshi Itohara, Susumu Tonegawa
Science
September 30th, 2016

The medial temporal lobe, including the hippocampus, has been implicated in social memory. However, it remains unknown which parts of these brain regions and their circuits hold social memory. Here, we show that ventral hippocampal CA1 (vCA1) neurons of a mouse and their projections to nucleus accumbens (NAc) shell play a necessary and sufficient role in social memory. Both the proportion of activated vCA1 cells and the strength and stability of the responding cells are greater in response to a familiar mouse than to a previously unencountered mouse.

Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action

Fernanda Carvalho Poyraz, Eva Holzner1, Matthew R. Bailey, Jozsef Meszaros, Lindsay Kenney, Mazen A. Kheirbek, Peter D. Balsam, Christoph Kellendonk
The Journal of Neuroscience
June 1st, 2016

Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OEdev mice) are reversed by decreasing function of the striatopallidal “no-go” pathway. To this end, we expressed the Gαi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO).

Frontiers in Neural Circuits

Calcium Imaging of Basal Forebrain Activity during Innate and Learned Behaviors

Thomas C. Harrison, Lucas Pinto, Julien R. Brock, Yang Dan
Frontiers in Neural Circuits
May 9th, 2016

The basal forebrain (BF) plays crucial roles in arousal, attention, and memory, and its impairment is associated with a variety of cognitive deficits. The BF consists of cholinergic, GABAergic, and glutamatergic neurons. Electrical or optogenetic stimulation of BF cholinergic neurons enhances cortical processing and behavioral performance, but the natural activity of these cells during behavior is only beginning to be characterized. Even less is known about GABAergic and glutamatergic neurons.

Frontiers in Neuroscience

Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice

Tamara K. Berdyyeva, E. Paxon Frady, Jonathan J. Nassi, Leah Aluisio, Yauheniya Cherkas, Stephani Otte, Ryan M. Wyatt, Christine Dugovic, Kunal K. Ghosh, Mark J. Schnitzer, Timothy Lovenberg, Pascal Bonaventure
Frontiers in Neuroscience
February 29th, 2016

Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). 

Nature Communications

Calcium imaging of sleep–wake related neuronal activity in the dorsal pons

Julia Cox, Lucas Pinto, Yang Dan
Nature Communications
February 25th, 2016

The dorsal pons has long been implicated in the generation of rapid eye movement (REM) sleep, but the underlying circuit mechanisms remain poorly understood. Using cell-type-specific microendoscopic Ca2+ imaging in and near the laterodorsal tegmental nucleus, we found that many glutamatergic neurons are maximally active during REM sleep (REM-max), while the majority of GABAergic neurons are maximally active during wakefulness (wake-max).

Nature Protocols

Visualization of cortical, subcortical and deep brain neural circuit dynamics during naturalistic mammalian behavior with head-mounted microscopes and chronically implanted lenses

Shanna L Resendez, Josh H Jennings, Randall L Ung, Vijay Mohan K Namboodiri, Zhe Charles Zhou, James M Otis, Hiroshi Nomura, Jenna A McHenry, Oksana Kosyk, Garret D Stuber
Nature Protocols
February 25th, 2016

Genetically encoded calcium indicators for visualizing dynamic cellular activity have greatly expanded our understanding of the brain. However, owing to the light-scattering properties of the brain, as well as the size and rigidity of traditional imaging technology, in vivo calcium imaging has been limited to superficial brain structures during head-fixed behavioral tasks.

Hippocampal ensemble dynamics timestamp events in long-term memory

Hippocampal ensemble dynamics timestamp events in long-term memory

Alon Rubin, Nitzan Geva, Liron Sheintuch, Yaniv Ziv
eLife Sciences
December 18th, 2015

The capacity to remember temporal relationships between different events is essential to episodic memory, but little is currently known about its underlying mechanisms. We performed time-lapse imaging of thousands of neurons over weeks in the hippocampal CA1 of mice as they repeatedly visited two distinct environments. Longitudinal analysis exposed ongoing environment-independent evolution of episodic representations, despite stable place field locations and constant remapping between the two environments.

Entorhinal Cortical Ocean Cells Encode Specific Contexts and Drive Context-Specific Fear Memory

Takashi Kitamura, Chen Sun, Jared Martin, Lacey J. Kitch, Mark J. Schnitzer, Susumu Tonegawa
Neuron
September 23rd, 2015

Forming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions, but the role of the entorhinal cortex (EC) is poorly understood.

Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells - PNAS Logo

Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells

Chen Sun, Takashi Kitamura, Jun Yamamoto, Jared Martin, Michele Pignatelli, Lacey J. Kitch, Mark J. Schnitzer, Susumu Tonegawa
PNAS
July 13th, 2015

Entorhinal–hippocampal circuits in the mammalian brain are crucial for an animal’s spatial and episodic experience, but the neural basis for different spatial computations remain unknown. Medial entorhinal cortex layer II contains pyramidal island and stellate ocean cells. Here, we performed cell type-specific Ca2+ imaging in freely exploring mice using cellular markers and a miniature head-mounted fluorescence microscope.

Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells - Neuron Journal  Logo

Cell-Type-Specific Activity in Prefrontal Cortex during Goal-Directed Behavior

Lucas Pinto, Yang Dan
Neuron
July 2nd, 2015

The prefrontal cortex (PFC) plays a key role in controlling goal-directed behavior. Although a variety of task-related signals have been observed in the PFC, whether they are differentially encoded by various cell types remains unclear. Here we performed cellular-resolution microendoscopic Ca2+ imaging from genetically defined cell types in the dorsomedial PFC of mice performing a PFC-dependent sensory discrimination task.

Mesoscopic Patterns of Neural Activity Support Songbird Cortical Sequences - PLOS Biology Logo

Mesoscopic Patterns of Neural Activity Support Songbird Cortical Sequences

Jeffrey E. Markowitz, William A. Liberti III, Grigori Guitchounts, Tarciso Velho, Carlos Lois, Timothy J. Gardner
PLOS Biology
June 3rd, 2015

Time-locked sequences of neural activity can be found throughout the vertebrate forebrain in various species and behavioral contexts. From “time cells” in the hippocampus of rodents to cortical activity controlling movement, temporal sequence generation is integral to many forms of learned behavior. However, the mechanisms underlying sequence generation are not well known. Here, we describe a spatial and temporal organization of the songbird premotor cortical microcircuit that supports sparse sequences of neural activity.

Neurons for hunger and thirst transmit a negative-valence teaching signal

J. Nicholas Betley, Shengjin Xu, Zhen Fang Huang Cao, Rong Gong, Christopher J. Magnus, Yang Yu & Scott M. Sternson
Nature
April 27th, 2015

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice.

Visualizing Hypothalamic Network Dynamics for Appetitive and Consummatory Behaviors

J. Jennings, R. L. Ung, S.L. Resendez, A.M. Stamatakis, J.G. Taylor, J. Huang, K. Veleta, P.A. Kantak, M. Aita, K. Shilling-Scrivo, C. Ramakrishnan, K. Deisseroth, S. Otte, G.D. Stuber
Cell
January 29th, 2015

Optimally orchestrating complex behavioral states, such as the pursuit and consumption of food, is critical for an organism's survival. The lateral hypothalamus (LH) is a neuroanatomical region essential for appetitive and consummatory behaviors, but whether individual neurons within the LH differentially contribute to these interconnected processes is unknown.

Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

Tamara Berdyyeva, Stephani Otte, Leah Aluisio, Yaniv Ziv, Laurie D. Burns, Christine Dugovic, Sujin Yun, Kunal K. Ghosh, Mark J. Schnitzer, Timothy Lovenberg, Pascal Bonaventure
PLOS ONE
November 5th, 2014

Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics.

Nature Neuroscience

Long-term dynamics of CA1 hippocampal place codes

Ziv Y., Burns L., Cocker E., Hamel E., Ghosh K., Kitch L., Gamal A., Schnitzer M.
Nature Neuroscience
February 10th, 2013

Using Ca2+ imaging in freely behaving mice that repeatedly explored a familiar environment, we tracked thousands of CA1 pyramidal cells' place fields over weeks. Place coding was dynamic, as each day the ensemble representation of this environment involved a unique subset of cells. However, cells in the ∼15-25% overlap between any two of these subsets retained the same place fields, which sufficed to preserve an accurate spatial representation across weeks.

A new design for a green calcium indicator with a smaller size and a reduced number of calcium-binding sites

Natalia V. Barykina, Oksana M. Subach, Danila A. Doronin, Vladimir P. Sotskov, Marina A. Roshchina, Tatiana A. Kunitsyna, Aleksey Y. Malyshev, Ivan V. Smirnov, Asya M. Azieva, Ilya S. Sokolov, Kiryl D. Piatkevich, Mikhail S. Burtsev, Anna M. Varizhuk, Galina E. Pozmogova, Konstantin V. Anokhin, Fedor V. Subach, Grigori N. Enikolopov
Scientific Reports
September 28th, 2016

Genetically encoded calcium indicators (GECIs) are mainly represented by two- or one-fluorophore-based sensors. One type of two-fluorophore-based sensor, carrying Opsanus troponin C (TnC) as the Ca2+-binding moiety, has two binding sites for calcium ions, providing a linear response to calcium ions. One-fluorophore-based sensors have four Ca2+-binding sites but are better suited for in vivo experiments.

Nature Protocols

Visualization of cortical, subcortical and deep brain neural circuit dynamics during naturalistic mammalian behavior with head-mounted microscopes and chronically implanted lenses

Shanna L Resendez, Josh H Jennings, Randall L Ung, Vijay Mohan K Namboodiri, Zhe Charles Zhou, James M Otis, Hiroshi Nomura, Jenna A McHenry, Oksana Kosyk, Garret D Stuber
Nature Protocols
February 25th, 2016

Genetically encoded calcium indicators for visualizing dynamic cellular activity have greatly expanded our understanding of the brain. However, owing to the light-scattering properties of the brain, as well as the size and rigidity of traditional imaging technology, in vivo calcium imaging has been limited to superficial brain structures during head-fixed behavioral tasks.

Neurons for hunger and thirst transmit a negative-valence teaching signal

J. Nicholas Betley, Shengjin Xu, Zhen Fang Huang Cao, Rong Gong, Christopher J. Magnus, Yang Yu & Scott M. Sternson
Nature
April 27th, 2015

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice.

Visualizing Hypothalamic Network Dynamics for Appetitive and Consummatory Behaviors

J. Jennings, R. L. Ung, S.L. Resendez, A.M. Stamatakis, J.G. Taylor, J. Huang, K. Veleta, P.A. Kantak, M. Aita, K. Shilling-Scrivo, C. Ramakrishnan, K. Deisseroth, S. Otte, G.D. Stuber
Cell
January 29th, 2015

Optimally orchestrating complex behavioral states, such as the pursuit and consumption of food, is critical for an organism's survival. The lateral hypothalamus (LH) is a neuroanatomical region essential for appetitive and consummatory behaviors, but whether individual neurons within the LH differentially contribute to these interconnected processes is unknown.

Nature Methods

Miniaturized integration of a fluorescence microscope

Ghosh K., Burns L., Cocker E., Nimmerjahn A., Ziv Y., Gamal A., Schnitzer M.
Nature Methods
September 11th, 2011

The light microscope is traditionally an instrument of substantial size and expense. Its miniaturized integration would enable many new applications based on mass-producible, tiny microscopes. Key prospective usages include brain imaging in behaving animals for relating cellular dynamics to animal behavior. Here we introduce a miniature (1.9 g) integrated fluorescence microscope made from mass-producible parts, including a semiconductor light source and sensor. This device enables high-speed cellular imaging across ∼0.5 mm2 areas in active mice.

Circuit-based interrogation of sleep control

Franz Weber, Yang Dan
Nature
October 5th, 2016

Sleep is a fundamental biological process observed widely in the animal kingdom, but the neural circuits generating sleep remain poorly understood. Understanding the brain mechanisms controlling sleep requires the identification of key neurons in the control circuits and mapping of their synaptic connections. Technical innovations over the past decade have greatly facilitated dissection of the sleep circuits. This has set the stage for understanding how a variety of environmental and physiological factors influence sleep.

Cold Spring Harbor Perspectives In Biology

Large-Scale Fluorescence Calcium-Imaging Methods for Studies of Long-Term Memory in Behaving Mammals

Pablo Jercog, Thomas Rogerson, Mark J. Schnitzer
Cold Spring Harbor Perspectives In Biology
April 5th, 2016

During long-term memory formation, cellular and molecular processes reshape how individual neurons respond to specific patterns of synaptic input. It remains poorly understood how such changes impact information processing across networks of mammalian neurons. To observe how networks encode, store, and retrieve information, neuroscientists must track the dynamics of large ensembles of individual cells in behaving animals, over timescales commensurate with long-term memory.

Hunger Logic

Richard Palmiter
Nature Neuroscience
May 26th, 2015

Activation of AgRP-expressing 'hunger' neurons promotes robust feeding. Recent studies reveal the valence, dynamics and neural circuits engaged by AgRP neurons.

Miniature microscopes for large-scale imaging of neuronal activity in freely behaving rodents

Yaniv Ziv, Kunal Ghosh
Current Opinion in Neurobiology
May 16th, 2015

Recording neuronal activity in behaving subjects has been instrumental in studying how information is represented and processed by the brain. Recent advances in optical imaging and bioengineering have converged to enable time-lapse, cell-type specific recordings of neuronal activities from large neuronal populations in deep-brain structures of freely behaving rodents. We will highlight these advancements, with an emphasis on miniaturized integrated microscopy for large-scale imaging in freely behaving mice.

Cellular Level Brain Imaging in Behaving Mammals: An Engineering Approach

Elizabeth J.O. Hamel, Benjamin F. Grewe, Jones G. Parker, Mark J. Schnitzer
Neuron
April 8th, 2015

Fluorescence imaging offers expanding capabilities for recording neural dynamics in behaving mammals, including the means to monitor hundreds of cells targeted by genetic type or connectivity, track cells over weeks, densely sample neurons within local microcircuits, study cells too inactive to isolate in extracellular electrical recordings, and visualize activity in dendrites, axons, or dendritic spines.

Tools for Resolving Functional Activity and Connectivity within Intact Neural Circuits

Joshua H. Jennings, Garret D. Stuber
Curr Biol. Cell Press
January 6th, 2014

Mammalian neural circuits are sophisticated biological systems that choreograph behavioral processes vital for survival. While the inherent complexity of discrete neural circuits has proven difficult to decipher, many parallel methodological developments promise to help delineate the function and connectivity of molecularly defined neural circuits. Here, we review recent technological advances designed to precisely monitor and manipulate neural circuit activity.

The Journal of Neuroscience

Imaging Neuronal Populations in Behaving Rodents: Paradigms for Studying Neural Circuits Underlying Behavior in the Mammalian Cortex

Chen J., Andermann M., Keck T., Xu N., Ziv Y.
The Journal of Neuroscience
November 6th, 2013

Understanding the neural correlates of behavior in the mammalian cortex requires measurements of activity in awake, behaving animals. Rodents have emerged as a powerful model for dissecting the cortical circuits underlying behavior attributable to the convergence of several methods. Genetically encoded calcium indicators combined with viral-mediated or transgenic tools enable chronic monitoring of calcium signals in neuronal populations and subcellular structures of identified cell types.

Engineering Approaches to Illuminating Brain Structure and Dynamics

Deisseroth K., Schnitzer M.
Neuron
October 30th, 2013

Historical milestones in neuroscience have come in diverse forms, ranging from the resolution of specific biological mysteries via creative experimentation to broad technological advances allowing neuroscientists to ask new kinds of questions. The continuous development of tools is driven with a special necessity by the complexity, fragility, and inaccessibility of intact nervous systems, such that inventive technique development and application drawing upon engineering and the applied sciences has long been essential to neuroscience.

ACS Nano

Nanotools for Neuroscience and Brain Activity Mapping

Alivisatos A.P., Andrews A., Boyden E., Chun M., Church G., Deisseroth K., Donoghue J., Fraser S., Lippincott-Schwartz J., Looger L., Masmanidis S., McEuen P., Nurmikko A., Park H., Peterka D., Reid C., Roukes M., Scherer A., Schnitzer M., Sejnowski T., Shepard K., Tsao D., Turrigiano G., Weiss P., Xu C., Yuste R., Zhuang X.
ACS Nano
March 20th, 2013

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters.

CSHL

In vivo microendoscopy of the hippocampus

Barretto R., Schnitzer M.
Cold Spring Harbor Protocols
October 1st, 2012

Conventional intravital microscopy has generally been limited to superficial brain areas such as the olfactory bulb, the neocortex, or the cerebellar cortex. In vivo optical microendoscopy uses gradient refractive index (GRIN) microlenses that can be inserted into tissue to image cells in deeper areas. This protocol describes in vivo microendoscopy of the mouse hippocampus. The general methodology can be applied to many deep brain regions and other areas of the body.

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