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The Striatum Organizes 3D Behavior via Moment-to-Moment Action Selection

Jeffrey E. Markowitz, Winthrop F. Gillis, Celia C. Beron, Shay Q. Neufeld, Keiramarie Robertson, Neha D. Bhagat, Ralph E. Peterson, Emalee Peterson, Minsuk Hyun, Scott W. Linderman, Bernardo L. Sabatini, Sandeep Robert Datta
Cell
May 17th, 2018

Many naturalistic behaviors are built from modular components that are expressed sequentially. Although striatal circuits have been implicated in action selection and implementation, the neural mechanisms that compose behavior in unrestrained animals are not well understood. Here, we record bulk and cellular neural activity in the direct and indirect pathways of dorsolateral striatum (DLS) as mice spontaneously express action sequences. These experiments reveal that DLS neurons systematically encode information about the identity and ordering of sub-second 3D behavioral motifs; this encoding is facilitated by fast-timescale decorrelations between the direct and indirect pathways. Furthermore, lesioning the DLS prevents appropriate sequence assembly during exploratory or odor-evoked behaviors. By characterizing naturalistic behavior at neural timescales, these experiments identify a code for elemental 3D pose dynamics built from complementary pathway dynamics, support a role for DLS in constructing meaningful behavioral sequences, and suggest models for how actions are sculpted over time.

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Diametric neural ensemble dynamics in parkinsonian and dyskinetic states

Jones G. Parker, Jesse D. Marshall, Biafra Ahanonu, Yu-Wei Wu, Tony Hyun Kim, Benjamin F. Grewe, Yanping Zhang, Jin Zhong Li, Jun B. Ding, Michael D. Ehlers & Mark J. Schnitzer
Nature
May 02nd, 2018

Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson’s disease with the dopamine precursor L-DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during L-DOPA-induced dyskinesia. Normally, intermingled clusters of dSPNs and iSPNs coactivated before movement. Dopamine depletion unbalanced SPN activity rates and disrupted the movement-encoding iSPN clusters. Matching their clinical efficacy, L-DOPA or agonism of the D2 dopamine receptor reversed these abnormalities more effectively than agonism of the D1dopamine receptor. The opposite pathophysiology arose in L-DOPA-induced dyskinesia, during which iSPNs showed hypoactivity and dSPNs showed unclustered hyperactivity. Therefore, both the spatiotemporal profiles and rates of SPN activity appear crucial to striatal function, and next-generation treatments for basal ganglia disorders should target both facets of striatal activity.

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The Same Hippocampal CA1 Population Simultaneously Codes Temporal Information over Multiple Timescales

William Mau, David W. Sullivan, Nathaniel R. Kinsky, Michael E. Hasselmo, Marc W. Howard, Howard Eichenbaum
Current Biology
April 26th, 2018

It has long been hypothesized that a primary function of the hippocampus is to discover and exploit temporal relationships between events. Previously, it has been reported that sequences of “time cells” in the hippocampus extend for tens of seconds. Other studies have shown that neuronal firing in the hippocampus fluctuates over hours and days. Both of these mechanisms could enable temporal encoding of events over very different timescales. However, thus far, these two classes of phenomena have never been observed simultaneously, which is necessary to ascribe broad-range temporal coding to the hippocampus. Using in vivo calcium imaging in unrestrained mice, we observed sequences of hippocampal neurons that bridged a 10 s delay. Similar sequences were observed over multiple days, but the set of neurons participating in those sequences changed gradually. Thus, the same population of neurons that encodes temporal information over seconds can also be used to distinguish periods of time over much longer timescales. These results unify two previously separate paradigms of temporal processing in the hippocampus that support episodic memory.

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Neural Circuit Mechanisms of Social Behavior

Patrick Chen, Weizhe Hong
Neuron
April 4th, 2018

We live in a world that is largely socially constructed, and we are constantly involved in and fundamentally influenced by a broad array of complex social interactions. Social behaviors among conspecifics, either conflictive or cooperative, are exhibited by all sexually reproducing animal species and are essential for the health, survival, and reproduction of animals. Conversely, impairment in social function is a prominent feature of several neuropsychiatric disorders, such as autism spectrum disorders and schizophrenia. Despite the importance of social behaviors, many fundamental questions remain unanswered. How is social sensory information processed and integrated in the nervous system? How are different social behavioral decisions selected and modulated in brain circuits? Here we discuss conceptual issues and recent advances in our understanding of brain regions and neural circuit mechanisms underlying the regulation of social behaviors.

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Encoding of Danger by Parabrachial CGRP Neurons

Carlos A. Campos, Anna J. Bowen, Carolyn W. Roman & Richard D. Palmiter
Nature
March 21st, 2018

Animals must respond to various threats to survive. Neurons that express calcitonin gene-related peptide in the parabrachial nucleus (CGRPPBN neurons) relay sensory signals that contribute to satiation and pain-induced fear behaviour, but it is unclear how they encode these distinct processes. Here, by recording calcium transients in vivo from individual neurons in mice, we show that most CGRPPBN neurons are activated by noxious cutaneous (shock, heat, itch) and visceral stimuli (lipopolysaccharide). The same neurons are inhibited during feeding, but become activated during satiation, consistent with evidence that CGRPPBN neurons prevent overeating. CGRPPBN neurons are also activated during consumption of novel foods or by an auditory cue that has previously been paired with electrical footshocks. Correspondingly, silencing of CGRPPBN neurons attenuates the expression of food neophobia and conditioned fear responses. Therefore, in addition to transducing primary sensory danger signals, CGRPPBN neurons promote affective-behavioural states that limit harm in response to potential threats.

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Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data

Pengcheng Zhou, Shanna L Resendez, Jose Rodriguez-Romaguera, Jessica C Jimenez, Shay Q Neufeld, Andrea Giovannucci, Johannes Friedrich, Eftychios A Pnevmatikakis, Garret D Stuber, Rene Hen, Mazen A Kheirbek, Bernardo L Sabatini, Robert E Kass, Liam Paninski
eLife
February 22, 2018

In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data.

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A Hypothalamic Switch for REM and Non-REM Sleep

Kai-Siang Chen, Min Xu, Zhe Zhang, Wei-Cheng Chang, Thomas Gaj, David V. Schaffer, Yang Dan
Neuron
February 22, 2018

Rapid eye movement (REM) and non-REM (NREM) sleep are controlled by specific neuronal circuits. Here we show that galanin-expressing GABAergic neurons in the dorsomedial hypothalamus (DMH) comprise separate subpopulations with opposing effects on REM versus NREM sleep. Microendoscopic calcium imaging revealed diverse sleep-wake activity of DMH GABAergic neurons, but the galanin-expressing subset falls into two distinct groups, either selectively activated (REM-on) or suppressed (REM-off) during REM sleep. Retrogradely labeled, preoptic area (POA)-projecting galaninergic neurons are REM-off, whereas the raphe pallidus (RPA)-projecting neurons are primarily REM-on. Bidirectional optogenetic manipulations showed that the POA-projecting neurons promote NREM sleep and suppress REM sleep, while the RPA-projecting neurons have the opposite effects. Thus, REM/NREM switch is regulated antagonistically by DMH galaninergic neurons with intermingled cell bodies but distinct axon projections.

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Genetically encoded calcium indicator with NTnC-like design and enhanced fluorescence contrast and kinetics

D. A. Doronin,N. V. Barykina†,O. M. Subach,V. P. Sotskov,V. V. Plusnin,O. A. Ivleva,E. A. Isaakova,A. M. Varizhuk,G. E. Pozmogova,A. Y. Malyshev,I. V. Smirnov,K. D. Piatkevich,K. V. Anokhin,G. N. Enikolopov and F. V. Subach
BMC Biotechnology
February 13th, 2018

We demonstrate that expanding the family of NTnC-like calcium indicators is a promising strategy for the development of the next generation of GECIs with smaller molecule size and lower Ca2+ ions buffering capacity as compared with commonly used GECIs.

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Fast-Spiking Interneurons Supply Feedforward Control of Bursting, Calcium, and Plasticity for Efficient Learning

Scott F. Owen, Joshua D. Berke, Anatol C. Kreitzer
Cell
February 8th, 2018

Fast-spiking interneurons (FSIs) are a prominent class of forebrain GABAergic cells implicated in two seemingly independent network functions: gain control and network plasticity. Little is known, however, about how these roles interact. Here, we use a combination of cell-type-specific ablation, optogenetics, electrophysiology, imaging, and behavior to describe a unified mechanism by which striatal FSIs control burst firing, calcium influx, and synaptic plasticity in neighboring medium spiny projection neurons (MSNs). In vivo silencing of FSIs increased bursting, calcium transients, and AMPA/NMDA ratios in MSNs. In a motor sequence task, FSI silencing increased the frequency of calcium transients but reduced the specificity with which transients aligned to individual task events. Consistent with this, ablation of FSIs disrupted the acquisition of striatum-dependent egocentric learning strategies. Together, our data support a model in which feedforward inhibition from FSIs temporally restricts MSN bursting and calcium-dependent synaptic plasticity to facilitate striatum-dependent sequence learning.

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Dopamine neuron activity before action initiation gates and invigorates future movements

Joaquim Alves da Silva, Fatuel Tecuapetla, Vitor Paixão & Rui M. Costa
Nature
January 31st, 2018

Deciding when and whether to move is critical for survival. Loss of dopamine neurons (DANs) of the substantia nigra pars compacta (SNc) in patients with Parkinson’s disease causes deficits in movement initiation and slowness of movement1. The role of DANs in self-paced movement has mostly been attributed to their tonic activity, whereas phasic changes in DAN activity have been linked to reward prediction2,3. This model has recently been challenged by studies showing transient changes in DAN activity before or during self-paced movement initiation4,5,6,7. Nevertheless, the necessity of this activity for spontaneous movement initiation has not been demonstrated, nor has its relation to initiation versus ongoing movement been described. Here we show that a large proportion of SNc DANs, which did not overlap with reward-responsive DANs, transiently increased their activity before self-paced movement initiation in mice. This activity was not action-specific, and was related to the vigour of future movements. Inhibition of DANs when mice were immobile reduced the probability and vigour of future movements. Conversely, brief activation of DANs when mice were immobile increased the probability and vigour of future movements. Manipulations of dopamine activity after movement initiation did not affect ongoing movements. Similar findings were observed for the initiation and execution of learned action sequences. These findings causally implicate DAN activity before movement initiation in the probability and vigour of future movements.

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Anxiety Cells in a Hippocampal-Hypothalamic Circuit

Jessica C. Jimenez, Katy Su, Alexander R. Goldberg, Victor M. Luna, Jeremy S. Biane, Gokhan Ordek, Pengcheng Zhou, Samantha K. Ong, Matthew A. Wright, Larry Zweifel, Liam Paninski, René Hen, Mazen A. Kheirbek
Neuron
January 31st, 2018

The hippocampus is traditionally thought to transmit contextual information to limbic structures where it acquires valence. Using freely moving calcium imaging and optogenetics, we show that while the dorsal CA1 subregion of the hippocampus is enriched in place cells, ventral CA1 (vCA1) is enriched in anxiety cells that are activated by anxiogenic environments and required for avoidance behavior. Imaging cells defined by their projection target revealed that anxiety cells were enriched in the vCA1 population projecting to the lateral hypothalamic area (LHA) but not to the basal amygdala (BA). Consistent with this selectivity, optogenetic activation of vCA1 terminals in LHA but not BA increased anxiety and avoidance, while activation of terminals in BA but not LHA impaired contextual fear memory. Thus, the hippocampus encodes not only neutral but also valence-related contextual information, and the vCA1-LHA pathway is a direct route by which the hippocampus can rapidly influence innate anxiety behavior.

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Reward-Predictive Neural Activities in Striatal Striosome Compartments

Tomohiko Yoshizawa, Makoto Ito and Kenji Doya
eNeuro
January 29th, 2018

The striatum has been shown to play a critical role in reward prediction. It is composed of two neurochemically and anatomically distinct compartments known as the striosomes and the matrix. The striosomes comprise only about 15% of the striatum by volume and are distributed mosaically therein. Accordingly, it has been difficult to identify striosomal neurons in electrophysiological recordings and it has been unclear whether striosomal neurons, which project to midbrain dopaminergic neurons, engage in reward prediction. In this study, we utilized a mouse line (Sepw1-NP67) selectively expressing Cre in striosomal neurons, combined with endoscopic in vivo calcium imaging to selectively record activities of striosomal neurons during an odor-conditioning task. As mice learned the task, striosomal neurons in the dorsomedial striatum showed predictive activities to odor cues that were associated with water rewards or aversive air puffs. These activities were proportional to the expected reward or air-puff intensity. Intriguingly, repeated recordings of the same striosomal neurons over a period of weeks revealed that predictive activities were learning-stage specific. That is, these activities disappeared after continuous training. Furthermore, presentations of rewards or air puffs activated some striosomal neurons. These findings suggest that the striosomes participate in reward prediction with learning stage-specific neural ensembles, and that they also send reward and aversive signals to dopaminergic neurons.

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Regulation of REM and Non-REM Sleep by Periaqueductal GABAergic Neurons

Franz Weber, Johnny Phong Hoang Do, Shinjae Chung, Kevin T. Beier, Mike Bikov , Mohammad Saffari Doost & Yang Dan
Nature Communications
January 24th, 2018

Mammalian sleep consists of distinct rapid eye movement (REM) and non-REM (NREM) states. The midbrain region ventrolateral periaqueductal gray (vlPAG) is known to be important for gating REM sleep, but the underlying neuronal mechanism is not well understood. Here, we show that activating vlPAG GABAergic neurons in mice suppresses the initiation and maintenance of REM sleep while consolidating NREM sleep, partly through their projection to the dorsolateral pons. Cell-type-specific recording and calcium imaging reveal that most vlPAG GABAergic neurons are strongly suppressed at REM sleep onset and activated at its termination. In addition to the rapid changes at brain state transitions, their activity decreases gradually between REM sleep and is reset by each REM episode in a duration-dependent manner, mirroring the accumulation and dissipation of REM sleep pressure. Thus, vlPAG GABAergic neurons powerfully gate REM sleep, and their firing rate modulation may contribute to the ultradian rhythm of REM/NREM alternation.

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Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context

Akiko Wagatsumaa, Teruhiro Okuyamaa, Chen Suna, Lillian M. Smitha, Kuniya Abeb, and Susumu Tonegawa
PNAS
December 26, 2017

The memory for a new episode is formed immediately upon experience and can last up to a lifetime. It has been shown that the hippocampal network plays a fundamental role in the rapid acquisition of a memory of a one-time experience, in which the novelty component of the experience promotes the prompt formation of the memory. However, it remains unclear which neural circuits convey the novelty signal to the hippocampus for the single-trial learning. Here, we show that during encoding neuromodulatory input from locus coeruleus (LC) to CA3, but not CA1 or to the dentate gyrus, is necessary to facilitate novel contextual learning. Silencing LC activity during exposure to a novel context reduced subsequent reactivation of the engram cell ensembles in CA3 neurons and in downstream CA1 upon reexposure to the same context. Calcium imaging of the cells reactivated in both novel and familiar contexts revealed that suppression of LC inputs at the time of encoding resulted in more variable place fields in CA3 neurons. These results suggest that neuromodulatory input from LC to CA3 is crucial for the formation of a persistent memory in the hippocampus.

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Modulation of SF1 Neuron Activity Coordinately Regulates Both Feeding Behavior and Associated Emotional States

Paulius Viskaitis, Elaine E. Irvine, Mark A. Smith, Agharul I. Choudhury, Elisa Alvarez-Curto, Justyna A. Glegola, Darran G. Hardy, Silvia M.A. Pedroni, Maria R. Paiva Pessoa, Anushka B.P. Fernando, Loukia Katsouri, Alessandro Sardini, Mark A. Ungless, Graeme Milligan, Dominic J. Withers
Cell Reports
December 19, 2017

Feeding requires the integration of homeostatic drives with emotional states relevant to food procurement in potentially hostile environments. The ventromedial hypothalamus (VMH) regulates feeding and anxiety, but how these are controlled in a concerted manner remains unclear. Using pharmacogenetic, optogenetic, and calcium imaging approaches with a battery of behavioral assays, we demonstrate that VMH steroidogenic factor 1 (SF1) neurons constitute a nutritionally sensitive switch, modulating the competing motivations of feeding and avoidance of potentially dangerous environments. Acute alteration of SF1 neuronal activity alters food intake via changes in appetite and feeding-related behaviors, including locomotion, exploration, anxiety, and valence. In turn, intrinsic SF1 neuron activity is low during feeding and increases with both feeding termination and stress. Our findings identify SF1 neurons as a key part of the neurocircuitry that controls both feeding and related affective states, giving potential insights into the relationship between disordered eating and stress-associated psychological disorders in humans.

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Combined Social and Spatial Coding in a Descending Projection from the Prefrontal Cortex

Malavika Murugan, Hee Jae Jang, Michelle Park, Ellia M. Miller, Julia Cox, Joshua P. Taliaferro, Nathan F. Parker, Varun Bhave, Hong Hur, Yupu Liang, Alexander R. Nectow, Jonathan W. Pillow, & Ilana B. Witten
Cell
December 7th, 2017

Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target. To determine what information PL-NAc neurons convey, we selectively recorded from them and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially specific manipulation of these neurons bidirectionally regulated the formation of a social-spatial association. Thus, the unexpected combination of social and spatial information within the PL-NAc may contribute to social behavior by supporting social-spatial learning.

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Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake

Philip J. Ryan, Silvano I. Ross, Carlos A. Campos, Victor A. Derkach & Richard D. Palmiter
Nature Neuroscience
November 27 2017

Brain regions that regulate fluid satiation are not well characterized, yet are essential for understanding fluid homeostasis. We found that oxytocin-receptor-expressing neurons in the parabrachial nucleus of mice (OxtrPBN neurons) are key regulators of fluid satiation. Chemogenetic activation of OxtrPBN neurons robustly suppressed noncaloric fluid intake, but did not decrease food intake after fasting or salt intake following salt depletion; inactivation increased saline intake after dehydration and hypertonic saline injection. Under physiological conditions, OxtrPBN neurons were activated by fluid satiation and hypertonic saline injection. OxtrPBN neurons were directly innervated by oxytocin neurons in the paraventricular hypothalamus (OxtPVH neurons), which mildly attenuated fluid intake. Activation of neurons in the nucleus of the solitary tract substantially suppressed fluid intake and activated OxtrPBN neurons. Our results suggest that OxtrPBN neurons act as a key node in the fluid satiation neurocircuitry, which acts to decrease water and/or saline intake to prevent or attenuate hypervolemia and hypernatremia.

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The central amygdala controls learning in the lateral amygdala

Kai Yu, Sandra Ahrens, Xian Zhang, Hillary Schiff, Charu Ramakrishnan, Lief Fenno, Karl Deisseroth, Fei Zhao, Min-Hua Luo, Ling Gong, Miao He, Pengcheng Zhou, Liam Paninski & Bo Li
Nature Neuroscience
October 23 2017

Experience-driven synaptic plasticity in the lateral amygdala is thought to underlie the formation of associations between sensory stimuli and an ensuing threat. However, how the central amygdala participates in such a learning process remains unclear. Here we show that PKC-δ-expressing central amygdala neurons are essential for the synaptic plasticity underlying learning in the lateral amygdala, as they convey information about the unconditioned stimulus to lateral amygdala neurons during fear conditioning.

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Neuronal Representation of Social Information in the Medial Amygdala of Awake Behaving Mice

Ying Li, Alexander Mathis, Benjamin F. Grewe, Jessica A. Osterhout, Biafra Ahanonu, Mark J. Schnitzer, Venkatesh N. Murthy, Catherine Dulac
Cell
October 26 2017

The medial amygdala (MeA) plays a critical role in processing species- and sex-specific signals that trigger social and defensive behaviors. However, the principles by which this deep brain structure encodes social information is poorly understood. We used a miniature microscope to image the Ca2+dynamics of large neural ensembles in awake behaving mice and tracked the responses of MeA neurons over several months. These recordings revealed spatially intermingled subsets of MeA neurons with distinct temporal dynamics. The encoding of social information in the MeA differed between males and females and relied on information from both individual cells and neuronal populations. By performing long-term Ca2+ imaging across different social contexts, we found that sexual experience triggers lasting and sex-specific changes in MeA activity, which, in males, involve signaling by oxytocin. These findings reveal basic principles underlying the brain’s representation of social information and its modulation by intrinsic and extrinsic factors.

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Tracking the Same Neurons across Multiple Days in Ca2+ Imaging Data

Liron Sheintuch, Alon Rubin, Noa Brande-Eilat, Nitzan Geva, Noa Sadeh, Or Pinchasof, Yaniv Ziv
Cell Reports
October 24, 2017

Ca2+ imaging techniques permit time-lapse recordings of neuronal activity from large populations over weeks. However, without identifying the same neurons across imaging sessions (cell registration), longitudinal analysis of the neural code is restricted to population-level statistics. Accurate cell registration becomes challenging with increased numbers of cells, sessions, and inter-session intervals. Current cell registration practices, whether manual or automatic, do not quantitatively evaluate registration accuracy, possibly leading to data misinterpretation. We developed a probabilistic method that automatically registers cells across multiple sessions and estimates the registration confidence for each registered cell. Using large-scale Ca2+ imaging data recorded over weeks from the hippocampus and cortex of freely behaving mice, we show that our method performs more accurate registration than previously used routines, yielding estimated error rates <5%, and that the registration is scalable for many sessions. Thus, our method allows reliable longitudinal analysis of the same neurons over long time periods.

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Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex

Ryan Remedios, Ann Kennedy, Moriel Zelikowsky, Benjamin F. Grewe, Mark J. Schnitzer & David J. Anderson
Nature
October 19, 2017

All animals possess a repertoire of innate (or instinctive1, 2) behaviours, which can be performed without training. Whether such behaviours are mediated by anatomically distinct and/or genetically specified neural pathways remains unknown3, 4, 5. Here we report that neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience. Oestrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents6, 7, 8. We used microendoscopy9 to image Esr1+ neuronal activity in the VMHvl of male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles and to induce an attack response 24 h later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.

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Deconstruction of Corticospinal Circuits for Goal-Directed Motor Skills

Xuhua Wang, Yuanyuan Liu, Xinjian Li, Zicong Zhang, Hengfu Yang, Yu Zhang, Philip R. Williams, Noaf S.A. Alwahab, Kush Kapur, Bin Yu, Yiming Zhang, Mengying Chen, Haixia Ding, Charles R. Gerfen, Kuan Hong Wang, Zhigang He
Cell
September 21, 2017

Corticospinal neurons (CSNs) represent the direct cortical outputs to the spinal cord and play important roles in motor control across different species. However, their organizational principle remains unclear. By using a retrograde labeling system, we defined the requirement of CSNs in the execution of a skilled forelimb food-pellet retrieval task in mice. In vivo imaging of CSN activity during performance revealed the sequential activation of topographically ordered functional ensembles with moderate local mixing. Region-specific manipulations indicate that CSNs from caudal or rostral forelimb area control reaching or grasping, respectively, and both are required in the transitional pronation step. These region-specific CSNs terminate in different spinal levels and locations, therefore preferentially connecting with the premotor neurons of muscles engaged in different steps of the task. Together, our findings suggest that spatially defined groups of CSNs encode different movement modules, providing a logic for parallel-ordered corticospinal circuits to orchestrate multistep motor skills.

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The Spatiotemporal Organization of the Striatum Encodes Action Space

Andreas Klaus, Gabriela J. Martins, Vitor B. Paixao, Pengcheng Zhou, Liam Paninski, Rui M. Costa
Neuron
August 30, 2017

Activity in striatal direct- and indirect-pathway spiny projection neurons (SPNs) is critical for proper movement. However, little is known about the spatiotemporal organization of this activity. We investigated the spatiotemporal organization of SPN ensemble activity in mice during self-paced, natural movements using microendoscopic imaging. Activity in both pathways showed predominantly local but also some long-range correlations. Using a novel approach to cluster and quantify behaviors based on continuous accelerometer and video data, we found that SPN ensembles active during specific actions were spatially closer and more correlated overall. Furthermore, similarity between different actions corresponded to the similarity between SPN ensemble patterns, irrespective of movement speed. Consistently, the accuracy of decoding behavior from SPN ensemble patterns was directly related to the dissimilarity between behavioral clusters. These results identify a predominantly local, but not spatially compact, organization of direct- and indirect-pathway SPN activity that maps action space independently of movement speed.

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Central amygdala circuits modulate food consumption through a positive-valence mechanism

Amelia M Douglass, Hakan Kucukdereli, Marion Ponserre, Milica Markovic, Jan Gründemann, Cornelia Strobel, Pilar L Alcala Morales, Karl-Klaus Conzelmann, Andreas Lüthi & Rüdiger Klein
Nature Neuroscience
August 21, 2017

The complex behaviors underlying reward seeking and consumption are integral to organism survival. The hypothalamus and mesolimbic dopamine system are key mediators of these behaviors, yet regulation of appetitive and consummatory behaviors outside of these regions is poorly understood. The central nucleus of the amygdala (CeA) has been implicated in feeding and reward, but the neurons and circuit mechanisms that positively regulate these behaviors remain unclear. Here, we defined the neuronal mechanisms by which CeA neurons promote food consumption. Using in vivo activity manipulations and Ca2+ imaging in mice, we found that GABAergic serotonin receptor 2a (Htr2a)-expressing CeA neurons modulate food consumption, promote positive reinforcement and are active in vivo during eating. We demonstrated electrophysiologically, anatomically and behaviorally that intra-CeA and long-range circuit mechanisms underlie these behaviors. Finally, we showed that CeAHtr2a neurons receive inputs from feeding-relevant brain regions. Our results illustrate how defined CeA neural circuits positively regulate food consumption.

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Skin suturing and cortical surface viral infusion improves imaging of neuronal ensemble activity with head-mounted miniature microscopes

XinjianLi, Vania Y.Cao, Wenyu Zhang, Surjeet S.Mastwal, Qing Liu, Stephani Otte, Kuan Hong Wang
Journal of Neuroscience Methods
August 19, 2017

In vivo optical imaging of neural activity provides important insights into brain functions at the single-cell level. Cranial windows and virally delivered calcium indicators are commonly used for imaging cortical activity through two-photon microscopes in head-fixed animals. Recently, head-mounted one-photon microscopes have been developed for freely behaving animals. However, minimizing tissue damage from the virus injection procedure and maintaining window clarity for imaging can be technically challenging.

We used a wide-diameter glass pipette at the cortical surface for infusing the viral calcium reporter AAV-GCaMP6 into the cortex. After infusion, the scalp skin over the implanted optical window was sutured to facilitate postoperative recovery. The sutured scalp was removed approximately two weeks later and a miniature microscope was attached above the window to image neuronal activity in freely moving mice.

We found that cortical surface virus infusion efficiently labeled neurons in superficial layers, and scalp skin suturing helped to maintain the long-term clarity of optical windows. As a result, several hundred neurons could be recorded in freely moving animals.

Compared to intracortical virus injection and open-scalp postoperative recovery, our methods minimized tissue damage and dura overgrowth underneath the optical window, and significantly increased the experimental success rate and the yield of identified neurons.

Our improved cranial surgery technique allows for high-yield calcium imaging of cortical neurons with head-mounted microscopes in freely behaving animals. This technique may be beneficial for other optical applications such as two-photon microscopy, multi-site imaging, and optogenetic modulation.

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Distinct Neural Circuits for the Formation and Retrieval of Episodic Memories

Dheeraj S. Roy, Takashi Kitamura, Teruhiro Okuyama, Sachie K. Ogawa, Chen Sun, Yuichi Obata, Atsushi Yoshiki, and Susumu Tonegawa
Cell
August 17, 2017

The formation and retrieval of a memory is thought to be accomplished by activation and reactivation, respectively, of the memory-holding cells (engram cells) by a common set of neural circuits, but this hypothesis has not been established. The medial temporal-lobe system is essential for the formation and retrieval of episodic memory for which individual hippocampal subfields and entorhinal cortex layers contribute by carrying out specific functions. One subfield whose function is poorly known is the subiculum. Here, we show that dorsal subiculum and the circuit, CA1 to dorsal subiculum to medial entorhinal cortex layer 5, play a crucial role selectively in the retrieval of episodic memories. Conversely, the direct CA1 to medial entorhinal cortex layer 5 circuit is essential specifically for memory formation. Our data suggest that the subiculum-containing detour loop is dedicated to meet the requirements associated with recall such as rapid memory updating and retrieval-driven instinctive fear responses.

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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
JoVE
June 13, 2017

In vivo circuit and cellular level functional imaging is a critical tool for understanding the brain in action. High resolution imaging of mouse cortical neurons with two-photon microscopy has provided unique insights into cortical structure, function and plasticity. However, these studies are limited to head fixed animals, greatly reducing the behavioral complexity available for study. In this paper, we describe a procedure for performing chronic fluorescence microscopy with cellular-resolution across multiple cortical layers in freely behaving mice. We used an integrated miniaturized fluorescence microscope paired with an implanted prism probe to simultaneously visualize and record the calcium dynamics of hundreds of neurons across multiple layers of the somatosensory cortex as the mouse engaged in a novel object exploration task, over several days. This technique can be adapted to other brain regions in different animal species for other behavioral paradigms.

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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 6, 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.

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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 15, 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.

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

Tsukasa Kamigaki, Yang Dan
Nature Neuroscience
April 24, 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.

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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 7, 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.

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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 3, 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.

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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 22, 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.

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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 20, 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.

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Circuit-based interrogation of sleep control

Franz Weber, Yang Dan
Nature
October 5, 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.

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Ventral CA1 neurons store social memory

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

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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 28, 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.

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Decreasing striatopallidal pathway function enhances motivation by energizing the initiation of goal-directed action

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

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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 9, 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.

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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 5, 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.

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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 29, 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). 

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

Julia Cox, Lucas Pinto, Yang Dan
Nature Communications
February 25, 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).

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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 25, 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.

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Hippocampal ensemble dynamics timestamp events in long-term memory

Alon Rubin, Nitzan Geva, Liron Sheintuch, Yaniv Ziv
eLife
December 18, 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.

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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 23, 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. Read
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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 13, 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.

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Cell-type-specific activity in prefrontal cortex during goal-directed behavior

Lucas Pinto, Yang Dan
Neuron
July 2, 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.

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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 3, 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.

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Hunger logic

Richard Palmiter
Nature Neuroscience
May 26, 2015

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

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

Yaniv Ziv, Kunal Ghosh
Current Opinion in Neurobiology
May 16, 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.

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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 27, 2016

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.

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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 8, 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.

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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 29, 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.

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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 5, 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.

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Tools for resolving functional activity and connectivity within intact neural circuits

Joshua H. Jennings, Garret D. Stuber
Current Biology
January 6, 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.

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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 6, 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.

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Engineering approaches to illuminating brain structure and dynamics

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

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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 20, 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. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function.

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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 10, 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.

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Miniaturized integration of a fluorescence microscope

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

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