@article {49369, title = {Inhibitory control of prefrontal cortex by the claustrum.}, journal = {Neuron}, volume = {99}, year = {2018}, month = {2018 Aug 07}, pages = {1029-39}, abstract = {

The claustrum is a small subcortical nucleus that has extensive excitatory connections with many cortical areas. While the anatomical connectivity from the claustrum to the cortex has been studied intensively, the physiological effect and underlying circuit mechanisms of claustrocortical communication remain elusive. Here we show that the claustrum provides strong, widespread, and long-lasting feedforward inhibition of the prefrontal cortex (PFC) sufficient to silence ongoing neural activity. This claustrocortical feedforward inhibition was predominantly mediated by interneurons containing neuropeptide Y, and to a lesser extent those containing parvalbumin. Therefore, in contrast to other long-range excitatory inputs to the PFC, the claustrocortical pathway is designed to provide overall inhibition of cortical activity. This unique circuit organization allows the claustrum to rapidly and powerfully suppress cortical networks and suggests a distinct role for the claustrum in regulating cognitive processes in prefrontal circuits.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2018.07.031}, author = {Jackson, Jesse and Karnani, Mahesh M and Zemelman, Boris V and Burdakov, Denis and Lee, Albert K} } @article {47087, title = {Inhibitory gating of input comparison in the CA1 microcircuit.}, journal = {Neuron}, volume = {87}, year = {2015}, month = {2015 Sep 23}, pages = {1274-89}, abstract = {

Spatial and temporal features of synaptic inputs engage integration mechanisms on multiple scales, including presynaptic release sites, postsynaptic dendrites, and networks of inhibitory interneurons. Here we investigate how these mechanisms cooperate to filter synaptic input in hippocampal area CA1. Dendritic recordings from CA1 pyramidal neurons reveal that proximal inputs from CA3 as well as distal inputs from entorhinal cortex layer III (ECIII) sum sublinearly or linearly at low firing rates due to feedforward inhibition, but sum supralinearly at high firing rates due to synaptic facilitation, producing a high-pass filter. However, during ECIII and CA3 input comparison, supralinear dendritic integration is dynamically balanced by feedforward and\ feedback inhibition, resulting in suppression of dendritic complex spiking. We find that a particular subpopulation of CA1 interneurons expressing neuropeptide Y (NPY) contributes prominently to this dynamic filter by integrating both ECIII and CA3 input pathways and potently inhibiting CA1 pyramidal neuron dendrites.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.08.025}, author = {Milstein, Aaron D and Bloss, Erik B and Apostolides, Pierre F and Vaidya, Sachin P and Dilly, Geoffrey A and Zemelman, Boris V and Magee, Jeffrey C} } @article {45852, title = {Live imaging of endogenous PSD-95 using ENABLED: a conditional strategy to fluorescently label endogenous proteins.}, journal = {Journal of Neuroscience}, volume = {34}, year = {2014}, month = {2014 Dec 10}, pages = {16698-712}, abstract = {

Stoichiometric labeling of endogenous synaptic proteins for high-contrast live-cell imaging in brain tissue remains challenging. Here, we describe a conditional mouse genetic strategy termed endogenous labeling via exon duplication (ENABLED), which can be used to fluorescently label endogenous proteins with near ideal properties in all neurons, a sparse subset of neurons, or specific neuronal subtypes. We used this method to label the postsynaptic density protein PSD-95 with mVenus without overexpression side effects. We demonstrated that mVenus-tagged PSD-95 is functionally equivalent to wild-type PSD-95 and that PSD-95 is present in nearly all dendritic spines in CA1 neurons. Within spines, while PSD-95 exhibited low mobility under basal conditions, its levels could be regulated by chronic changes in neuronal activity. Notably, labeled PSD-95 also allowed us to visualize and unambiguously examine otherwise-unidentifiable excitatory shaft synapses in aspiny neurons, such as parvalbumin-positive interneurons and dopaminergic neurons. Our results demonstrate that the ENABLED strategy provides a valuable new approach to study the dynamics of endogenous synaptic proteins in vivo.

}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.3888-14.2014}, author = {Fortin, Dale A and Tillo, Shane E and Yang, Guang and Rah, Jong-Cheol and Melander, Joshua B and Bai, Suxia and Soler-Cede{\~n}o, Omar and Qin, Maozhen and Zemelman, Boris V and Guo, Caiying and Mao, Tianyi and Zhong, Haining} } @article {5924, title = {Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition.}, journal = {Nature neuroscience}, volume = {15}, year = {2012}, month = {2012 May}, pages = {769-75}, abstract = {A consortium of inhibitory neurons control the firing patterns of pyramidal cells, but their specific roles in the behaving animal are largely unknown. We performed simultaneous physiological recordings and optogenetic silencing of either perisomatic (parvalbumin (PV) expressing) or dendrite-targeting (somatostatin (SOM) expressing) interneurons in hippocampal area CA1 of head-fixed mice actively moving a treadmill belt rich with visual-tactile stimuli. Silencing of either PV or SOM interneurons increased the firing rates of pyramidal cells selectively in their place fields, with PV and SOM interneurons having their largest effect during the rising and decaying parts of the place field, respectively. SOM interneuron silencing powerfully increased burst firing without altering the theta phase of spikes. In contrast, PV interneuron silencing had no effect on burst firing, but instead shifted the spikes{\textquoteright} theta phase toward the trough of theta. These findings indicate that perisomatic and dendritic inhibition have distinct roles in controlling the rate, burst and timing of hippocampal pyramidal cells.}, keywords = {Action Potentials, Animal, Animals, Behavior, Biophysics, Dendrites, Electric Stimulation, Exercise Test, Green Fluorescent Proteins, Halorhodopsins, Hippocampus, Humans, Inbred C57BL, Light, Mice, Movement, Neural Inhibition, Neurons, Optics and Photonics, Parvalbumins, Patch-Clamp Techniques, Photic Stimulation, Probability, Somatostatin, Spectrum Analysis, Time Factors, Time Perception, Touch, Transgenic}, issn = {1546-1726}, doi = {10.1038/nn.3077}, author = {Royer, S{\'e}bastien and Zemelman, Boris V and Losonczy, Attila and Kim, Jinhyun and Chance, Frances and Magee, Jeffrey C and Buzs{\'a}ki, Gy{\"o}rgy} } @article {4594, title = {Regulation of neuronal input transformations by tunable dendritic inhibition.}, journal = {Nature Neuroscience}, volume = {15}, year = {2012}, month = {2012 Jan 15}, pages = {423-30}, abstract = {

Transforming synaptic input into action potential output is a fundamental function of neurons. The pattern of action potential output from principal cells of the mammalian hippocampus encodes spatial and nonspatial information, but the cellular and circuit mechanisms by which neurons transform their synaptic input into a given output are unknown. Using a combination of optical activation and cell type-specific pharmacogenetic silencing in vitro, we found that dendritic inhibition is the primary regulator of input-output transformations in mouse hippocampal CA1 pyramidal cells, and acts by gating the dendritic electrogenesis driving burst spiking. Dendrite-targeting interneurons are themselves modulated by interneurons targeting pyramidal cell somata, providing a synaptic substrate for tuning pyramidal cell output through interactions in the local inhibitory network. These results provide evidence for a division of labor in cortical circuits, where distinct computational functions are implemented by subtypes of local inhibitory neurons.

}, issn = {1546-1726}, doi = {10.1038/nn.3024}, author = {Lovett-Barron, Matthew and Turi, Gergely F and Kaifosh, Patrick and Lee, Peter H and Bolze, Fr{\'e}d{\'e}ric and Sun, Xiao-Hua and Nicoud, Jean-Fran\c cois and Zemelman, Boris V and Sternson, Scott M and Losonczy, Attila} } @article {3930, title = {Imaging light responses of targeted neuron populations in the rodent retina.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {31}, year = {2011}, month = {2011 Feb 23}, pages = {2855-67}, abstract = {

Decoding the wiring diagram of the retina requires simultaneous observation of activity in identified neuron populations. Available recording methods are limited in their scope: electrodes can access only a small fraction of neurons at once, whereas synthetic fluorescent indicator dyes label tissue indiscriminately. Here, we describe a method for studying retinal circuitry at cellular and subcellular levels combining two-photon microscopy and a genetically encoded calcium indicator. Using specific viral and promoter constructs to drive expression of GCaMP3, we labeled all five major neuron classes in the adult mouse retina. Stimulus-evoked GCaMP3 responses as imaged by two-photon microscopy permitted functional cell type annotation. Fluorescence responses were similar to those measured with the small molecule dye OGB-1. Fluorescence intensity correlated linearly with spike rates \>10 spikes/s, and a significant change in fluorescence always reflected a significant change in spike firing rate. GCaMP3 expression had no apparent effect on neuronal function. Imaging at subcellular resolution showed compartment-specific calcium dynamics in multiple identified cell types.

}, keywords = {Action Potentials, Animals, Female, Inbred C57BL, Male, Mice, Neurons, Ocular, Organ Culture Techniques, Retina, Vision, Voltage-Sensitive Dye Imaging}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.6064-10.2011}, author = {Borghuis, Bart G and Tian, Lin and Xu, Ying and Nikonov, Sergei S and Vardi, Noga and Zemelman, Boris V and Looger, Loren L} } @article {2121, title = {Multi-array silicon probes with integrated optical fibers: light-assisted perturbation and recording of local neural circuits in the behaving animal.}, journal = {The European Journal of Neuroscience}, volume = {31}, year = {2010}, month = {2010 Jun}, pages = {2279-91}, abstract = {

Recordings of large neuronal ensembles and neural stimulation of high spatial and temporal precision are important requisites for studying the real-time dynamics of neural networks. Multiple-shank silicon probes enable large-scale monitoring of individual neurons. Optical stimulation of genetically targeted neurons expressing light-sensitive channels or other fast (milliseconds) actuators offers the means for controlled perturbation of local circuits. Here we describe a method to equip the shanks of silicon probes with micron-scale light guides for allowing the simultaneous use of the two approaches. We then show illustrative examples of how these compact hybrid electrodes can be used in probing local circuits in behaving rats and mice. A key advantage of these devices is the enhanced spatial precision of stimulation that is achieved by delivering light close to the recording sites of the probe. When paired with the expression of light-sensitive actuators within genetically specified neuronal populations, these devices allow the relatively straightforward and interpretable manipulation of network activity.

}, keywords = {Action Potentials, Animal, Animals, Behavior, Electric Stimulation, Electrophysiology, Light, Mice, Neurons, Neuropsychological Tests, Optical Fibers, Photic Stimulation, Rats, Recombinant Fusion Proteins, Silicon}, issn = {1460-9568}, doi = {10.1002/cbic.201000254}, author = {Royer, S{\'e}bastien and Zemelman, Boris V and Barbic, Mladen and Losonczy, Attila and Buzs{\'a}ki, Gy{\"o}rgy and Magee, Jeffrey C} } @article {3911, title = {Network mechanisms of theta related neuronal activity in hippocampal CA1 pyramidal neurons.}, journal = {Nature Neuroscience}, volume = {13}, year = {2010}, month = {2010 Aug}, pages = {967-72}, abstract = {

Although hippocampal theta oscillations represent a prime example of temporal coding in the mammalian brain, little is known about the specific biophysical mechanisms. Intracellular recordings support a particular abstract oscillatory interference model of hippocampal theta activity, the soma-dendrite interference model. To gain insight into the cellular and circuit level mechanisms of theta activity, we implemented a similar form of interference using the actual hippocampal network in mice in vitro. We found that pairing increasing levels of phasic dendritic excitation with phasic stimulation of perisomatic projecting inhibitory interneurons induced a somatic polarization and action potential timing profile that reproduced most common features. Alterations in the temporal profile of inhibition were required to fully capture all features. These data suggest that theta-related place cell activity is generated through an interaction between a phasic dendritic excitation and a phasic perisomatic shunting inhibition delivered by interneurons, a subset of which undergo activity-dependent presynaptic modulation.

}, keywords = {Animals, Gene Knock-In Techniques, Hippocampus, Inbred C57BL, Inhibitory Postsynaptic Potentials, Mice, Nerve Net, Organ Culture Techniques, Patch-Clamp Techniques, Pyramidal Cells, Theta Rhythm}, issn = {1546-1726}, doi = {10.1038/nn.2597}, author = {Losonczy, Attila and Zemelman, Boris V and Vaziri, Alipasha and Magee, Jeffrey C} } @article {4284, title = {Two-photon single-cell optogenetic control of neuronal activity by sculpted light.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, year = {2010}, month = {2010 Jun 29}, pages = {11981-6}, abstract = {

Recent advances in optogenetic techniques have generated new tools for controlling neuronal activity, with a wide range of neuroscience applications. The most commonly used approach has been the optical activation of the light-gated ion channel channelrhodopsin-2 (ChR2). However, targeted single-cell-level optogenetic activation with temporal precessions comparable to the spike timing remained challenging. Here we report fast (\< or = 1 ms), selective, and targeted control of neuronal activity with single-cell resolution in hippocampal slices. Using temporally focused laser pulses (TEFO) for which the axial beam profile can be controlled independently of its lateral distribution, large numbers of channels on individual neurons can be excited simultaneously, leading to strong (up to 15 mV) and fast (\< or = 1 ms) depolarizations. Furthermore, we demonstrated selective activation of cellular compartments, such as dendrites and large presynaptic terminals, at depths up to 150 microm. The demonstrated spatiotemporal resolution and the selectivity provided by TEFO allow manipulation of neuronal activity, with a large number of applications in studies of neuronal microcircuit function in vitro and in vivo.

}, keywords = {Action Potentials, Animals, Cell Line, Dendrites, Electrophysiological Phenomena, Hippocampus, Humans, Lasers, Mice, Nerve Tissue Proteins, Neurons, Optical Phenomena, Patch-Clamp Techniques, Photic Stimulation, Photons, Presynaptic Terminals, Rats, Recombinant Fusion Proteins, Rhodopsin, Sprague-Dawley, Transgenic}, issn = {1091-6490}, doi = {10.1073/pnas.1006620107}, author = {Andrasfalvy, Bertalan K and Zemelman, Boris V and Tang, Jianyong and Vaziri, Alipasha} } @article {3913, title = {Fast synaptic subcortical control of hippocampal circuits.}, journal = {Science}, volume = {326}, year = {2009}, month = {2009 Oct 16}, pages = {449-53}, abstract = {

Cortical information processing is under state-dependent control of subcortical neuromodulatory systems. Although this modulatory effect is thought to be mediated mainly by slow nonsynaptic metabotropic receptors, other mechanisms, such as direct synaptic transmission, are possible. Yet, it is currently unknown if any such form of subcortical control exists. Here, we present direct evidence of a strong, spatiotemporally precise excitatory input from an ascending neuromodulatory center. Selective stimulation of serotonergic median raphe neurons produced a rapid activation of hippocampal interneurons. At the network level, this subcortical drive was manifested as a pattern of effective disynaptic GABAergic inhibition that spread throughout the circuit. This form of subcortical network regulation should be incorporated into current concepts of normal and pathological cortical function.

}, keywords = {Afferent, Animals, Electric Stimulation, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Inhibitory Postsynaptic Potentials, Interneurons, Mice, Neural Inhibition, Neural Pathways, Neurons, Patch-Clamp Techniques, Photic Stimulation, Raphe Nuclei, Rats, Serotonin, Sprague-Dawley, Synapses, Synaptic Potentials}, issn = {1095-9203}, doi = {10.1126/science.1178307}, author = {Varga, Viktor and Losonczy, Attila and Zemelman, Boris V and Borhegyi, Zsolt and Nyiri, G{\'a}bor and Domonkos, Andor and Hangya, Bal{\'a}zs and Holderith, No{\'e}mi and Magee, Jeffrey C and Freund, Tam{\'a}s F} }