Publications by authors named "Alex C Kwan"

34 Publications

A visuomotor microcircuit in frontal cortex.

Nat Neurosci 2021 10;24(10):1345-1347

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1038/s41593-021-00915-4DOI Listing
October 2021

A database and deep learning toolbox for noise-optimized, generalized spike inference from calcium imaging.

Nat Neurosci 2021 09 2;24(9):1324-1337. Epub 2021 Aug 2.

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

Inference of action potentials ('spikes') from neuronal calcium signals is complicated by the scarcity of simultaneous measurements of action potentials and calcium signals ('ground truth'). In this study, we compiled a large, diverse ground truth database from publicly available and newly performed recordings in zebrafish and mice covering a broad range of calcium indicators, cell types and signal-to-noise ratios, comprising a total of more than 35 recording hours from 298 neurons. We developed an algorithm for spike inference (termed CASCADE) that is based on supervised deep networks, takes advantage of the ground truth database, infers absolute spike rates and outperforms existing model-based algorithms. To optimize performance for unseen imaging data, CASCADE retrains itself by resampling ground truth data to match the respective sampling rate and noise level; therefore, no parameters need to be adjusted by the user. In addition, we developed systematic performance assessments for unseen data, openly released a resource toolbox and provide a user-friendly cloud-based implementation.
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http://dx.doi.org/10.1038/s41593-021-00895-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611618PMC
September 2021

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.

Neuron 2021 08 5;109(16):2535-2544.e4. Epub 2021 Jul 5.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA; Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address:

Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and timescale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.
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http://dx.doi.org/10.1016/j.neuron.2021.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376772PMC
August 2021

Ketamine for a Boost of Neural Plasticity: How, but Also When?

Biol Psychiatry 2021 06;89(11):1030-1032

Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2021.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190578PMC
June 2021

Secondary motor cortex: Broadcasting and biasing animal's decisions through long-range circuits.

Int Rev Neurobiol 2021 25;158:443-470. Epub 2020 Dec 25.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States; Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States. Electronic address:

Medial secondary motor cortex (MOs or M2) constitutes the dorsal aspect of the rodent medial frontal cortex. We previously proposed that the function of MOs is to link antecedent conditions, including sensory stimuli and prior choices, to impending actions. In this review, we focus on the long-range pathways between MOs and other cortical and subcortical regions. We highlight three circuits: (1) connections with visual and auditory cortices that are essential for predictive coding of perceptual inputs; (2) connections with motor cortex and brainstem that are responsible for top-down, context-dependent modulation of movements; (3) connections with retrosplenial cortex, orbitofrontal cortex, and basal ganglia that facilitate reward-based learning. Together, these long-range circuits allow MOs to broadcast choice signals for feedback and to bias decision-making processes.
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http://dx.doi.org/10.1016/bs.irn.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190828PMC
December 2020

Applying Reinforcement Learning to Rodent Stress Research.

Chronic Stress (Thousand Oaks) 2021 Jan-Dec;5:2470547020984732. Epub 2021 Feb 1.

Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, USA.

Rodent models are an invaluable tool for studying the pathophysiological mechanisms underlying stress and depressive disorders. However, the widely used behavioral assays to measure depressive-like states in rodents have serious limitations. In this commentary, we suggest that learning tasks, particularly those that can be analyzed with the framework of reinforcement learning, are ideal for assaying reward processing deficits relevant to depression. The key advantages of these tasks are their repeatable, quantifiable nature and the link to clinical studies. By optimizing the behavioral readout of stress-induced phenotypes in rodents, a reinforcement learning-based approach may help bridge the translational gap and advance antidepressant discovery.
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http://dx.doi.org/10.1177/2470547020984732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863143PMC
February 2021

A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics.

Trends Neurosci 2021 04 21;44(4):260-275. Epub 2020 Dec 21.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address:

Pilot studies have hinted that serotonergic psychedelics such as psilocybin may relieve depression, and could possibly do so by promoting neural plasticity. Intriguingly, another psychotomimetic compound, ketamine, is a fast-acting antidepressant and induces synapse formation. The similarities in behavioral and neural effects have been puzzling because the compounds target distinct molecular receptors in the brain. In this opinion article, we develop a conceptual framework that suggests the actions of ketamine and serotonergic psychedelics may converge at the dendrites, to both enhance and suppress membrane excitability. We speculate that mismatches in the opposing actions on dendritic excitability may relate to these compounds' cell-type and region selectivity, their moderate range of effects and toxicity, and their plasticity-promoting capacities.
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http://dx.doi.org/10.1016/j.tins.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990695PMC
April 2021

Fosfomycin for bacterial prostatitis: a review.

Int J Antimicrob Agents 2020 Oct 25;56(4):106106. Epub 2020 Jul 25.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 1C9. Electronic address:

There has been growing interest in fosfomycin for the treatment of bacterial prostatitis due to evidence suggesting that it achieves adequate prostatic concentrations for antimicrobial effect, has activity against resistant micro-organisms, and has a low-toxicity profile. This review evaluated the current clinical evidence for fosfomycin in acute and chronic bacterial prostatitis to elucidate the clinical implications of fosfomycin in an era of increasing antimicrobial resistance. PubMed, Scopus, EMBASE, Web of Science, Google Scholar and ClinicalTrials.gov were searched for studies published in the English language from January 1984 to November 2019. The inclusion criteria were met if the study reported the use of fosfomycin (more than one dose) to treat bacterial prostatitis. Ten observational studies were identified that met the inclusion criteria. The evidence for the use of fosfomycin in acute bacterial prostatitis is sparse. The majority of the available evidence is for chronic bacterial prostatitis caused by Escherichia coli. Despite the implementation of variable dosing regimens, extended courses of fosfomycin appear to be safe and effective in achieving clinical and microbiological cure. In these studies, the use of fosfomycin was restricted to cases of treatment failure, intolerance to first-line therapy, or multi-resistant organisms. However, given the development of resistant organisms and the undesirable adverse effects of many first-line therapeutic options, fosfomycin has the potential to be considered as an effective first-line alternative for acute and chronic bacterial prostatitis in the future. Further studies, including randomized controlled trials, would be helpful to firmly establish its optimal dosing regimen, efficacy and place in therapy.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106106DOI Listing
October 2020

Nanoscopic Visualization of Restricted Nonvolume Cholinergic and Monoaminergic Transmission with Genetically Encoded Sensors.

Nano Lett 2020 06 12;20(6):4073-4083. Epub 2020 May 12.

State Key Laboratory of Membrane Biology and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.

How neuromodulatory transmitters diffuse into the extracellular space remains an unsolved fundamental biological question, despite wide acceptance of the volume transmission model. Here, we report development of a method combining genetically encoded fluorescent sensors with high-resolution imaging and analysis algorithms which permits the first direct visualization of neuromodulatory transmitter diffusion at various neuronal and non-neuronal cells. Our analysis reveals that acetylcholine and monoamines diffuse at individual release sites with a spread length constant of ∼0.75 μm. These transmitters employ varied numbers of release sites, and when spatially close-packed release sites coactivate they can spillover into larger subcellular areas. Our data indicate spatially restricted (i.e., nonvolume) neuromodulatory transmission to be a prominent intercellular communication mode, reshaping current thinking of control and precision of neuromodulation crucial for understanding behaviors and diseases.
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http://dx.doi.org/10.1021/acs.nanolett.9b04877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519949PMC
June 2020

Cumulative Effects of Social Stress on Reward-Guided Actions and Prefrontal Cortical Activity.

Biol Psychiatry 2020 10 19;88(7):541-553. Epub 2020 Feb 19.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut; Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Background: When exposed to chronic social stress, animals display behavioral changes that are relevant to depressive-like phenotypes. However, the cascading relationship between incremental stress exposure and neural dysfunctions over time remains incompletely understood.

Methods: We characterized the longitudinal effect of social defeat on goal-directed actions and prefrontal cortical activity in mice using a novel head-fixed sucrose preference task and two-photon calcium imaging.

Results: Behaviorally, stress-induced loss of reward sensitivity intensifies over days. Motivational anhedonia, the failure to translate positive reinforcements into future actions, requires multiple sessions of stress exposure to become fully established. For neural activity, individual layer 2/3 pyramidal neurons in the cingulate and medial secondary motor subregions of the medial prefrontal cortex have heterogeneous responses to stress. Changes in ensemble activity differ significantly between susceptible and resilient mice after the first defeat session and continue to diverge following successive stress episodes before reaching persistent abnormal levels.

Conclusions: Collectively, these results demonstrate that the cumulative impact of an ethologically relevant stress can be observed at the level of cellular activity of individual prefrontal neurons. The distinct neural responses associated with resilience versus susceptibility suggests the hypothesis that the negative impact of social stress is neutralized in resilient animals, in part through an adaptive reorganization of prefrontal cortical activity.
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http://dx.doi.org/10.1016/j.biopsych.2020.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434704PMC
October 2020

Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation.

Mol Psychiatry 2021 06 11;26(6):1945-1966. Epub 2020 Mar 11.

Department of Psychiatry, Yale University School of Medicine, 300 George St, Suite 901, New Haven, CT, 06511, USA.

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.
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http://dx.doi.org/10.1038/s41380-020-0708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483244PMC
June 2021

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines.

Nat Commun 2020 01 7;11(1):72. Epub 2020 Jan 7.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06511, USA.

A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine's actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.
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http://dx.doi.org/10.1038/s41467-019-13809-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946708PMC
January 2020

Parvalbumin-Positive Neuron Loss and Amyloid-β Deposits in the Frontal Cortex of Alzheimer's Disease-Related Mice.

J Alzheimers Dis 2019 ;72(4):1323-1339

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Alzheimer's disease (AD) has several hallmark features including amyloid-β (Aβ) plaque deposits and neuronal loss. Here, we characterized Aβ plaque aggregation and parvalbumin-positive (PV) GABAergic neurons in 6-9-month-old 5xFAD mice harboring mutations associated with familial AD. We used immunofluorescence staining to compare three regions in the frontal cortex-prelimbic (PrL), cingulate (Cg, including Cg1 and Cg2), and secondary motor (M2) cortices-along with primary somatosensory (S1) cortex. We quantified the density of Aβ plaques, which showed significant laminar and regional vulnerability. There were more plaques of larger sizes in deep layers compared to superficial layers. Total plaque burden was higher in frontal regions compared to S1. We also found layer- and region-specific differences across genotype in the density of PV interneurons. PV neuron density was lower in 5xFAD mice than wild-type, particularly in deep layers of frontal regions, with Cg (-50%) and M2 (-39%) exhibiting the largest reduction. Using in vivo two-photon imaging, we longitudinally visualized the loss of frontal cortical PV neurons across four weeks in the AD mouse model. Overall, these results provide information about Aβ deposits and PV neuron density in a widely used mouse model for AD, implicating deep layers of frontal cortical regions as being especially vulnerable.
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http://dx.doi.org/10.3233/JAD-181190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123545PMC
December 2020

Interpreting calcium signals from neuronal cell bodies, axons, and dendrites: a review.

Neurophotonics 2020 Jan 30;7(1):011402. Epub 2019 Jul 30.

Yale University, Department of Psychiatry, School of Medicine, New Haven, Connecticut, United States.

Calcium imaging is emerging as a popular technique in neuroscience. A major reason is that intracellular calcium transients are reflections of electrical events in neurons. For example, calcium influx in the soma and axonal boutons accompanies spiking activity, whereas elevations in dendrites and dendritic spines are associated with synaptic inputs and local regenerative events. However, calcium transients have complex spatiotemporal dynamics, and since most optical methods visualize only one of the somatic, axonal, and dendritic compartments, a straightforward inference of the underlying electrical event is typically challenging. We highlight experiments that have directly calibrated calcium signals recorded using fluorescent indicators against electrophysiological events. We address commonly asked questions such as: Can calcium imaging be used to characterize neurons with high firing rates? Can the fluorescent signal report a decrease in spiking activity? What is the evidence that calcium transients in subcellular compartments correspond to distinct presynaptic axonal and postsynaptic dendritic events? By reviewing the empirical evidence and limitations, we suggest that, despite some caveats, calcium imaging is a versatile method to characterize a variety of neuronal events .
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http://dx.doi.org/10.1117/1.NPh.7.1.011402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664352PMC
January 2020

Enhanced Population Coding for Rewarded Choices in the Medial Frontal Cortex of the Mouse.

Cereb Cortex 2019 09;29(10):4090-4106

Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, USA.

Instrumental behavior is characterized by the selection of actions based on the degree to which they lead to a desired outcome. However, we lack a detailed understanding of how rewarded actions are reinforced and preferentially implemented. In rodents, the medial frontal cortex is hypothesized to play an important role in this process, based in part on its capacity to encode chosen actions and their outcomes. We therefore asked how neural representations of choice and outcome might interact to facilitate instrumental behavior. To investigate this question, we imaged neural ensemble activity in layer 2/3 of the secondary motor region (M2) while mice engaged in a two-choice auditory discrimination task with probabilistic outcomes. Correct choices could result in one of three reward amounts (single, double or omitted reward), which allowed us to measure neural and behavioral effects of reward magnitude, as well as its categorical presence or absence. Single-unit and population decoding analyses revealed a consistent influence of outcome on choice signals in M2. Specifically, rewarded choices were more robustly encoded relative to unrewarded choices, with little dependence on the exact magnitude of reinforcement. Our results provide insight into the integration of past choices and outcomes in the rodent brain during instrumental behavior.
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http://dx.doi.org/10.1093/cercor/bhy292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735259PMC
September 2019

Same lesson, varied choices by frontal cortex.

Nat Neurosci 2018 12;21(12):1648-1650

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1038/s41593-018-0282-2DOI Listing
December 2018

Targeted two-photon chemical apoptotic ablation of defined cell types in vivo.

Nat Commun 2017 06 16;8:15837. Epub 2017 Jun 16.

Department of Neurology, Yale School of Medicine, New Haven, Connecticut 06511, USA.

A major bottleneck limiting understanding of mechanisms and consequences of cell death in complex organisms is the inability to induce and visualize this process with spatial and temporal precision in living animals. Here we report a technique termed two-photon chemical apoptotic targeted ablation (2Phatal) that uses focal illumination with a femtosecond-pulsed laser to bleach a nucleic acid-binding dye causing dose-dependent apoptosis of individual cells without collateral damage. Using 2Phatal, we achieve precise ablation of distinct populations of neurons, glia and pericytes in the mouse brain and in zebrafish. When combined with organelle-targeted fluorescent proteins and biosensors, we uncover previously unrecognized cell-type differences in patterns of apoptosis and associated dynamics of ribosomal disassembly, calcium overload and mitochondrial fission. 2Phatal provides a powerful and rapidly adoptable platform to investigate in vivo functional consequences and neural plasticity following cell death as well as apoptosis, cell clearance and tissue remodelling in diverse organs and species.
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http://dx.doi.org/10.1038/ncomms15837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501159PMC
June 2017

Secondary Motor Cortex: Where 'Sensory' Meets 'Motor' in the Rodent Frontal Cortex.

Trends Neurosci 2017 03 22;40(3):181-193. Epub 2016 Dec 22.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address:

In rodents, the medial aspect of the secondary motor cortex (M2) is known by other names, including medial agranular cortex (AGm), medial precentral cortex (PrCm), and frontal orienting field (FOF). As a subdivision of the medial prefrontal cortex (mPFC), M2 can be defined by a distinct set of afferent and efferent connections, microstimulation responses, and lesion outcomes. However, the behavioral role of M2 remains mysterious. Here, we focus on evidence from rodent studies, highlighting recent findings of early and context-dependent choice-related activity in M2 during voluntary behavior. Based on the current understanding, we suggest that a major function for M2 is to flexibly map antecedent signals such as sensory cues to motor actions, thereby enabling adaptive choice behavior.
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http://dx.doi.org/10.1016/j.tins.2016.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339050PMC
March 2017

Fast and slow transitions in frontal ensemble activity during flexible sensorimotor behavior.

Nat Neurosci 2016 09 11;19(9):1234-42. Epub 2016 Jul 11.

Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut, USA.

The ability to shift between repetitive and goal-directed actions is a hallmark of cognitive control. Previous studies have reported that adaptive shifts in behavior are accompanied by changes of neural activity in frontal cortex. However, neural and behavioral adaptations can occur at multiple time scales, and their relationship remains poorly defined. Here we developed an adaptive sensorimotor decision-making task for head-fixed mice, requiring them to shift flexibly between multiple auditory-motor mappings. Two-photon calcium imaging of secondary motor cortex (M2) revealed different ensemble activity states for each mapping. When adapting to a conditional mapping, transitions in ensemble activity were abrupt and occurred before the recovery of behavioral performance. By contrast, gradual and delayed transitions accompanied shifts toward repetitive responding. These results demonstrate distinct ensemble signatures associated with the start versus end of sensory-guided behavior and suggest that M2 leads in engaging goal-directed response strategies that require sensorimotor associations.
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http://dx.doi.org/10.1038/nn.4342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003707PMC
September 2016

Longitudinal Effects of Ketamine on Dendritic Architecture In Vivo in the Mouse Medial Frontal Cortex.

eNeuro 2016 Mar-Apr;3(2). Epub 2016 Apr 4.

Department of Psychiatry, Yale University, New Haven, Connecticut 06511; Department of Neuroscience, Yale University, New Haven, Connecticut 06511.

A single subanesthetic dose of ketamine, an NMDA receptor antagonist, leads to fast-acting antidepressant effects. In rodent models, systemic ketamine is associated with higher dendritic spine density in the prefrontal cortex, reflecting structural remodeling that may underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo, and the longitudinal effects of ketamine on structural plasticity remain unclear. The purpose of the current study is to use subcellular resolution optical imaging to determine the time course of dendritic alterations in vivo following systemic ketamine administration in mice. We used two-photon microscopy to visualize repeatedly the same set of dendritic branches in the mouse medial frontal cortex (MFC) before and after a single injection of ketamine or saline. Compared to controls, ketamine-injected mice had higher dendritic spine density in MFC for up to 2 weeks. This prolonged increase in spine density was driven by an elevated spine formation rate, and not by changes in the spine elimination rate. A fraction of the new spines following ketamine injection was persistent, which is indicative of functional synapses. In a few cases, we also observed retraction of distal apical tuft branches on the day immediately after ketamine administration. These results indicate that following systemic ketamine administration, certain dendritic inputs in MFC are removed immediately, while others are added gradually. These dynamic structural modifications are consistent with a model of ketamine action in which the net effect is a rebalancing of synaptic inputs received by frontal cortical neurons.
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http://dx.doi.org/10.1523/ENEURO.0133-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819286PMC
December 2016

Interneuron subtypes and orientation tuning.

Nature 2014 Apr;508(7494):E1-2

Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.

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http://dx.doi.org/10.1038/nature13128DOI Listing
April 2014

Fast modulation of visual perception by basal forebrain cholinergic neurons.

Nat Neurosci 2013 Dec 27;16(12):1857-1863. Epub 2013 Oct 27.

Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720.

The basal forebrain provides the primary source of cholinergic input to the cortex, and it has a crucial function in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking; these changes could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception.
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http://dx.doi.org/10.1038/nn.3552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201942PMC
December 2013

Activation of specific interneurons improves V1 feature selectivity and visual perception.

Nature 2012 Aug;488(7411):379-83

Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA.

Inhibitory interneurons are essential components of the neural circuits underlying various brain functions. In the neocortex, a large diversity of GABA (γ-aminobutyric acid) interneurons has been identified on the basis of their morphology, molecular markers, biophysical properties and innervation pattern. However, how the activity of each subtype of interneurons contributes to sensory processing remains unclear. Here we show that optogenetic activation of parvalbumin-positive (PV+) interneurons in the mouse primary visual cortex (V1) sharpens neuronal feature selectivity and improves perceptual discrimination. Using multichannel recording with silicon probes and channelrhodopsin-2 (ChR2)-mediated optical activation, we found that increased spiking of PV+ interneurons markedly sharpened orientation tuning and enhanced direction selectivity of nearby neurons. These effects were caused by the activation of inhibitory neurons rather than a decreased spiking of excitatory neurons, as archaerhodopsin-3 (Arch)-mediated optical silencing of calcium/calmodulin-dependent protein kinase IIα (CAMKIIα)-positive excitatory neurons caused no significant change in V1 stimulus selectivity. Moreover, the improved selectivity specifically required PV+ neuron activation, as activating somatostatin or vasointestinal peptide interneurons had no significant effect. Notably, PV+ neuron activation in awake mice caused a significant improvement in their orientation discrimination, mirroring the sharpened V1 orientation tuning. Together, these results provide the first demonstration that visual coding and perception can be improved by increased spiking of a specific subtype of cortical inhibitory interneurons.
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http://dx.doi.org/10.1038/nature11312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422431PMC
August 2012

Dissection of cortical microcircuits by single-neuron stimulation in vivo.

Curr Biol 2012 Aug 28;22(16):1459-67. Epub 2012 Jun 28.

Division of Neurobiology, Department of Molecular Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.

Background: A fundamental process underlying all brain functions is the propagation of spiking activity in networks of excitatory and inhibitory neurons. In the neocortex, although functional connections between pairs of neurons have been studied extensively in brain slices, they remain poorly characterized in vivo, where the high background activity, global brain states, and neuromodulation can powerfully influence synaptic transmission. To understand how spikes are transmitted in cortical circuits in vivo, we used two-photon calcium imaging to monitor ensemble activity and targeted patching to stimulate a single neuron in mouse visual cortex.

Results: Burst spiking of a single pyramidal neuron can drive spiking activity in both excitatory and inhibitory neurons within a ∼100 μm radius. For inhibitory neurons, ∼30% of the somatostatin interneurons fire reliably in response to a presynaptic burst of ≥5 spikes. In contrast, parvalbumin interneurons showed no detectable responses to single-neuron stimulation, but their spiking is highly correlated with the local network activity.

Conclusions: Our results demonstrate the feasibility of mapping functional connectivity at cellular resolution in vivo and reveal distinct operations of two major inhibitory circuits, one detecting single-neuron spike bursts and the other reflecting distributed network activity.
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http://dx.doi.org/10.1016/j.cub.2012.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467311PMC
August 2012

Dopamine-induced oscillations of the pyloric pacemaker neuron rely on release of calcium from intracellular stores.

J Neurophysiol 2011 Sep 15;106(3):1288-98. Epub 2011 Jun 15.

Department of Neurobiology and Behavior, Cornell University, W 159 Seeley G. Mudd Hall, Ithaca, NY 14853, USA.

Endogenously bursting neurons play central roles in many aspects of nervous system function, ranging from motor control to perception. The properties and bursting patterns generated by these neurons are subject to neuromodulation, which can alter cycle frequency and amplitude by modifying the properties of the neuron's ionic currents. In the stomatogastric ganglion (STG) of the spiny lobster, Panulirus interruptus, the anterior burster (AB) neuron is a conditional oscillator in the presence of dopamine (DA) and other neuromodulators and serves as the pacemaker to drive rhythmic output from the pyloric network. We analyzed the mechanisms by which DA evokes bursting in the AB neuron. Previous work showed that DA-evoked bursting is critically dependent on external calcium (Harris-Warrick RM, Flamm RE. J Neurosci 7: 2113-2128, 1987). Using two-photon microscopy and calcium imaging, we show that DA evokes the release of calcium from intracellular stores well before the emergence of voltage oscillations. When this release from intracellular stores is blocked by antagonists of ryanodine or inositol trisphosphate (IP(3)) receptor channels, DA fails to evoke AB bursting. We further demonstrate that DA enhances the calcium-activated inward current, I(CAN), despite the fact that it significantly reduces voltage-activated calcium currents. This suggests that DA-induced release of calcium from intracellular stores activates I(CAN), which provides a depolarizing ramp current that underlies endogenous bursting in the AB neuron.
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http://dx.doi.org/10.1152/jn.00456.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174818PMC
September 2011

Spatiotemporal dynamics of rhythmic spinal interneurons measured with two-photon calcium imaging and coherence analysis.

J Neurophysiol 2010 Dec 22;104(6):3323-33. Epub 2010 Sep 22.

School of Applied and Engineering Physics, Cornell University, Ithaca, New York, USA.

In rhythmic neural circuits, a neuron often fires action potentials with a constant phase to the rhythm, a timing relationship that can be functionally significant. To characterize these phase preferences in a large-scale, cell type-specific manner, we adapted multitaper coherence analysis for two-photon calcium imaging. Analysis of simulated data showed that coherence is a simple and robust measure of rhythmicity for calcium imaging data. When applied to the neonatal mouse hindlimb spinal locomotor network, the phase relationships between peak activity of >1,000 ventral spinal interneurons and motor output were characterized. Most interneurons showed rhythmic activity that was coherent and in phase with the ipsilateral motor output during fictive locomotion. The phase distributions of two genetically identified classes of interneurons were distinct from the ensemble population and from each other. There was no obvious spatial clustering of interneurons with similar phase preferences. Together, these results suggest that cell type, not neighboring neuron activity, is a better indicator of an interneuron's response during fictive locomotion. The ability to measure the phase preferences of many neurons with cell type and spatial information should be widely applicable for studying other rhythmic neural circuits.
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http://dx.doi.org/10.1152/jn.00679.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3007658PMC
December 2010

Toward reconstructing spike trains from large-scale calcium imaging data.

Authors:
Alex C Kwan

HFSP J 2010 Feb 22;4(1):1-5. Epub 2010 Jan 22.

Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, California 94120, USA.

Neural activity can be captured by state-of-the-art optical imaging methods although the analysis of the resulting data sets is often manual and not standardized. Therefore, laboratories using large-scale calcium imaging eagerly await software toolboxes that can automate the process of identifying cells and inferring spikes. An algorithm proposed and implemented in a recent paper by Mukamel et al. [Neuron 63, 747-760 (2009)] used independent component analysis and offers significant improvements over conventional methods. The approach should be widely applicable, as tested with data obtained from the mouse cerebellum, neocortex, and spinal cord. The emergence of analysis tools in parallel with the rapid advances in optical imaging is an exciting development that will stimulate new discoveries and further elucidate the functions of neural circuits.
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http://dx.doi.org/10.2976/1.3284977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880024PMC
February 2010

Electrophysiological characterization of V2a interneurons and their locomotor-related activity in the neonatal mouse spinal cord.

J Neurosci 2010 Jan;30(1):170-82

Department of Neurobiology and Behavior, Cornell University, Ithaca, New York 14853, USA.

The V2a class of Chx10-expressing interneurons has been implicated in frequency-dependent control of left-right phase during locomotion in the mouse. We have used the Chx10::CFP mouse line to further investigate the properties and locomotion-related activity of V2a interneurons in the isolated neonatal spinal cord. V2a interneurons can be divided into three classes, based on their tonic, phasic, or delayed-onset responses to step depolarization. Electrical coupling is found only between neurons of same class and helps to synchronize neuronal activity within the class. Serotonin (5-HT) excites isolated tonic V2a interneurons by depolarizing the neurons and increasing their membrane input resistance, with no significant effects on action potential properties, a mechanism distinct from 5-HT excitation of commissural interneurons. During NMDA-/5-HT-induced locomotor-like activity, patch-clamp recordings and two-photon calcium imaging experiments show that approximately half of V2a interneurons fire rhythmically with ventral root-recorded motor activity; the rhythmic V2a interneurons fired during one half of the cycle, in phase with either the ipsilateral or the contralateral L2 ventral root bursts. The percentage of rhythmically firing V2a interneurons increases during higher-frequency fictive locomotion, and they become significantly more rhythmic in their firing during the locomotor cycle; this may help to explain the frequency-dependent shift in left-right coupling in Chx10::DTA mice, which lack these neurons. Our results together with data from the accompanying paper (Dougherty and Kiehn, 2009) reinforce earlier proposals that the V2a interneurons are components of the hindlimb central pattern generator, helping to organize left-right locomotor coordination in the neonatal mouse spinal cord.
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http://dx.doi.org/10.1523/JNEUROSCI.4849-09.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824326PMC
January 2010
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