@article {70292, title = {Correlates of head-fixed directional forelimb movements in mouse superior colliculus and substantia nigra pars reticulata.}, journal = {Neuroscience}, year = {2026}, month = {2026 Feb 12}, abstract = {

Coordinated lateralized movements are critical for natural orienting behaviors, but their neural bases remain poorly understood. The deep superior colliculus (dSC) integrates a wide range of inputs to select targets for orienting movements and coordinates downstream activity to initiate and execute movement. The substantia nigra pars reticulata (SNr) is thought to disinhibit dSC to facilitate movement, but much remains unknown about the relationship between SNr activity, dSC activity, and movement. We recorded from both regions using high-density probes in head-fixed mice performing directional orienting tasks. We found that dSC and SNr activity reflected task variables preceding and throughout movement. However, the direction-dependence of dSC activity was weaker than in other orienting behaviors, and the relationship between movement-related dSC and SNr activity was inconsistent with disinhibition of dSC determining the initiation or direction of movement. Analyses of similar data curated by the International Brain Laboratory yielded consistent results. These findings suggest diverse roles for modulatory input from SNr to dSC in shaping motor behavior.

}, issn = {1873-7544}, doi = {10.1016/j.neuroscience.2026.02.010}, url = {https://doi.org/10.1016/j.neuroscience.2026.02.010}, author = {Doykos, Ted K and Yamauchi, Taylor and Buteau, Anna and Hanson, Spencer and Dudman, Joshua T and Felsen, Gidon and Stubblefield, Elizabeth A} } @article {70118, title = {Composing trajectories for rapid inference of navigational goals}, journal = {bioRxiv}, year = {2025}, month = {2025 Sep 24}, abstract = {

Animals efficiently learn to navigate their environment. In the laboratory, naive mice explore their environment via highly structured trajectories and can learn to localize new spatial targets in as few as a handful of trials. It is unclear how such efficient learning is possible, since existing computational models of spatial navigation require far more experience to achieve comparable performance and do not attempt to explain the evolving structure of animal behavior during learning. To inform a new algorithm for rapid learning of navigational goals, we took inspiration from the reliable structure of behavior as mice learned to intercept hidden spatial targets. We designed agents that generate behavioral trajectories by controlling the speed and angular velocity of smooth path segments between anchor points. To rapidly learn good anchors, we use Bayesian inference on the history of rewarded and unrewarded trajectories to infer the probability that an anchor will be successful, and active sampling to trim hypothesized anchors. Agents learn within tens of trials to generate compact trajectories that intercept a target, capturing the evolution of behavioral structure and matching the upper limits of learning efficiency observed in mice. We further show that this algorithm can explain how mice avoid obstacles and rapidly adapt to target switches. Finally, we show that this framework naturally encompasses both egocentric and allocentric strategies for navigation.

}, doi = {10.1101/2025.09.24.678123}, url = {https://www.biorxiv.org/content/early/2025/09/24/2025.09.24.678123}, author = {AbdelRahman, Nada Y and Jiang, Wanchen and Coddington, Luke T and Gong, Sheng and Dudman, Joshua T and Hermundstad, Ann M} } @article {69659, title = {A global dopaminergic learning rate enables adaptive foraging across many options}, journal = {bioRxiv}, year = {2024}, month = {2024 Nov 05}, abstract = {

In natural environments, animals must efficiently allocate their choices across multiple concurrently available resources when foraging, a complex decision-making process not fully captured by existing models. To understand how rodents learn to navigate this challenge we developed a novel paradigm in which untrained, water-restricted mice were free to sample from six options rewarded at a range of deterministic intervals and positioned around the walls of a large ( 2m) arena. Mice exhibited rapid learning, matching their choices to integrated reward ratios across six options within the first session. A reinforcement learning model with separate states for staying or leaving an option and a dynamic, global learning rate was able to accurately reproduce mouse learning and decision-making. Fiber photometry recordings revealed that dopamine in the nucleus accumbens core (NAcC), but not dorsomedial striatum (DMS), more closely reflected the global learning rate than local error-based updating. Altogether, our results provide insight into the neural substrate of a learning algorithm that allows mice to rapidly exploit multiple options when foraging in large spatial environments.

}, doi = {10.1101/2024.11.04.621923}, url = {https://doi.org/10.1101/2024.11.04.621923}, author = {Grima, Laura L and Guo, Yipei and Narayan, Lakshmi and Hermundstad, Ann M and Dudman, Joshua T} } @article {69215, title = {Integrating across behaviors and timescales to understand the neural control of movement.}, journal = {Current Opinion in Neurobiology}, volume = {85}, year = {2024}, month = {2024 Feb 13}, pages = {102843}, abstract = {

The nervous system evolved to enable navigation throughout the environment in the pursuit of resources. Evolutionarily newer structures allowed increasingly complex adaptations but necessarily added redundancy. A dominant view of movement neuroscientists is that there is a one-to-one mapping between brain region and function. However, recent experimental data is hard to reconcile with the most conservative interpretation of this framework, suggesting a degree of functional redundancy during the performance of well-learned, constrained behaviors. This apparent redundancy likely stems from the bidirectional interactions between the various cortical and subcortical structures involved in motor control. We posit that these bidirectional connections enable flexible interactions across structures that change depending upon behavioral demands, such as during acquisition, execution or adaptation of a skill. Observing the system across both multiple actions and behavioral timescales can help isolate the functional contributions of individual structures, leading to an integrated understanding of the neural control of movement.

}, issn = {1873-6882}, doi = {10.1016/j.conb.2024.102843}, author = {Gmaz, Jimmie M and Keller, Jason A and Dudman, Joshua T and Gallego, Juan A} } @article {68586, title = {Mesolimbic dopamine adapts the rate of learning from action.}, journal = {Nature}, year = {2023}, month = {2023 Jan 18}, abstract = {

Recent success in training artificial agents and robots derives from a combination of direct learning of behavioural policies and indirect learning through value functions. Policy learning and value learning use distinct algorithms that optimize behavioural performance and reward prediction, respectively. In animals, behavioural learning and the role of mesolimbic dopamine signalling have been extensively evaluated with respect to reward prediction; however, so far there has been little consideration of how direct policy learning might inform our understanding. Here we used a comprehensive dataset of orofacial and body movements to understand how behavioural policies evolved as naive, head-restrained mice learned a trace conditioning paradigm. Individual differences in initial dopaminergic reward responses correlated with the emergence of learned behavioural policy, but not the emergence of putative value encoding for a predictive cue. Likewise, physiologically calibrated manipulations of mesolimbic dopamine produced several effects inconsistent with value learning but predicted by a neural-network-based model that used dopamine signals to set an adaptive rate, not an error signal, for behavioural policy learning. This work provides strong evidence that phasic dopamine activity can regulate direct learning of behavioural policies, expanding the explanatory power of reinforcement learning models for animal learning.

}, issn = {1476-4687}, doi = {10.1038/s41586-022-05614-z}, author = {Coddington, Luke T and Lindo, Sarah E and Dudman, Joshua T} } @article {68918, title = {Nonlinear manifolds underlie neural population activity during behaviour.}, journal = {bioRxiv}, year = {2023}, month = {2023 Jul 21}, abstract = {

There is rich variety in the activity of single neurons recorded during behaviour. Yet, these diverse single neuron responses can be well described by relatively few patterns of neural co-modulation. The study of such low-dimensional structure of neural population activity has provided important insights into how the brain generates behaviour. Virtually all of these studies have used linear dimensionality reduction techniques to estimate these population-wide co-modulation patterns, constraining them to a flat "neural manifold". Here, we hypothesised that since neurons have nonlinear responses and make thousands of distributed and recurrent connections that likely amplify such nonlinearities, neural manifolds should be intrinsically nonlinear. Combining neural population recordings from monkey motor cortex, mouse motor cortex, mouse striatum, and human motor cortex, we show that: 1) neural manifolds are intrinsically nonlinear; 2) the degree of their nonlinearity varies across architecturally distinct brain regions; and 3) manifold nonlinearity becomes more evident during complex tasks that require more varied activity patterns. Simulations using recurrent neural network models confirmed the proposed relationship between circuit connectivity and manifold nonlinearity, including the differences across architecturally distinct regions. Thus, neural manifolds underlying the generation of behaviour are inherently nonlinear, and properly accounting for such nonlinearities will be critical as neuroscientists move towards studying numerous brain regions involved in increasingly complex and naturalistic behaviours.

}, doi = {10.1101/2023.07.18.549575}, url = {https://doi.org/10.1101/2023.07.18.549575}, author = {Fortunato, C{\'a}tia and Bennasar-V{\'a}zquez, Jorge and Park, Junchol and Chang, Joanna C and Miller, Lee E and Dudman, Joshua T and Perich, Matthew G and Gallego, Juan A} } @article {69075, title = {Preserved neural dynamics across animals performing similar behaviour.}, journal = {Nature}, year = {2023}, month = {2023 Nov 08}, abstract = {

Animals of the same species exhibit similar behaviours that are advantageously adapted to their body and environment. These behaviours are shaped at the species level by selection pressures over evolutionary timescales. Yet, it remains unclear how these common behavioural adaptations emerge from the idiosyncratic neural circuitry of each individual. The overall organization of neural circuits is preserved across individuals because of their common evolutionarily specified developmental programme. Such organization at the circuit level may constrain neural activity, leading to low-dimensional latent dynamics across the neural population. Accordingly, here we suggested that the shared circuit-level constraints within a species would lead to suitably preserved latent dynamics across individuals. We analysed recordings of neural populations from monkey and mouse motor cortex to demonstrate that neural dynamics in individuals from the same species are surprisingly preserved when they perform similar behaviour. Neural population dynamics were also preserved when animals consciously planned future movements without overt behaviour and enabled the decoding of planned and ongoing movement across different individuals. Furthermore, we found that preserved neural dynamics extend beyond cortical regions to the dorsal striatum, an evolutionarily older structure. Finally, we used neural network models to demonstrate that behavioural similarity is necessary but not sufficient for this preservation. We posit that these emergent dynamics result from evolutionary constraints on brain development and thus reflect fundamental properties of the neural basis of behaviour.

}, issn = {1476-4687}, doi = {10.1038/s41586-023-06714-0}, author = {Safaie, Mostafa and Chang, Joanna C and Park, Junchol and Miller, Lee E and Dudman, Joshua T and Perich, Matthew G and Gallego, Juan A} } @article {68516, title = {Hippocampal representations of foraging trajectories depend upon spatial context.}, journal = {Nature Neuroscience}, volume = {25}, year = {2022}, month = {2022 Dec 02}, pages = {1693-1705}, abstract = {

Animals learn trajectories to rewards in both spatial, navigational contexts and relational, non-navigational contexts. Synchronous reactivation of hippocampal activity is thought to be critical for recall and evaluation of trajectories for learning. Do hippocampal representations differentially contribute to experience-dependent learning of trajectories across spatial and relational contexts? In this study, we trained mice to navigate to a hidden target in a physical arena or manipulate a joystick to a virtual target to collect delayed rewards. In a navigational context, calcium imaging in freely moving mice revealed that synchronous CA1 reactivation was retrospective and important for evaluation of prior navigational trajectories. In a non-navigational context, reactivation was prospective and important for initiation of joystick trajectories, even in the same animals trained in both contexts. Adaptation of trajectories to a new target was well-explained by a common learning algorithm in which hippocampal activity makes dissociable contributions to reinforcement learning computations depending upon spatial context.

}, keywords = {Animals, Hippocampus, Mental Recall, Mice, Prospective Studies, Retrospective Studies, Spatial Navigation}, issn = {1546-1726}, doi = {10.1038/s41593-022-01201-7}, author = {Jiang, Wan-Chen and Xu, Shengjin and Dudman, Joshua T} } @article {67962, title = {Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes.}, journal = {Science Advances}, volume = {8}, year = {2022}, month = {2022 Mar 11}, pages = {eabj5167}, abstract = {

The interaction of descending neocortical outputs and subcortical premotor circuits is critical for shaping skilled movements. Two broad classes of motor cortical output projection neurons provide input to many subcortical motor areas: pyramidal tract (PT) neurons, which project throughout the neuraxis, and intratelencephalic (IT) neurons, which project within the cortex and subcortical striatum. It is unclear whether these classes are functionally in series or whether each class carries distinct components of descending motor control signals. Here, we combine large-scale neural recordings across all layers of motor cortex with cell type-specific perturbations to study cortically dependent mouse motor behaviors: kinematically variable manipulation of a joystick and a kinematically precise reach-to-grasp. We find that striatum-projecting IT neuron activity preferentially represents amplitude, whereas pons-projecting PT neurons preferentially represent the variable direction of forelimb movements. Thus, separable components of descending motor cortical commands are distributed across motor cortical projection cell classes.

}, issn = {2375-2548}, doi = {10.1126/sciadv.abj5167}, author = {Park, Junchol and Phillips, James W and Guo, Jian-Zhong and Martin, Kathleen A and Hantman, Adam W and Dudman, Joshua T} } @article {67723, title = {Dissociable contributions of phasic dopamine activity to reward and prediction.}, journal = {Cell Reports}, volume = {36}, year = {2021}, month = {2021 Sep 07}, pages = {109684}, abstract = {

Sensory cues that precede reward acquire predictive (expected value) and incentive (drive reward-seeking action) properties. Mesolimbic dopamine neurons{\textquoteright} responses to sensory cues correlate with both expected value and reward-seeking action. This has led to the proposal that phasic dopamine responses may be sufficient to inform value-based decisions, elicit actions, and/or induce motivational states; however, causal tests are incomplete. Here, we show that direct dopamine neuron stimulation, both calibrated to physiological and greater intensities, at the time of reward can be sufficient to induce and maintain reward seeking (reinforcing) although replacement of a cue with stimulation is insufficient to induce reward seeking or act as an informative cue. Stimulation of descending cortical inputs, one synapse upstream, are sufficient for reinforcement and cues to future reward. Thus, physiological activation of mesolimbic dopamine neurons can be sufficient for reinforcing properties of reward without being sufficient for the predictive and incentive properties of cues.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2021.109684}, author = {Pan, Wei-Xing and Coddington, Luke T and Dudman, Joshua T} } @article {65815, title = {In vivo optogenetics with stimulus calibration.}, journal = {Methods in Molecular Biology}, volume = {2188}, year = {2021}, month = {2020 Nov 06}, pages = {273-283}, abstract = {

Optogenetic reagents allow for depolarization and hyperpolarization of cells with light. This provides unprecedented spatial and temporal resolution to the control of neuronal activity both in vitro and in vivo. In the intact animal this requires strategies to deliver light deep into the highly scattering tissue of the brain. A general approach that we describe here is to implant optical fibers just above brain regions targeted for light delivery. In part due to the fact that expression of optogenetic proteins is accomplished by techniques with inherent variability (e.g., viral expression\ levels), it also requires strategies to measure and calibrate the effect of stimulation. Here we describe general procedures that allow one to simultaneously stimulate neurons and use photometry with genetically encoded activity indicators to precisely calibrate stimulation.

}, issn = {1940-6029}, doi = {10.1007/978-1-0716-0818-0_14}, author = {Coddington, Luke T and Dudman, Joshua T} } @article {67232, title = {Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings.}, journal = {Science}, volume = {372}, year = {2021}, month = {2021 Apr 16}, abstract = {

Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice.

}, issn = {1095-9203}, doi = {10.1126/science.abf4588}, author = {Steinmetz, Nicholas A and Ayd{\i}n, {\c C}a{\u g}atay and Lebedeva, Anna and Okun, Michael and Pachitariu, Marius and Bauza, Marius and Beau, Maxime and Bhagat, Jai and B{\"o}hm, Claudia and Broux, Martijn and Chen, Susu and Colonell, Jennifer and Gardner, Richard J and Karsh, Bill and Kloosterman, Fabian and Kostadinov, Dimitar and Mora-Lopez, Carolina and O{\textquoteright}Callaghan, John and Park, Junchol and Putzeys, Jan and Sauerbrei, Britton and van Daal, Rik J J and Vollan, Abraham Z and Wang, Shiwei and Welkenhuysen, Marleen and Ye, Zhiwen and Dudman, Joshua T and Dutta, Barundeb and Hantman, Adam W and Harris, Kenneth D and Lee, Albert K and Moser, Edvard I and O{\textquoteright}Keefe, John and Renart, Alfonso and Svoboda, Karel and H{\"a}usser, Michael and Haesler, Sebastian and Carandini, Matteo and Harris, Timothy D} } @article {65389, title = {Basal ganglia circuits for action specification.}, journal = {Annual Review Neuroscience}, volume = {43}, year = {2020}, month = {2020 Jul 8}, pages = {485-507}, abstract = {

Behavior is readily classified into patterns of movements with inferred common goals-actions. Goals may be discrete; movements are continuous. Through the careful study of isolated movements in laboratory settings, or via introspection, it has become clear that animals can exhibit exquisite graded specification to their movements. Moreover, graded control can be as fundamental to success as the selection of which action to perform under many naturalistic scenarios: a predator adjusting its speed to intercept moving prey, or a tool-user exerting the perfect amount of force to complete a delicate task. The basal ganglia are a collection of nuclei in vertebrates that extend from the forebrain (telencephalon) to the midbrain (mesencephalon), constituting a major descending extrapyramidal pathway for control over midbrain and brainstem premotor structures. Here we discuss how this pathway contributes to the continuous specification of movements that endows our voluntary actions with vigor and grace. Expected final online publication date for the , Volume 43 is July 8, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

}, issn = {1545-4126}, doi = {10.1146/annurev-neuro-070918-050452}, author = {Park, Junchol and Coddington, Luke T and Dudman, Joshua T} } @article {65171, title = {Learning from action: reconsidering movement signaling in midbrain dopamine neuron activity.}, journal = {Neuron}, volume = {104}, year = {2019}, month = {2019 Oct 09}, pages = {63-77}, abstract = {

Animals infer when and where a reward is available from experience with informative sensory stimuli and their own actions. In vertebrates, this is thought to depend upon the release of dopamine from midbrain dopaminergic neurons. Studies of the role of dopamine have focused almost exclusively on their encoding of informative sensory stimuli; however, many dopaminergic neurons are active just prior to movement initiation, even in the absence of sensory stimuli. How should current frameworks for understanding the role of dopamine incorporate these observations? To address this question, we review recent anatomical and functional evidence for action-related dopamine signaling. We conclude by proposing a framework in which dopaminergic neurons encode subjective signals of action initiation to solve an internal credit assignment problem.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2019.08.036}, author = {Coddington, Luke T and Dudman, Joshua T} } @article {65159, title = {A repeated molecular architecture across thalamic pathways.}, journal = {Nature Neuroscience}, volume = {22}, year = {2019}, month = {2019 Sep 16}, pages = {1925-35}, abstract = {

The thalamus is the central communication hub of the forebrain and provides the cerebral cortex with inputs from sensory organs, subcortical systems and the cortex itself. Multiple thalamic regions send convergent information to each cortical region, but the organizational logic of thalamic projections has remained elusive. Through comprehensive transcriptional analyses of retrogradely labeled thalamic neurons in adult mice, we identify three major profiles of thalamic pathways. These profiles exist along a continuum that is repeated across all major projection systems, such as those for vision, motor control and cognition. The largest component of gene expression variation in the mouse thalamus is topographically organized, with features conserved in humans. Transcriptional differences between these thalamic neuronal identities are tied to cellular features that are critical for function, such as axonal morphology and membrane properties. Molecular profiling therefore reveals covariation in the properties of thalamic pathways serving all major input modalities and output targets, thus establishing a molecular framework for understanding the thalamus.

}, issn = {1546-1726}, doi = {10.1038/s41593-019-0483-3}, author = {Phillips, James W and Schulmann, Anton and Hara, Erina and Winnubst, Johan and Liu, Chenghao and Valakh, Vera and Wang, Lihua and Shields, Brenda C and Korff, Wyatt and Chandrashekar, Jayaram and Lemire, Andrew L and Mensh, Brett and Dudman, Joshua T and Nelson, Sacha B and Hantman, Adam W} } @article {49474, title = {Expanding the optogenetics toolkit by topological inversion of rhodopsins.}, journal = {Cell}, volume = {175}, year = {2018}, month = {2018 Oct 16}, pages = {1131-40}, abstract = {

Targeted manipulation of activity in specific populations of neurons is important for investigating the neural circuit basis of behavior. Optogenetic approaches using light-sensitive microbial rhodopsins have permitted manipulations to reach a level of temporal precision that is enabling functional circuit dissection. As demand for more precise perturbations to serve specific experimental goals increases, a palette of opsins with diverse selectivity, kinetics, and spectral properties will be needed. Here, we introduce a novel approach of "topological engineering"-inversion of opsins in the plasma membrane-and demonstrate that it can produce variants with unique functional properties of interest for circuit neuroscience. In one striking example, inversion of a Channelrhodopsin variant converted it from a potent activator into a fast-acting inhibitor that operates as a cation pump. Our findings argue that membrane topology provides a useful orthogonal dimension of protein engineering that immediately permits as much as a doubling of the available toolkit.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2018.09.026}, author = {Brown, Jennifer and Behnam, Reza and Coddington, Luke and Tervo, D G R and Martin, Kathleen and Proskurin, Mikhail and Kuleshova, Elena and Park, Junchol and Phillips, James and Bergs, Amelie C F and Gottschalk, Alexander and Dudman, Joshua T and Karpova, Alla Y} } @article {49469, title = {The timing of action determines reward prediction signals in identified midbrain dopamine neurons.}, journal = {Nature Neuroscience}, volume = {21}, year = {2018}, month = {2018 Oct 15}, pages = {1563-73}, abstract = {

Animals adapt their behavior in response to informative sensory cues using multiple brain circuits. The activity of midbrain dopaminergic neurons is thought to convey a critical teaching signal: reward-prediction error. Although reward-prediction error signals are thought to be essential to learning, little is known about the dynamic changes in the activity of midbrain dopaminergic neurons as animals learn about novel sensory cues and appetitive rewards. Here we describe a large dataset of cell-attached recordings of identified dopaminergic neurons as naive mice learned a novel cue-reward association. During learning midbrain dopaminergic neuron activity results from the summation of sensory cue-related and movement initiation-related response components. These components are both a function of reward expectation yet they are dissociable. Learning produces an increasingly precise coordination of action initiation following sensory cues that results in apparent reward-prediction error correlates. Our data thus provide new insights into the circuit mechanisms that underlie a critical computation in a highly conserved learning circuit.

}, issn = {1546-1726}, doi = {10.1038/s41593-018-0245-7}, author = {Coddington, Luke T and Dudman, Joshua T} } @article {48413, title = {Deconstructing behavioral neuropharmacology with cellular specificity.}, journal = {Science (New York, N.Y.)}, volume = {356}, year = {2017}, month = {2017 Apr 07}, abstract = {

Behavior has molecular, cellular, and circuit determinants. However, because many proteins are broadly expressed, their acute manipulation within defined cells has been difficult. Here, we combined the speed and molecular specificity of pharmacology with the cell type specificity of genetic tools. DART (drugs acutely restricted by tethering) is a technique that rapidly localizes drugs to the surface of defined cells, without prior modification of the native target. We first developed an AMPAR antagonist DART, with validation in cultured neuronal assays, in slices of mouse dorsal striatum, and in behaving mice. In parkinsonian animals, motor deficits were causally attributed to AMPARs in indirect spiny projection neurons (iSPNs) and to excess phasic firing of tonically active interneurons (TANs). Together, iSPNs and TANs (i.e., D2 cells) drove akinesia, whereas movement execution deficits reflected the ratio of AMPARs in D2 versus D1 cells. Finally, we designed a muscarinic antagonist DART in one iteration, demonstrating applicability of the method to diverse targets.

}, issn = {1095-9203}, doi = {10.1126/science.aaj2161}, author = {Shields, Brenda C and Kahuno, Elizabeth and Kim, Charles and Apostolides, Pierre F and Brown, Jennifer and Lindo, Sarah and Mensh, Brett D and Dudman, Joshua T and Lavis, Luke D and Tadross, Michael R} } @article {48648, title = {Desensitized D2 autoreceptors are resistant to trafficking.}, journal = {Scientific Reports}, volume = {7}, year = {2017}, month = {2017 Jun 29}, pages = {4379}, abstract = {

Dendritic release of dopamine activates dopamine D2 autoreceptors, which are inhibitory G protein-coupled receptors (GPCRs), to decrease the excitability of dopamine neurons. This study used tagged D2 receptors to identify the localization and distribution of these receptors in living midbrain dopamine neurons. GFP-tagged D2 receptors were found to be unevenly clustered on the soma and dendrites of dopamine neurons within the substantia nigra pars compacta (SNc). Physiological signaling and desensitization of the tagged receptors were not different from wild type receptors. Unexpectedly, upon desensitization the tagged D2 receptors were not internalized. When tagged D2 receptors were expressed in locus coeruleus neurons, a desensitizing protocol induced significant internalization. Likewise, when tagged {\textmu}-opioid receptors were expressed in dopamine neurons they too were internalized. The distribution and lack of agonist-induced internalization of D2 receptors on dopamine neurons indicate a purposefully regulated localization of these receptors.

}, issn = {2045-2322}, doi = {10.1038/s41598-017-04728-z}, author = {Robinson, Brooks G and Bunzow, James R and Grimm, Jonathan B and Lavis, Luke D and Dudman, Joshua T and Brown, Jennifer and Neve, Kim A and Williams, John T} } @article {48994, title = {Emergence of reward expectation signals in identified dopamine neurons.}, journal = {bioRxiv}, year = {2017}, month = {2017 Dec 22}, abstract = {

Coherent control of purposive actions emerges from the coordination of multiple brain circuits during learning. Dissociable brain circuits and cell-types are thought to preferentially participate in distinct learning mechanisms. For example, the activity of midbrain dopamine (mDA) neurons is proposed to primarily, or even exclusively, reflect reward prediction error signals in well-trained animals. To study the specific contribution of individual circuits requires observing changes before tight functional coordination is achieved. However, little is known about the detailed timing of the emergence of reward-related representations in dopaminergic neurons. Here we recorded activity of identified dopaminergic neurons as naive mice learned a novel stimulus-reward association. We found that at early stages of learning mDA neuron activity reflected both external (sensory) and internal (action initiation) causes of reward expectation. The increasingly precise correlation of action initiation with sensory stimuli rather than an evaluation of outcomes governed mDA neuron activity. Thus, our data demonstrate that mDA neuron activity early in learning does not reflect errors, but is more akin to a Hebbian learning signal - providing new insight into a critical computation in a highly conserved, essential learning circuit.

}, doi = {10.1101/238881}, author = {Coddington, Luke T and Dudman, Joshua T} } @article {48985, title = {A topographic axis of transcriptional identity in thalamus.}, journal = {bioRxiv}, year = {2017}, month = {2017 Dec 31}, pages = {241315}, abstract = {

A fundamental goal in neuroscience is to uncover common principles by which different modalities of information are processed. In the mammalian brain, thalamus acts as the essential hub for forebrain circuits handling inputs from sensory, motor, limbic, and cognitive pathways. Whether thalamus imposes common transformations on each of these modalities is unknown. Molecular characterization offers a principled approach to revealing the organization of thalamus. Using near-comprehensive and projection-specific transcriptomic sequencing, we found that almost all thalamic nuclei fit into one of three profiles. These profiles lie on a single axis of genetic variance which is aligned with the mediolateral spatial axis of thalamus. Genes defining this axis of variance include receptors and ion channels, providing a systematic diversification of input/output transformations across the topography of thalamus. Single cell transcriptional profiling revealed graded heterogeneity within individual thalamic nuclei, demonstrating that a spectrum of cell types and potentially diverse input/output transforms exist within a given thalamic nucleus. Together, our data argue for an archetypal organization of pathways serving diverse input modalities, and provides a comprehensive organizational scheme for thalamus.

}, doi = {10.1101/241315}, author = {Phillips, James W and Schulman, Anton and Hara, Erina and Liu, Chenghao and Shields, Brenda C and Korff, Wyatt and Lemire, Andrew and Dudman, Joshua T and Nelson, Sacha B and Hantman, Adam W} } @article {47393, title = {The basal ganglia: from motor commands to the control of vigor.}, journal = {Current Opinion in Neurobiology}, volume = {37}, year = {2016}, month = {2016 Mar 21}, pages = {158-66}, abstract = {

Vertebrates are remarkable for their ability to select and execute goal-directed actions: motor skills critical for thriving in complex, competitive environments. A key aspect of a motor skill is the ability to execute its component movements over a range of speeds, amplitudes and frequencies (vigor). Recent work has indicated that a subcortical circuit, the basal ganglia, is a critical determinant of movement vigor in rodents and primates. We propose that the basal ganglia evolved from a circuit that in lower vertebrates and some mammals is sufficient to directly command simple or stereotyped movements to one that indirectly controls the vigor of goal-directed movements. The implications of a dual role of the basal ganglia in the control of vigor and response to reward are also discussed.

}, issn = {1873-6882}, doi = {10.1016/j.conb.2016.02.005}, author = {Dudman, Joshua T and Krakauer, John W} } @article {47934, title = {A designer AAV variant permits efficient retrograde access to projection neurons.}, journal = {Neuron}, volume = {92}, year = {2016}, month = {2016 Oct 19}, pages = {372-82}, abstract = {

Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in\ vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV), a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers and enables sufficient sensor/effector expression for functional circuit interrogation and in\ vivo genome editing in targeted neuronal populations. VIDEO ABSTRACT.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2016.09.021}, author = {Tervo, D Gowanlock R and Hwang, Bum-Yeol and Viswanathan, Sarada and Gaj, Thomas and Lavzin, Maria and Ritola, Kimberly D and Lindo, Sarah and Michael, Susan and Kuleshova, Elena and Ojala, David and Huang, Cheng-Chiu and Gerfen, Charles R and Schiller, Jackie and Dudman, Joshua T and Hantman, Adam W and Looger, Loren L and Schaffer, David V and Karpova, Alla Y} } @article {47468, title = {Opponent and bidirectional control of movement velocity in the basal ganglia.}, journal = {Nature}, year = {2016}, month = {2016 May 2}, abstract = {

For goal-directed behaviour it is critical that we can both select the appropriate action and learn to modify the underlying movements (for example, the pitch of a note or velocity of a reach) to improve outcomes. The basal ganglia are a critical nexus where circuits necessary for the production of behaviour, such as the neocortex and thalamus, are integrated with reward signalling to reinforce successful, purposive actions. The dorsal striatum, a major input structure of basal ganglia, is composed of two opponent pathways, direct and indirect, thought to select actions that elicit positive outcomes and suppress actions that do not, respectively. Activity-dependent plasticity modulated by reward is thought to be sufficient for selecting actions in the striatum. Although perturbations of basal ganglia function produce profound changes in movement, it remains unknown whether activity-dependent plasticity is sufficient to produce learned changes in movement kinematics, such as velocity. Here we use cell-type-specific stimulation in mice delivered in closed loop during movement to demonstrate that activity in either the direct or indirect pathway is sufficient to produce specific and sustained increases or decreases in velocity, without affecting action selection or motivation. These behavioural changes were a form of learning that accumulated over trials, persisted after the cessation of stimulation, and were abolished in the presence of dopamine antagonists. Our results reveal that the direct and indirect pathways can each bidirectionally control movement velocity, demonstrating unprecedented specificity and flexibility in the control of volition by the basal ganglia.

}, issn = {1476-4687}, doi = {10.1038/nature17639}, author = {Yttri, Eric A and Dudman, Joshua T} } @article {47036, title = {Dopamine is required for the neural representation and control of movement vigor.}, journal = {Cell}, volume = {162}, year = {2015}, month = {2015 Sep 10}, pages = {1418-30}, abstract = {

Progressive depletion of midbrain dopamine neurons (PDD) is associated with deficits in the initiation, speed, and fluidity of voluntary movement. Models of\ basal ganglia function focus on initiation deficits; however, it is unclear how they account for deficits in the speed or amplitude of movement (vigor). Using an effort-based operant conditioning task for head-fixed mice, we discovered distinct functional classes of neurons in the dorsal striatum that represent movement vigor. Mice with PDD exhibited a progressive reduction in vigor, along with a selective impairment of its neural representation in striatum. Restoration of dopaminergic tone with a synthetic precursor ameliorated deficits in movement vigor and its neural representation, while suppression of striatal activity during movement was sufficient to reduce vigor. Thus, dopaminergic input to the dorsal striatum is indispensable for the emergence of striatal activity that mediates adaptive changes in movement vigor. These results suggest refined intervention strategies for Parkinson{\textquoteright}s disease.

}, doi = {10.1016/j.cell.2015.08.014}, author = {Panigrahi, Babita and Martin, Kathleen A and Li, Yi and Graves, Austin R and Vollmer, Alison and Olson, Lars and Mensh, Brett D and Karpova, Alla Y and Dudman, Joshua T} } @article {47239, title = {Minimally invasive microendoscopy system for in vivo functional imaging of deep nuclei in the mouse brain.}, journal = {Biomedical Optics Express}, volume = {6}, year = {2015}, month = {2015 Nov 1}, pages = {4546-56}, abstract = {

The ability to image neurons anywhere in the mammalian brain is a major goal of optical microscopy. Here we describe a minimally invasive microendoscopy system for studying the morphology and function of neurons at depth. Utilizing a guide cannula with an ultrathin wall, we demonstrated in vivo two-photon fluorescence imaging of deeply buried nuclei such as the striatum (2.5 mm depth), substantia nigra (4.4 mm depth) and lateral hypothalamus (5.0 mm depth) in mouse brain. We reported, for the first time, the observation of neuronal activity with subcellular resolution in the lateral hypothalamus and substantia nigra of head-fixed awake mice.

}, issn = {2156-7085}, doi = {10.1364/BOE.6.004546}, author = {Bocarsly, Miriam E and Jiang, Wan-Chen and Wang, Chen and Dudman, Joshua T and Ji, Na and Aponte, Yeka} } @article {46942, title = {A specific component of the evoked potential mirrors phasic dopamine neuron activity during conditioning.}, journal = {The Journal of Neuroscience : the official journal of the Society for Neuroscience}, volume = {35}, year = {2015}, month = {2015 Jul 22}, pages = {10451-9}, abstract = {

UNLABELLED: Midbrain dopamine (DA) neurons are thought to be a critical node in the circuitry that mediates reward learning. DA neurons receive diverse inputs from regions distributed throughout the neuraxis from frontal neocortex to the mesencephalon. While a great deal is known about changes in the activity of individual DA neurons during learning, much less is known about the functional changes in the microcircuits in which DA neurons are embedded. Here we used local field potentials recorded from the midbrain of behaving mice to show that the midbrain evoked potential (mEP) faithfully reflects the temporal and spatial structure of the phasic response of midbrain neuron populations during conditioning. By comparing the mEP to simultaneously recorded single units, we identified specific components of the mEP that corresponded to phasic DA and non-DA responses to salient stimuli. The DA component of the mEP emerged with the acquisition of a conditioned stimulus, was extinguished following changes in reinforcement contingency, and could be inhibited by pharmacological manipulations that attenuate the phasic responses of DA neurons. In contrast to single-unit recordings, the mEP permitted relatively dense sampling of the midbrain circuit during conditioning and thus could be used to reveal the spatiotemporal structure of multiple intermingled midbrain circuits. Finally, the mEP response was stable for months and thus provides a new approach to study long-term changes in the organization of ventral midbrain microcircuits during learning.

SIGNIFICANCE STATEMENT: Neurons that synthesize and release the neurotransmitter dopamine play a critical role in voluntary reward-seeking behavior. Much of our insight into the function of dopamine neurons comes from recordings of individual cells in behaving animals; however, it is notoriously difficult to record from dopamine neurons due to their sparsity and depth, as well as the presence of intermingled non-dopaminergic neurons. Here we show that much of the information that can be learned from recordings of individual dopamine and non-dopamine neurons is also revealed by changes in specific components of the local field potential. This technique provides an accessible measurement that could prove critical to our burgeoning understanding of the molecular, functional, and anatomical diversity of neuron populations in the midbrain.

}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4096-14.2015}, author = {Pan, Wei-Xing and Dudman, Joshua T} } @inbook {47132, title = {The basal ganglia }, booktitle = {The Rat Nervous System}, year = {2014}, pages = {391-440}, edition = {Fourth Edition}, abstract = {

The basal ganglia plays a significant role in transforming activity in the cerebral cortex into directed behavior, involving motor learning, habit formation and the selection of actions based on desirable outcomes, and the organization of the basal ganglia is intimately linked to that of the cerebral cortex. In this chapter, we focus primarily on the neocortical part of the basal ganglia. A general canonical organizational plan of the neocortical-related basal ganglia is described. An understanding of the canonical organization of the neostriatal part of the basal ganglia, provides a framework for determining the general organizational principles of the parts of the basal ganglia connected with allocortical areas and the amygdala, and this is discussed. While it has been proposed that the basal ganglia provide interactions between disparate functional circuits, another approach might be that there are parallel functional circuits, in which distinct functions are for the most part maintained, or segregated, one from the other. This chapter, however, is biased toward the view that there is maintenance of functional parallel circuits in the organization of the basal ganglia, but that the circuit contains neuroanatomical features that provide for considerable interaction between adjacent circuits.

}, doi = {10.1016/B978-0-12-374245-2.00017-6}, author = {Dudman, Joshua T and Cerfan, C R} } @article {45067, title = {Precise spatial coding is preserved along the longitudinal hippocampal axis.}, journal = {Hippocampus}, volume = {24}, year = {2014}, month = {2014 Jul 18}, pages = {1-16}, abstract = {

Compared to the dorsal hippocampus, relatively few studies have characterized neuronal responses in the ventral hippocampus. In particular, it is unclear whether and how cells in the ventral region represent space and/or respond to contextual changes. We recorded from dorsal and ventral CA1 neurons in freely moving mice exposed to manipulations of visuospatial and olfactory contexts. We found that ventral cells respond to alterations of the visuospatial environment such as exposure to novel local cues, cue rotations, and contextual expansion in similar ways to dorsal cells, with the exception of cue rotations. Furthermore, we found that ventral cells responded to odors much more strongly than dorsal cells, particularly to odors of high valence. Similar to earlier studies recording from the ventral hippocampus in CA3, we also found increased scaling of place cell field size along the longitudinal hippocampal axis. Although the increase in place field size observed toward the ventral pole has previously been taken to suggest a decrease in spatial information coded by ventral place cells, we hypothesized that a change in spatial scaling could instead signal a shift in representational coding that preserves the resolution of spatial information. To explore this possibility, we examined population activity using principal component analysis (PCA) and neural location reconstruction techniques. Our results suggest that ventral populations encode a distributed representation of space, and that the resolution of spatial information at the population level is comparable to that of dorsal populations of similar size. Finally, through the use of neural network modeling, we suggest that the redundancy in spatial representation along the longitudinal hippocampal axis may allow the hippocampus to overcome the conflict between memory interference and generalization inherent in neural network memory. Our results suggest that ventral population activity is well suited for generalization across locations and contexts. {\textcopyright} 2014 Wiley Periodicals, Inc.

}, issn = {1098-1063}, doi = {10.1002/hipo.22333}, author = {Keinath, Alexander T and Wang, Melissa E and Wann, Ellen G and Yuan, Robin K and Dudman, Joshua T and Muzzio, Isabel A} } @article {6885, title = {RIVETS: A mechanical system for in vivo and in vitro electrophysiology and imaging.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014 Feb 14}, pages = {e89007}, abstract = {

A number of recent studies have provided compelling demonstrations that both mice and rats can be trained to perform a variety of behavioral tasks while restrained by mechanical elements mounted to the skull. The independent development of this technique by a number of laboratories has led to diverse solutions. We found that these solutions often used expensive materials and impeded future development and modification in the absence of engineering support. In order to address these issues, here we report on the development of a flexible single hardware design for electrophysiology and imaging both in brain tissue in vitro. Our hardware facilitates the rapid conversion of a single preparation between physiology and imaging system and the conversion of a given system between preparations. In addition, our use of rapid prototyping machines ("3D printers") allows for the deployment of new designs within a day. Here, we present specifications for design and manufacturing as well as some data from our lab demonstrating the suitability of the design for physiology in behaving animals and imaging in vitro and in vivo.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0089007}, author = {Osborne, Jason E and Dudman, Joshua T} } @article {2311, title = {Inputs to the dorsal striatum of the mouse reflect the parallel circuit architecture of the forebrain.}, journal = {Frontiers in Neuroanatomy}, volume = {4}, year = {2011}, month = {2011}, pages = {147}, abstract = {

The basal ganglia play a critical role in the regulation of voluntary action in vertebrates. Our understanding of the function of the basal ganglia relies heavily upon anatomical information, but continued progress will require an understanding of the specific functional roles played by diverse cell types and their connectivity. An increasing number of mouse lines allow extensive identification, characterization, and manipulation of specified cell types in the basal ganglia. Despite the promise of genetically modified mice for elucidating the functional roles of diverse cell types, there is relatively little anatomical data obtained directly in the mouse. Here we have characterized the retrograde labeling obtained from a series of tracer injections throughout the dorsal striatum of adult mice. We found systematic variations in input along both the medial-lateral and anterior-posterior neuraxes in close agreement with canonical features of basal ganglia anatomy in the rat. In addition to the canonical features we have provided experimental support for the importance of non-canonical inputs to the striatum from the raphe nuclei and the amygdala. To look for organization at a finer scale we have analyzed the correlation structure of labeling intensity across our entire dataset. Using this analysis we found substantial local heterogeneity within the large-scale order. From this analysis we conclude that individual striatal sites receive varied combinations of cortical and thalamic input from multiple functional areas, consistent with some earlier studies in the rat that have suggested the presence of a combinatorial map.

}, issn = {1662-5129}, doi = {10.3389/fnana.2010.00147}, author = {Pan, Weixing X and Mao, Tianyi and Dudman, Joshua T} } @article {2312, title = {Stochastically gating ion channels enable patterned spike firing through activity-dependent modulation of spike probability.}, journal = {PLoS Computational Biology}, volume = {5}, year = {2009}, month = {2009 Feb}, pages = {e1000290}, abstract = {

The transformation of synaptic input into patterns of spike output is a fundamental operation that is determined by the particular complement of ion channels that a neuron expresses. Although it is well established that individual ion channel proteins make stochastic transitions between conducting and non-conducting states, most models of synaptic integration are deterministic, and relatively little is known about the functional consequences of interactions between stochastically gating ion channels. Here, we show that a model of stellate neurons from layer II of the medial entorhinal cortex implemented with either stochastic or deterministically gating ion channels can reproduce the resting membrane properties of stellate neurons, but only the stochastic version of the model can fully account for perithreshold membrane potential fluctuations and clustered patterns of spike output that are recorded from stellate neurons during depolarized states. We demonstrate that the stochastic model implements an example of a general mechanism for patterning of neuronal output through activity-dependent changes in the probability of spike firing. Unlike deterministic mechanisms that generate spike patterns through slow changes in the state of model parameters, this general stochastic mechanism does not require retention of information beyond the duration of a single spike and its associated afterhyperpolarization. Instead, clustered patterns of spikes emerge in the stochastic model of stellate neurons as a result of a transient increase in firing probability driven by activation of HCN channels during recovery from the spike afterhyperpolarization. Using this model, we infer conditions in which stochastic ion channel gating may influence firing patterns in vivo and predict consequences of modifications of HCN channel function for in vivo firing patterns.

}, keywords = {Action Potentials, Animals, Cyclic Nucleotide-Gated Cation Channels, Entorhinal Cortex, Humans, Ion Channel Gating, Ion Transport, Models, Neural Conduction, Neurological, Potassium Channels, Stochastic Processes, Synaptic Transmission}, issn = {1553-7358}, doi = {10.3389/fnana.2010.00147}, author = {Dudman, Joshua T and Nolan, Matthew F} } @article {4047, title = {HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons.}, journal = {Neuron}, volume = {56}, year = {2007}, month = {2007 Dec 20}, pages = {1076-89}, abstract = {

HCN1 hyperpolarization-activated cation channels act as an inhibitory constraint of both spatial learning and synaptic integration and long-term plasticity in the distal dendrites of hippocampal CA1 pyramidal neurons. However, as HCN1 channels provide an excitatory current, the mechanism of their inhibitory action remains unclear. Here we report that HCN1 channels also constrain CA1 distal dendritic Ca2+ spikes, which have been implicated in the induction of LTP at distal excitatory synapses. Our experimental and computational results indicate that HCN1 channels provide both an active shunt conductance that decreases the temporal integration of distal EPSPs and a tonic depolarizing current that increases resting inactivation of T-type and N-type voltage-gated Ca2+ channels, which contribute to the Ca2+ spikes. This dual mechanism may provide a general means by which HCN channels regulate dendritic excitability.

}, keywords = {Animals, Calcium, Calcium Channel Blockers, Computer Simulation, Cyclic Nucleotide-Gated Cation Channels, Dendrites, Dose-Response Relationship, Electric Stimulation, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Hippocampus, Knockout, Mice, Newborn, Patch-Clamp Techniques, Potassium Channels, Pyramidal Cells, Pyrimidines, Radiation, Reaction Time, Synapses}, issn = {0896-6273}, doi = {10.1016/j.neuron.2007.11.015}, author = {Tsay, David and Dudman, Joshua T and Siegelbaum, Steven A} } @article {4050, title = {HCN1 channels control resting and active integrative properties of stellate cells from layer II of the entorhinal cortex.}, journal = {The Journal of Neuroscience}, volume = {27}, year = {2007}, month = {2007 Nov 14}, pages = {12440-51}, abstract = {

Whereas recent studies have elucidated principles for representation of information within the entorhinal cortex, less is known about the molecular basis for information processing by entorhinal neurons. The HCN1 gene encodes ion channels that mediate hyperpolarization-activated currents (I(h)) that control synaptic integration and influence several forms of learning and memory. We asked whether hyperpolarization-activated, cation nonselective 1 (HCN1) channels control processing of information by stellate cells found within layer II of the entorhinal cortex. Axonal projections from these neurons form a major component of the synaptic input to the dentate gyrus of the hippocampus. To determine whether HCN1 channels control either the resting or the active properties of stellate neurons, we performed whole-cell recordings in horizontal brain slices prepared from adult wild-type and HCN1 knock-out mice. We found that HCN1 channels are required for rapid and full activation of hyperpolarization-activated currents in stellate neurons. HCN1 channels dominate the membrane conductance at rest, are not required for theta frequency (4-12 Hz) membrane potential fluctuations, but suppress low-frequency (\<4 Hz) components of spontaneous and evoked membrane potential activity. During sustained activation of stellate cells sufficient for firing of repeated action potentials, HCN1 channels control the pattern of spike output by promoting recovery of the spike afterhyperpolarization. These data suggest that HCN1 channels expressed by stellate neurons in layer II of the entorhinal cortex are key molecular components in the processing of inputs to the hippocampal dentate gyrus, with distinct integrative roles during resting and active states.

}, keywords = {Action Potentials, Animals, Cyclic Nucleotide-Gated Cation Channels, Dentate Gyrus, Entorhinal Cortex, Female, Ion Channel Gating, Knockout, Male, Membrane Potentials, Memory, Mice, Neural Inhibition, Neural Pathways, Neurons, Organ Culture Techniques, Patch-Clamp Techniques, Potassium Channels, Synaptic Membranes, Synaptic Transmission, Theta Rhythm}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.2358-07.2007}, author = {Nolan, Matthew F and Dudman, Joshua T and Dodson, Paul D and Santoro, Bina} } @article {4048, title = {A role for synaptic inputs at distal dendrites: instructive signals for hippocampal long-term plasticity.}, journal = {Neuron}, volume = {56}, year = {2007}, month = {2007 Dec 6}, pages = {866-79}, abstract = {

Synaptic potentials originating at distal dendritic locations are severely attenuated when they reach the soma and, thus, are poor at driving somatic spikes. Nonetheless, distal inputs convey essential information, suggesting that such inputs may be important for compartmentalized dendritic signaling. Here we report a new plasticity rule in which stimulation of distal perforant path inputs to hippocampal CA1 pyramidal neurons induces long-term potentiation at the CA1 proximal Schaffer collateral synapses when the two inputs are paired at a precise interval. This subthreshold form of heterosynaptic plasticity occurs in the absence of somatic spiking but requires activation of both NMDA receptors and IP(3) receptor-dependent release of Ca(2+) from internal stores. Our results suggest that direct sensory information arriving at distal CA1 synapses through the perforant path provide compartmentalized, instructive signals that assess the saliency of mnemonic information propagated through the hippocampal circuit to proximal synapses.

}, keywords = {4, 5-Trisphosphate Receptors, Absorptiometry, AMPA, Animals, Calcium, Computer Simulation, Dendrites, Dendritic Spines, Electrophysiology, Excitatory Postsynaptic Potentials, Hippocampus, Inositol 1, Memory, Mice, Models, N-Methyl-D-Aspartate, Neurological, Neuronal Plasticity, Neurophysiological, Patch-Clamp Techniques, Photon, Pyramidal Cells, Receptors, Recruitment, Signal Transduction, Synapses, Synaptic Transmission}, issn = {0896-6273}, doi = {10.1016/j.neuron.2007.10.020}, author = {Dudman, Joshua T and Tsay, David and Siegelbaum, Steven A} } @article {2316, title = {Making the grade with models of persistent activity.}, journal = {Neuron}, volume = {49}, year = {2006}, month = {2006 Mar 2}, pages = {649-51}, abstract = {

Persistent neural activity that outlasts an initial stimulus is thought to provide a mechanism for the transient storage of memory. In this issue of Neuron, Frans{\'e}n et al. identify important principles for a cell-autonomous mechanism of graded persistent firing using an elegant combination of experimental and computational approaches.

}, keywords = {Action Potentials, Animals, Calcium, Electric Stimulation, Models, Neurological, Neurons}, issn = {0896-6273}, doi = {10.3389/fnana.2010.00147}, author = {Dudman, Joshua T and Siegelbaum, Steven A} } @article {2318, title = {Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat.}, journal = {Biological Psychiatry}, volume = {57}, year = {2005}, month = {2005 May 1}, pages = {1041-51}, abstract = {

Molecular adaptations are believed to contribute to the mechanism of action of antipsychotic drugs (APDs). We attempted to establish common gene regulation patterns induced by chronic treatment with APDs.

}, keywords = {Animals, Antipsychotic Agents, Cluster Analysis, Corpus Striatum, Frontal Lobe, Gene Expression, Male, Messenger, Microtubules, Oligonucleotide Array Sequence Analysis, Presynaptic Terminals, Rats, Reverse Transcriptase Polymerase Chain Reaction, RNA, Sprague-Dawley, Synaptic Vesicles}, issn = {0006-3223}, doi = {10.3389/fnana.2010.00147}, author = {MacDonald, Matthew L and Eaton, Molly E and Dudman, Joshua T and Konradi, Christine} } @article {2317, title = {Mechanism of positive allosteric modulators acting on AMPA receptors.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {25}, year = {2005}, month = {2005 Sep 28}, pages = {9027-36}, abstract = {

Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer{\textquoteright}s disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the "hinge" in the ligand-binding core "clamshell" that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.

}, keywords = {Allosteric Regulation, AMPA, Benzothiadiazines, Binding Sites, Cell Line, Crystallography, Dimerization, Drug Synergism, Electric Conductivity, Humans, Ligands, Molecular Conformation, Oxazines, Patch-Clamp Techniques, Protein Structure, Pyrrolidinones, Receptors, Tertiary, Time Factors}, issn = {1529-2401}, doi = {10.3389/fnana.2010.00147}, author = {Jin, Rongsheng and Clark, Suzanne and Weeks, Autumn M and Dudman, Joshua T and Gouaux, Eric and Partin, Kathryn M} } @article {2319, title = {Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces.}, journal = {Neuron}, volume = {44}, year = {2004}, month = {2004 Dec 16}, pages = {1043-55}, abstract = {

Responses to threat-related stimuli are influenced by conscious and unconscious processes, but the neural systems underlying these processes and their relationship to anxiety have not been clearly delineated. Using fMRI, we investigated the neural responses associated with the conscious and unconscious (backwardly masked) perception of fearful faces in healthy volunteers who varied in threat sensitivity (Spielberger trait anxiety scale). Unconscious processing modulated activity only in the basolateral subregion of the amygdala, while conscious processing modulated activity only in the dorsal amygdala (containing the central nucleus). Whereas activation of the dorsal amygdala by conscious stimuli was consistent across subjects and independent of trait anxiety, activity in the basolateral amygdala to unconscious stimuli, and subjects{\textquoteright} reaction times, were predicted by individual differences in trait anxiety. These findings provide a biological basis for the unconscious emotional vigilance characteristic of anxiety and a means for investigating the mechanisms and efficacy of treatments for anxiety.

}, keywords = {Adult, Amygdala, Anxiety, Brain Mapping, Emotions, Facial Expression, Fear, Female, Humans, Individuality, Male, Photic Stimulation, Predictive Value of Tests, Reaction Time, Unconscious (Psychology)}, issn = {0896-6273}, doi = {10.3389/fnana.2010.00147}, author = {Etkin, Amit and Klemenhagen, Kristen C and Dudman, Joshua T and Rogan, Michael T and Hen, Ren{\'e} and Kandel, Eric R and Hirsch, Joy} } @article {2320, title = {L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons.}, journal = {Brain Research. Molecular Brain Research}, volume = {131}, year = {2004}, month = {2004 Nov 24}, pages = {65-72}, abstract = {

Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson{\textquoteright}s disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.

}, keywords = {2, 3, 4, 5-Tetrahydro-7, 8-dihydroxy-1-phenyl-1H-3-benzazepine, Animals, Antisense, Calcium, Calcium Channel Blockers, Calcium Channels, Cells, Corpus Striatum, Cultured, Cyclic AMP Response Element-Binding Protein, Dizocilpine Maleate, Dopamine Antagonists, Dopamine D1, Drug Interactions, Excitatory Amino Acid Antagonists, Female, L-Type, N-Methyl-D-Aspartate, Neurons, Nifedipine, Oligonucleotides, Phosphorylation, Pregnancy, Rats, Receptors, Sprague-Dawley}, issn = {0169-328X}, doi = {10.3389/fnana.2010.00147}, author = {Eaton, Molly E and Mac{\'\i}as, Wendy and Youngs, Rachael M and Rajadhyaksha, Anjali and Dudman, Joshua T and Konradi, Christine} } @article {2322, title = {Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1.}, journal = {Journal of Neurochemistry}, volume = {87}, year = {2003}, month = {2003 Nov}, pages = {922-34}, abstract = {

Addictive drugs such as amphetamine and cocaine stimulate the dopaminergic system, activate dopamine receptors and induce gene expression throughout the striatum. The signal transduction pathway leading from dopamine receptor stimulation at the synapse to gene expression in the nucleus has not been fully elucidated. Here, we present evidence that D1 receptor stimulation leads to phosphorylation of the transcription factor Ca2+ and cyclic AMP response element binding protein (CREB) in the nucleus by means of NMDA receptor-mediated Ca2+ signaling. Stimulation of D1 receptors induces the phosphorylation of Ser897 on the NR1 subunit by protein kinase A (PKA). This phosphorylation event is crucial for D1 receptor-mediated CREB phosphorylation. Dopamine cannot induce CRE-mediated gene expression in neurons transfected with a phosphorylation-deficient NR1 construct. Moreover, stimulation of D1 receptors or increase in cyclic AMP levels leads to an increase in cytosolic Ca2+ in the presence of glutamate, but not in the absence of glutamate, indicating the ability of dopamine and cyclic AMP to facilitate NMDA channel activity. The recruitment of the NMDA receptor signal transduction pathway by D1 receptors may provide a general mechanism for gene regulation that is fundamental for mechanisms of drug addiction and long-term memory.

}, keywords = {Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinases, Cells, Corpus Striatum, Cultured, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Dopamine D1, Glutamic Acid, Mutagenesis, N-Methyl-D-Aspartate, Neurons, Phosphorylation, Rats, Receptors, Signal Transduction, Site-Directed, Sprague-Dawley}, issn = {0022-3042}, doi = {10.3389/fnana.2010.00147}, author = {Dudman, Joshua T and Eaton, Molly E and Rajadhyaksha, Anjali and Mac{\'\i}as, Wendy and Taher, Muffadal and Barczak, Amy and Kameyama, Kimihiko and Huganir, Richard and Konradi, Christine} } @article {2321, title = {The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells.}, journal = {Cell}, volume = {115}, year = {2003}, month = {2003 Nov 26}, pages = {551-64}, abstract = {

In contrast to our increasingly detailed understanding of how synaptic plasticity provides a cellular substrate for learning and memory, it is less clear how a neuron{\textquoteright}s voltage-gated ion channels interact with plastic changes in synaptic strength to influence behavior. We find, using generalized and regional knockout mice, that deletion of the HCN1 channel causes profound motor learning and memory deficits in swimming and rotarod tasks. In cerebellar Purkinje cells, which are a key component of the cerebellar circuit for learning of correctly timed movements, HCN1 mediates an inward current that stabilizes the integrative properties of Purkinje cells and ensures that their input-output function is independent of the previous history of their activity. We suggest that this nonsynaptic integrative function of HCN1 is required for accurate decoding of input patterns and thereby enables synaptic plasticity to appropriately influence the performance of motor activity.

}, keywords = {Action Potentials, Afferent Pathways, Animals, Cells, Conditioning (Psychology), Cultured, Cyclic Nucleotide-Gated Cation Channels, Ion Channels, Knockout, Learning, Maze Learning, Mice, Motor Skills, Movement, Nerve Tissue Proteins, Neuronal Plasticity, Potassium Channels, Purkinje Cells, Synapses, Synaptic Transmission}, issn = {0092-8674}, doi = {10.3389/fnana.2010.00147}, author = {Nolan, Matthew F and Malleret, Ga{\"e}l and Lee, Ka Hung and Gibbs, Emma and Dudman, Joshua T and Santoro, Bina and Yin, Deqi and Thompson, Richard F and Siegelbaum, Steven A and Kandel, Eric R and Morozov, Alexei} } @article {2323, title = {Striatal proenkephalin gene induction: coordinated regulation by cyclic AMP and calcium pathways.}, journal = {Brain Research. Molecular Brain Research}, volume = {115}, year = {2003}, month = {2003 Jul 23}, pages = {157-61}, abstract = {

Enkephalin modulates striatal function, thereby affecting motor performance and addictive behaviors. The proenkephalin gene is also used as a model to study cyclic AMP-mediated gene expression in striatal neurons. The second messenger pathway leading to proenkephalin expression demonstrates how cyclic AMP pathways are synchronized with depolarization. We show that cyclic AMP-mediated regulation of the proenkephalin gene is dependent on the activity of L-type Ca2+ channels. Inhibition of L-type Ca2+ channels blocks forskolin-mediated induction of proenkephalin. The Ca2+-activated kinase, Ca2+/calmodulin kinase, as well as the cyclic AMP-activated kinase, protein kinase A (PKA), are both necessary for the induction of the proenkephalin promoter. Similarly, both kinases are needed for the L-type Ca2+ channel-mediated induction of proenkephalin. This synchronization of second messenger pathways provides a coincidence mechanism that gates proenkephalin synthesis in striatal neurons, ensuring that levels are increased only in the presence of activated PKA and depolarization.

}, keywords = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Animals, Antihypertensive Agents, Calcium, Calcium Channel Agonists, Calcium Channel Blockers, Carcinogens, Cells, Corpus Striatum, Cultured, Cyclic AMP, Developmental, Drug Interactions, Embryo, Enkephalins, Enzyme Inhibitors, Forskolin, Gene Expression Regulation, Humans, Isoquinolines, Mammalian, Neurons, Nifedipine, Protein Precursors, Pyrroles, Rats, Sprague-Dawley, Sulfonamides, Tetradecanoylphorbol Acetate, Transcriptional Activation, Transfection}, issn = {0169-328X}, doi = {10.3389/fnana.2010.00147}, author = {Konradi, Christine and Mac{\'\i}as, Wendy and Dudman, Joshua T and Carlson, Richard R} }