Bio


Ivan Soltesz received his doctorate in Budapest and conducted postdoctoral research at universities at Oxford, London, Stanford and Dallas. He established his laboratory at the University of California, Irvine, in 1995. He became full Professor in 2003, and served as department Chair from 2006 to July 2015. He returned to Stanford in 2015 as the James R. Doty Professor of Neurosurgery and Neurosciences at Stanford University School of Medicine. His major research interest is focused on neuronal microcircuits, network oscillations, cannabinoid signaling and the mechanistic bases of circuit dysfunction in epilepsy.
His laboratory employs a combination of closely integrated experimental and theoretical techniques, including closed-loop in vivo optogenetics, paired patch clamp recordings, in vivo electrophysiological recordings from identified interneurons in awake mice, 2-photon imaging, machine learning-aided 3D video analysis of behavior, video-EEG recordings, behavioral approaches, and large-scale computational modeling methods using supercomputers. He is the author of a book on GABAergic microcircuits (Diversity in the Neuronal Machine, Oxford University Press), and editor of a book on Computational Neuroscience in Epilepsy (Academic Press/Elsevier). He co-founded the first Gordon Research Conference on the Mechanisms of neuronal synchronization and epilepsy, and taught for five years in the Ion Channels Course at Cold Springs Harbor. He has over 30 years of research experience, with over 20 years as a faculty involved in the training of graduate students (total of 16, 6 of them MD/PhDs) and postdoctoral fellows (20), many of whom received fellowship awards, K99 grants, joined prestigious residency programs and became independent faculty.

Administrative Appointments


  • Assistant Professor, University of California, Irvine (1995 - 1999)
  • Associate Professor, University of California, Irvine (1999 - 2003)
  • Professor, University of California, Irvine (2003 - 2015)
  • Chair of Anatomy & Neurobiology, University of California, Irvine (2006 - 2015)
  • Chancellor's Professor, University of California, Irvine (2011 - 2015)
  • James R Doty Professor of Neurosurgery and Neurosciences, Stanford University (2015 - Present)
  • Vice Chair, Neurosurgery, Stanford University (2015 - Present)

Honors & Awards


  • Athalie Clark Research Award, University of California, Irvine (2005)
  • Javits Neuroscience Investigator Award, NINDS-NIH (2005)
  • Michael Prize in Epilepsy Research, Stiftung Michael, Germany (2009)
  • Research Recognition Award, Basic Science, American Epilepsy Society (2011)
  • Foreign Member, Hungarian Academy of Sciences (2016)

Boards, Advisory Committees, Professional Organizations


  • Co-Chair, Founder, Gordon Research Conference on Mechanisms of Epilepsy and Neuronal Synchronization (2006 - 2006)
  • Chair, Basic Science Committee, American Epilepsy Society (2006 - 2009)
  • Associate Editor, Journal of Neuroscience (2007 - 2012)
  • Member, Editorial Board, Epilepsy Research (2008 - 2015)
  • Member, Scientific Advisory Board, Citizens United in Research in Epilepsy (CURE) (2009 - 2012)
  • Co-Chair, Grants and Fellowship Review Panel, Epilepsy Foundation (2010 - 2012)
  • Chair, Clinical Neuroplasticity and Neurotransmitters (CNNT) study section, NIH (2011 - 2013)
  • Member, Professional Advisory Board, Epilepsy Foundation (2011 - Present)
  • Member, Editorial Board, Experimental Neurology (2013 - Present)
  • Chair, Research recognition Awards Committee, American Epilepsy Society (2016 - Present)

Professional Education


  • Postdoc, UT Southwestern, Neuroscience (1994)
  • Postdoc, Stanford University, Neuroscience (1993)
  • Postdoc, Universite Laval, Neuroscience (1992)
  • Postdoc, University of London, Neuroscience (1991)
  • Postdoc, Oxford University, Neuroscience (1990)
  • Ph.D., Eotvos University, Budapest, Comparative Physiology (1989)
  • University Diploma, Eotvos University, Budapest, Biology (1988)

2023-24 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • Artificial Intelligence in Epilepsy Phenotyping. Epilepsia Knight, A., Gschwind, T., Galer, P., Worrell, G. A., Litt, B., Soltesz, I., Beniczky, S. 2023

    Abstract

    Artificial intelligence (AI) allows data analysis and integration at an unprecedented granularity and scale. Here we review the technological advances, challenges and future perspectives of using AI for electro-clinical phenotyping of animal models and patients with epilepsy. In translational research AI models accurately identify behavioral states in animal models of epilepsy, allowing identification of correlations between neural activity and interictal and ictal behavior. Clinical applications of AI-based automated and semi-automated analysis of audio and video recordings of people with epilepsy, allow significant data reduction and reliable detection and classification of major motor seizures. AI models can accurately identify electrographic biomarkers of epilepsy, such as spikes, high-frequency oscillations and seizure patterns. Integrating AI analysis of EEG, clinical and behavioral data will contribute to optimizing therapy of patients with epilepsy.

    View details for DOI 10.1111/epi.17833

    View details for PubMedID 37983589

  • Creation of an albino squid line by CRISPR-Cas9 and its application for invivo functional imaging of neural activity. Current biology : CB Ahuja, N., Hwaun, E., Pungor, J. R., Rafiq, R., Nemes, S., Sakmar, T., Vogt, M. A., Grasse, B., Diaz Quiroz, J., Montague, T. G., Null, R. W., Dallis, D. N., Gavriouchkina, D., Marletaz, F., Abbo, L., Rokhsar, D. S., Niell, C. M., Soltesz, I., Albertin, C. B., Rosenthal, J. J. 2023

    Abstract

    Cephalopods are remarkable among invertebrates for their cognitive abilities, adaptive camouflage, novel structures, and propensity for recoding proteins through RNA editing. Due to the lack of genetically tractable cephalopod models, however, the mechanisms underlying these innovations are poorly understood. Genome editing tools such as CRISPR-Cas9 allow targeted mutations in diverse species to better link genes and function. One emerging cephalopod model, Euprymna berryi, produces large numbers of embryos that can be easily cultured throughout their life cycle and has a sequenced genome. As proof of principle, we used CRISPR-Cas9 in E.berryi to target the gene for tryptophan 2,3 dioxygenase (TDO), an enzyme required for the formation of ommochromes, the pigments present in the eyes and chromatophores of cephalopods. CRISPR-Cas9 ribonucleoproteins targeting tdo were injected into early embryos and then cultured to adulthood. Unexpectedly, the injected specimens were pigmented, despite verification of indels at the targeted sites by sequencing in injected animals (G0s). A homozygote knockout line for TDO, bred through multiple generations, was also pigmented. Surprisingly, a gene encoding indoleamine 2,3, dioxygenase (IDO), an enzyme that catalyzes the same reaction as TDO in vertebrates, was also present in E.berryi. Double knockouts of both tdo and ido with CRISPR-Cas9 produced an albino phenotype. We demonstrate the utility of these albinos for invivo imaging of Ca2+ signaling in the brain using two-photon microscopy. These data show the feasibility of making gene knockout cephalopod lines that can be used for live imaging of neural activity in these behaviorally sophisticated organisms.

    View details for DOI 10.1016/j.cub.2023.05.066

    View details for PubMedID 37343558

  • Hidden behavioral fingerprints in epilepsy. Neuron Gschwind, T., Zeine, A., Raikov, I., Markowitz, J. E., Gillis, W. F., Felong, S., Isom, L. L., Datta, S. R., Soltesz, I. 2023

    Abstract

    Epilepsy is a major disorder affecting millions of people. Although modern electrophysiological and imaging approaches provide high-resolution access to the multi-scale brain circuit malfunctions in epilepsy, our understanding of how behavior changes with epilepsy has remained rudimentary. As a result, screening for new therapies for children and adults with devastating epilepsies still relies on the inherently subjective, semi-quantitative assessment of a handful of pre-selected behavioral signs of epilepsy in animal models. Here, we use machine learning-assisted 3D video analysis to reveal hidden behavioral phenotypes in mice with acquired and genetic epilepsies and track their alterations during post-insult epileptogenesis and in response to anti-epileptic drugs. These results show the persistent reconfiguration of behavioral fingerprints in epilepsy and indicate that they can be employed for rapid, automated anti-epileptic drug testing at scale.

    View details for DOI 10.1016/j.neuron.2023.02.003

    View details for PubMedID 36841241

  • Galactic cosmic radiation exposure causes multifaceted neurocognitive impairments. Cellular and molecular life sciences : CMLS Alaghband, Y., Klein, P. M., Kramar, E. A., Cranston, M. N., Perry, B. C., Shelerud, L. M., Kane, A. E., Doan, N., Ru, N., Acharya, M. M., Wood, M. A., Sinclair, D. A., Dickstein, D. L., Soltesz, I., Limoli, C. L., Baulch, J. E. 2023; 80 (1): 29

    Abstract

    Technological advancements have facilitated the implementation of realistic, terrestrial-based complex 33-beam galactic cosmic radiation simulations (GCR Sim) to now probe central nervous system functionality. This work expands considerably on prior, simplified GCR simulations, yielding new insights into responses of male and female mice exposed to 40-50cGy acute or chronic radiations relevant to deep space travel. Results of the object in updated location task suggested that exposure to acute or chronic GCR Sim induced persistent impairments in hippocampus-dependent memory formation and reconsolidation in female mice that did not manifest robustly in irradiated male mice. Interestingly, irradiated male mice, but not females, were impaired in novel object recognition and chronically irradiated males exhibited increased aggressive behavior on the tube dominance test. Electrophysiology studies used to evaluate synaptic plasticity in the hippocampal CA1 region revealed significant reductions in long-term potentiation after each irradiation paradigm in both sexes. Interestingly, network-level disruptions did not translate to altered intrinsic electrophysiological properties of CA1 pyramidal cells, whereas acute exposures caused modest drops in excitatory synaptic signaling in males. Ultrastructural analyses of CA1 synapses found smaller postsynaptic densities in larger spines of chronically exposed mice compared to controls and acutely exposed mice. Myelination was also affected by GCR Sim with acutely exposed mice exhibiting an increase in the percent of myelinated axons; however, the myelin sheathes on small calibur (<0.3mm) and larger (>0.5mm) axons were thinner when compared to controls. Present findings might have been predicted based on previous studies using single and mixed beam exposures and provide further evidence that space-relevant radiation exposures disrupt critical cognitive processes and underlying neuronal network-level plasticity, albeit not to the extent that might have been previously predicted.

    View details for DOI 10.1007/s00018-022-04666-8

    View details for PubMedID 36607431

  • A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy. Proceedings of the National Academy of Sciences of the United States of America Murphy, K. R., Farrell, J. S., Gomez, J. L., Stedman, Q. G., Li, N., Leung, S. A., Good, C. H., Qiu, Z., Firouzi, K., Butts Pauly, K., Khuri-Yakub, B. P., Michaelides, M., Soltesz, I., de Lecea, L. 2022; 119 (46): e2206828119

    Abstract

    Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.

    View details for DOI 10.1073/pnas.2206828119

    View details for PubMedID 36343238

  • A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations. Nature communications Liu, A. A., Henin, S., Abbaspoor, S., Bragin, A., Buffalo, E. A., Farrell, J. S., Foster, D. J., Frank, L. M., Gedankien, T., Gotman, J., Guidera, J. A., Hoffman, K. L., Jacobs, J., Kahana, M. J., Li, L., Liao, Z., Lin, J. J., Losonczy, A., Malach, R., van der Meer, M. A., McClain, K., McNaughton, B. L., Norman, Y., Navas-Olive, A., de la Prida, L. M., Rueckemann, J. W., Sakon, J. J., Skelin, I., Soltesz, I., Staresina, B. P., Weiss, S. A., Wilson, M. A., Zaghloul, K. A., Zugaro, M., Buzsaki, G. 2022; 13 (1): 6000

    Abstract

    Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

    View details for DOI 10.1038/s41467-022-33536-x

    View details for PubMedID 36224194

  • The Neurodata Without Borders ecosystem for neurophysiological data science. eLife Rubel, O., Tritt, A., Ly, R., Dichter, B. K., Ghosh, S., Niu, L., Baker, P., Soltesz, I., Ng, L., Svoboda, K., Frank, L., Bouchard, K. E. 2022; 11

    Abstract

    The neurophysiology of cells and tissues are monitored electrophysiologically and optically in diverse experiments and species, ranging from flies to humans. Understanding the brain requires integration of data across this diversity, and thus these data must be findable, accessible, interoperable, and reusable (FAIR). This requires a standard language for data and metadata that can coevolve with neuroscience. We describe design and implementation principles for a language for neurophysiology data. Our open-source software (Neurodata Without Borders, NWB) defines and modularizes the interdependent, yet separable, components of a data language. We demonstrate NWB's impact through unified description of neurophysiology data across diverse modalities and species. NWB exists in an ecosystem, which includes data management, analysis, visualization, and archive tools. Thus, the NWB data language enables reproduction, interchange, and reuse of diverse neurophysiology data. More broadly, the design principles of NWB are generally applicable to enhance discovery across biology through data FAIRness.

    View details for DOI 10.7554/eLife.78362

    View details for PubMedID 36193886

  • Offline memory replay in recurrent neuronal networks emerges from constraints on online dynamics. The Journal of physiology Milstein, A. D., Tran, S., Ng, G., Soltesz, I. 2022

    Abstract

    KEY POINTS: A recurrent spiking network model of hippocampal area CA3 was optimized to recapitulate experimentally-observed network dynamics during simulated spatial exploration. During simulated offline rest, the network exhibited the emergent property of generating flexible forward, reverse, and mixed direction memory replay events. Network perturbations and analysis of model diversity and degeneracy identified associative synaptic connectivity and key features of network dynamics as important for offline sequence generation. Network simulations demonstrate that population over-representation of salient positions like the site of reward results in biased memory replay.ABSTRACT: During spatial exploration, neural circuits in the hippocampus store memories of sequences of sensory events encountered in the environment. When sensory information is absent during 'offline' resting periods, brief neuronal population bursts can 'replay' sequences of activity that resemble bouts of sensory experience. These sequences can occur in either forward or reverse order, and can even include spatial trajectories that have not been experienced, but are consistent with the topology of the environment. The neural circuit mechanisms underlying this variable and flexible sequence generation are unknown. Here we demonstrate in a recurrent spiking network model of hippocampal area CA3 that experimental constraints on network dynamics such as population sparsity, stimulus selectivity, rhythmicity, and spike rate adaptation, as well as associative synaptic connectivity, enable additional emergent properties, including variable offline memory replay. In an online stimulus-driven state, we observed the emergence of neuronal sequences that swept from representations of past to future stimuli on the timescale of the theta rhythm. In an offline state driven only by noise, the network generated both forward and reverse neuronal sequences, and recapitulated the experimental observation that offline memory replay events tend to include salient locations like the site of a reward. These results demonstrate that biological constraints on the dynamics of recurrent neural circuits are sufficient to enable memories of sensory events stored in the strengths of synaptic connections to be flexibly read out during rest and sleep, which is thought to be important for memory consolidation and planning of future behaviour. Abstract figure legend During simulated rodent spatial navigation, place cells in hippocampal area CA3 fire at specific locations in space, generating a sequence in the order that the animal traverses. Recurrent network models of excitatory (E) place cells and inhibitory (I) interneurons that included associative synaptic connectivity between E cells, rhythmic synchrony in E and I cells, and spike rate adaptation in E cells, were found to generate sequences in an offline state in the absence of structured sensory inputs. These sequences replayed those generated during navigation, but occurred in either forward or reverse order. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1113/JP283216

    View details for PubMedID 35907087

  • From single-neuron dynamics to higher-order circuit motifs in control and pathological brain networks. The Journal of physiology Hadjiabadi, D., Soltesz, I. 2022

    Abstract

    The convergence of advanced single-cell in vivo functional imaging techniques, computational modeling tools, and graph-based network analytics has heralded new opportunities to study single-cell dynamics across large-scale networks, providing novel insights into principles of brain communication and pointing towards potential new strategies for treating neurological disorders. A major recent finding has been the identification of unusually richly connected hub cells that have capacity to synchronize networks and may be also critical in network dysfunction. While hub neurons are traditionally defined by measures that consider solely the number and strength of connections, novel higher-order graph analytics now enables the mining of massive networks for repeating subgraph patterns called motifs. As an illustration of the power offered by higher order analysis of neuronal networks, we highlight how recent methodological advances uncovered a new functional cell type, the superhub, that is predicted to play a major role in regulating network dynamics. Finally, we discuss open questions that will be critical for assessing the importance of higher order cellular-scale network analytics in understanding brain function in health and disease. Abstract figure legend This article is protected by copyright. All rights reserved.

    View details for DOI 10.1113/JP282749

    View details for PubMedID 35815823

  • Ripple-selective GABAergic projection cells in the hippocampus. Neuron Szabo, G. G., Farrell, J. S., Dudok, B., Hou, W. H., Ortiz, A. L., Varga, C., Moolchand, P., Gulsever, C. I., Gschwind, T., Dimidschstein, J., Capogna, M., Soltesz, I. 2022

    Abstract

    Ripples are brief high-frequency electrographic events with important roles in episodic memory. However, the in vivo circuit mechanisms coordinating ripple-related activity among local and distant neuronal ensembles are not well understood. Here, we define key characteristics of a long-distance projecting GABAergic cell group in the mouse hippocampus that selectively exhibits high-frequency firing during ripples while staying largely silent during theta-associated states when most other GABAergic cells are active. The high ripple-associated firing commenced before ripple onset and reached its maximum before ripple peak, with the signature theta-OFF, ripple-ON firing pattern being preserved across awake and sleep states. Controlled by septal GABAergic, cholinergic, and CA3 glutamatergic inputs, these ripple-selective cells innervate parvalbumin and cholecystokinin-expressing local interneurons while also targeting a variety of extra-hippocampal regions. These results demonstrate the existence of a hippocampal GABAergic circuit element that is uniquely positioned to coordinate ripple-related neuronal dynamics across neuronal assemblies.

    View details for DOI 10.1016/j.neuron.2022.04.002

    View details for PubMedID 35489331

  • Topological supramolecular network enabled high-conductivity, stretchable organic bioelectronics. Science (New York, N.Y.) Jiang, Y., Zhang, Z., Wang, Y. X., Li, D., Coen, C. T., Hwaun, E., Chen, G., Wu, H. C., Zhong, D., Niu, S., Wang, W., Saberi, A., Lai, J. C., Wu, Y., Wang, Y., Trotsyuk, A. A., Loh, K. Y., Shih, C. C., Xu, W., Liang, K., Zhang, K., Bai, Y., Gurusankar, G., Hu, W., Jia, W., Cheng, Z., Dauskardt, R. H., Gurtner, G. C., Tok, J. B., Deisseroth, K., Soltesz, I., Bao, Z. 2022; 375 (6587): 1411-1417

    Abstract

    Intrinsically stretchable bioelectronic devices based on soft and conducting organic materials have been regarded as the ideal interface for seamless and biocompatible integration with the human body. A remaining challenge is to combine high mechanical robustness with good electrical conduction, especially when patterned at small feature sizes. We develop a molecular engineering strategy based on a topological supramolecular network, which allows for the decoupling of competing effects from multiple molecular building blocks to meet complex requirements. We obtained simultaneously high conductivity and crack-onset strain in a physiological environment, with direct photopatternability down to the cellular scale. We further collected stable electromyography signals on soft and malleable octopus and performed localized neuromodulation down to single-nucleus precision for controlling organ-specific activities through the delicate brainstem.

    View details for DOI 10.1126/science.abj7564

    View details for PubMedID 35324282

  • Imaging the endocannabinoid signaling system. Journal of neuroscience methods Dudok, B., Soltesz, I. 1800: 109451

    Abstract

    The endocannabinoid (eCB) system is one of the most widespread neuromodulatory systems in the mammalian brain, with a multifaceted role in functions ranging from development to synaptic plasticity. Endocannabinoids are synthesized on demand from membrane lipid precursors, and act primarily on a single G-protein coupled receptor type, CB1, to carry out diverse functions. Despite the importance of the eCB system both in healthy brain function and in disease, critically important details of eCB signaling remained unknown. How eCBs are released from the membrane, how these lipid molecules are transported between cells, and how the distribution of their receptors is controlled, remained elusive. Recent advances in optical microscopy methods and biosensor engineering may open up new avenues for studying eCB signaling. We summarize applications of superresolution microscopy using single molecule localization to reveal distinct patterns of nanoscale CB1 distribution in neuronal axons and axon terminals. We review single particle tracking studies using quantum dots that allowed visualizing CB1 trajectories. We highlight the recent development of fluorescent eCB biosensors, that revealed spatiotemporally specific eCB release in live cells and live animals. Finally, we discuss future directions where method development may help to advance a precise understanding of eCB signaling.

    View details for DOI 10.1016/j.jneumeth.2021.109451

    View details for PubMedID 34921843

  • Bidirectional synaptic plasticity rapidly modifies hippocampal representations. eLife Milstein, A. D., Li, Y., Bittner, K. C., Grienberger, C., Soltesz, I., Magee, J. C., Romani, S. 2021; 10

    Abstract

    Learning requires neural adaptations thought to be mediated by activity-dependent synaptic plasticity. A relatively non-standard form of synaptic plasticity driven by dendritic calcium spikes, or plateau potentials, has been reported to underlie place field formation in rodent hippocampal CA1 neurons. Here we found that this behavioral timescale synaptic plasticity (BTSP) can also reshape existing place fields via bidirectional synaptic weight changes that depend on the temporal proximity of plateau potentials to pre-existing place fields. When evoked near an existing place field, plateau potentials induced less synaptic potentiation and more depression, suggesting BTSP might depend inversely on postsynaptic activation. However, manipulations of place cell membrane potential and computational modeling indicated that this anti-correlation actually results from a dependence on current synaptic weight such that weak inputs potentiate and strong inputs depress. A network model implementing this bidirectional synaptic learning rule suggested that BTSP enables population activity, rather than pairwise neuronal correlations, to drive neural adaptations to experience.

    View details for DOI 10.7554/eLife.73046

    View details for PubMedID 34882093

  • Bidirectional synaptic plasticity rapidly modifies hippocampal representations ELIFE Milstein, A. D., Li, Y., Bittner, K. C., Grienberger, C., Soltesz, I., Magee, J. C., Romani, S. 2021; 10
  • A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo. Nature biotechnology Dong, A., He, K., Dudok, B., Farrell, J. S., Guan, W., Liput, D. J., Puhl, H. L., Cai, R., Wang, H., Duan, J., Albarran, E., Ding, J., Lovinger, D. M., Li, B., Soltesz, I., Li, Y. 2021

    Abstract

    Endocannabinoids (eCBs) are retrograde neuromodulators with important functions in a wide range of physiological processes, but their in vivo dynamics remain largely uncharacterized. Here we developed a genetically encoded eCB sensor called GRABeCB2.0. GRABeCB2.0 consists of a circular-permutated EGFP and the human CB1 cannabinoid receptor, providing cell membrane trafficking, second-resolution kinetics with high specificity for eCBs, and shows a robust fluorescence response at physiological eCB concentrations. Using GRABeCB2.0, we monitored evoked and spontaneous changes in eCB dynamics in cultured neurons and acute brain slices. We observed spontaneous compartmentalized eCB transients in cultured neurons and eCB transients from single axonal boutons in acute brain slices, suggesting constrained, localized eCB signaling. When GRABeCB2.0 was expressed in the mouse brain, we observed foot shock-elicited and running-triggered eCB signaling in the basolateral amygdala and hippocampus, respectively. In a mouse model of epilepsy, we observed a spreading wave of eCB release that followed a Ca2+ wave through the hippocampus. GRABeCB2.0 is a robust probe for eCB release in vivo.

    View details for DOI 10.1038/s41587-021-01074-4

    View details for PubMedID 34764491

  • Toward Understanding the Diverse Roles of Perisomatic Interneurons in Epilepsy. Epilepsy currents Dudok, B., Klein, P. M., Soltesz, I. 2021; 22 (1): 54-60

    Abstract

    Epileptic seizures are associated with excessive neuronal spiking. Perisomatic γ-aminobutyric acid (GABA)ergic interneurons specifically innervate the subcellular domains of postsynaptic excitatory cells that are critical for spike generation. With a revolution in transcriptomics-based cell taxonomy driving the development of novel transgenic mouse lines, selectively monitoring and modulating previously elusive interneuron types is becoming increasingly feasible. Emerging evidence suggests that the three types of hippocampal perisomatic interneurons, axo-axonic cells, along with parvalbumin- and cholecystokinin-expressing basket cells, each follow unique activity patterns in vivo, suggesting distinctive roles in regulating epileptic networks.

    View details for DOI 10.1177/15357597211053687

    View details for PubMedID 35233202

    View details for PubMedCentralID PMC8832350

  • Toward Understanding the Diverse Roles of Perisomatic Interneurons in Epilepsy EPILEPSY CURRENTS Dudok, B., Klein, P. M., Soltesz, I. 2021
  • Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior. Neuron Dudok, B., Szoboszlay, M., Paul, A., Klein, P. M., Liao, Z., Hwaun, E., Szabo, G. G., Geiller, T., Vancura, B., Wang, B., McKenzie, S., Homidan, J., Klaver, L. M., English, D. F., Huang, Z. J., Buzsaki, G., Losonczy, A., Soltesz, I. 2021

    Abstract

    The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier" or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their invivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory invivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state-specific dynamics of a critical inhibitory controller of cortical circuits.

    View details for DOI 10.1016/j.neuron.2021.09.033

    View details for PubMedID 34648750

  • Acute, Low-Dose Neutron Exposures Adversely Impact Central Nervous System Function. International journal of molecular sciences Klein, P. M., Alaghband, Y., Doan, N., Ru, N., Drayson, O. G., Baulch, J. E., Kramar, E. A., Wood, M. A., Soltesz, I., Limoli, C. L. 2021; 22 (16)

    Abstract

    A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment.

    View details for DOI 10.3390/ijms22169020

    View details for PubMedID 34445726

  • Invivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity. Neuron Farrell, J. S., Colangeli, R., Dong, A., George, A. G., Addo-Osafo, K., Kingsley, P. J., Morena, M., Wolff, M. D., Dudok, B., He, K., Patrick, T. A., Sharkey, K. A., Patel, S., Marnett, L. J., Hill, M. N., Li, Y., Teskey, G. C., Soltesz, I. 2021; 109 (15): 2398

    Abstract

    The brain's endocannabinoid system is a powerful controller of neurotransmitter release, shaping synaptic communication under physiological and pathological conditions. However, our understanding of endocannabinoid signaling invivo is limited by the inability to measure their changes at timescales commensurate with the high lability of lipid signals, leaving fundamental questions of whether, how, and which endocannabinoids fluctuate with neural activity unresolved. Using novel imaging approaches in awake behaving mice, we now demonstrate that the endocannabinoid 2-arachidonoylglycerol, not anandamide, is dynamically coupled to hippocampal neural activity with high spatiotemporal specificity. Furthermore, we show that seizures amplify the physiological endocannabinoid increase by orders of magnitude and drive the downstream synthesis of vasoactive prostaglandins that culminate in a prolonged stroke-like event. These results shed new light on normal and pathological endocannabinoid signaling invivo.

    View details for DOI 10.1016/j.neuron.2021.05.026

    View details for PubMedID 34352214

  • Epistemic Autonomy: Self-supervised Learning in the Mammalian Hippocampus. Trends in cognitive sciences Santos-Pata, D., Amil, A. F., Raikov, I. G., Renno-Costa, C., Mura, A., Soltesz, I., Verschure, P. F. 2021

    Abstract

    Biological cognition is based on the ability to autonomously acquire knowledge, or epistemic autonomy. Such self-supervision is largely absent in artificial neural networks (ANN) because they depend on externally set learning criteria. Yet training ANN using error backpropagation has created the current revolution in artificial intelligence, raising the question of whether the epistemic autonomy displayed in biological cognition can be achieved with error backpropagation-based learning. We present evidence suggesting that the entorhinal-hippocampal complex combines epistemic autonomy with error backpropagation. Specifically, we propose that the hippocampus minimizes the error between its input and output signals through a modulatory counter-current inhibitory network. We further discuss the computational emulation of this principle and analyze it in the context of autonomous cognitive systems.

    View details for DOI 10.1016/j.tics.2021.03.016

    View details for PubMedID 33906817

  • Entorhinal mismatch: A model of self-supervised learning in the hippocampus. iScience Santos-Pata, D., Amil, A. F., Raikov, I. G., Renno-Costa, C., Mura, A., Soltesz, I., Verschure, P. F. 2021; 24 (4): 102364

    Abstract

    The hippocampal formation displays a wide range of physiological responses to different spatial manipulations of the environment. However, very few attempts have been made to identify core computational principles underlying those hippocampal responses. Here, we capitalize on the observation that the entorhinal-hippocampal complex (EHC) forms a closed loop and projects inhibitory signals "countercurrent" to the trisynaptic pathway to build a self-supervised model that learns to reconstruct its own inputs by error backpropagation. The EHC is then abstracted as an autoencoder, with the hidden layers acting as an information bottleneck. With the inputs mimicking the firing activity of lateral and medial entorhinal cells, our model is shown to generate place cells and to respond to environmental manipulations as observed in rodent experiments. Altogether, we propose that the hippocampus builds conjunctive compressed representations of the environment by learning to reconstruct its own entorhinal inputs via gradient descent.

    View details for DOI 10.1016/j.isci.2021.102364

    View details for PubMedID 33997671

  • Alternating sources of perisomatic inhibition during behavior. Neuron Dudok, B., Klein, P. M., Hwaun, E., Lee, B. R., Yao, Z., Fong, O., Bowler, J. C., Terada, S., Sparks, F. T., Szabo, G. G., Farrell, J. S., Berg, J., Daigle, T. L., Tasic, B., Dimidschstein, J., Fishell, G., Losonczy, A., Zeng, H., Soltesz, I. 2021

    Abstract

    Interneurons expressing cholecystokinin (CCK) and parvalbumin (PV) constitute two key GABAergic controllers of hippocampal pyramidal cell output. Although the temporally precise and millisecond-scale inhibitory regulation of neuronal ensembles delivered by PV interneurons is well established, the invivo recruitment patterns of CCK-expressing basket cell (BC) populations has remained unknown. We show in the CA1 of the mouse hippocampus that the activity of CCK BCs inversely scales with both PV and pyramidal cell activity at the behaviorally relevant timescales of seconds. Intervention experiments indicated that the inverse coupling of CCK and PV GABAergic systems arises through a mechanism involving powerful inhibitory control of CCK BCs by PV cells. The tightly coupled complementarity of two key microcircuit regulatory modules demonstrates a novel form of brain-state-specific segregation of inhibition during spontaneous behavior.

    View details for DOI 10.1016/j.neuron.2021.01.003

    View details for PubMedID 33529646

  • Detrimental impacts of mixed-ion radiation on nervous system function. Neurobiology of disease Klein, P. M., Parihar, V. K., Szabo, G. G., Zöldi, M. n., Angulo, M. C., Allen, B. D., Amin, A. N., Nguyen, Q. A., Katona, I. n., Baulch, J. E., Limoli, C. L., Soltesz, I. n. 2021: 105252

    Abstract

    Galactic cosmic radiation (GCR), composed of highly energetic and fully ionized atomic nuclei, can produce diverse deleterious effects on the body. In researching the neurological risks of GCR exposures, including during human spaceflight, various single-ion GCR irradiation paradigms have been shown to differentially disrupt cellular activity and overall behavior. However, it remains unclear how combined irradiation with a mix of multiple ions, more accurately recapitulating the space GCR environment, impacts the central nervous system. We therefore examined how mixed-ion GCR irradiation (containing combinations of protons, helium, oxygen, silicon and iron ions) influenced neuronal connectivity, functional generation of activity within neural circuits and cognitive behavior in mice. In electrophysiological recordings we find that space-relevant doses of mixed-ion GCR preferentially alter hippocampal inhibitory neurotransmission and produce related disruptions in the local field potentials of hippocampal oscillations. Such underlying perturbation in hippocampal network activity correspond to a range of deficits in cognitive tasks.

    View details for DOI 10.1016/j.nbd.2021.105252

    View details for PubMedID 33418069

  • Supramammillary regulation of locomotion and hippocampal activity. Science (New York, N.Y.) Farrell, J. S., Lovett-Barron, M., Klein, P. M., Sparks, F. T., Gschwind, T., Ortiz, A. L., Ahanonu, B., Bradbury, S., Terada, S., Oijala, M., Hwaun, E., Dudok, B., Szabo, G., Schnitzer, M. J., Deisseroth, K., Losonczy, A., Soltesz, I. 2021; 374 (6574): 1492-1496

    Abstract

    [Figure: see text].

    View details for DOI 10.1126/science.abh4272

    View details for PubMedID 34914519

  • Maximally selective single-cell target for circuit control in epilepsy models. Neuron Hadjiabadi, D., Lovett-Barron, M., Raikov, I. G., Sparks, F. T., Liao, Z., Baraban, S. C., Leskovec, J., Losonczy, A., Deisseroth, K., Soltesz, I. 2021

    Abstract

    Neurological and psychiatric disorders are associated with pathological neural dynamics. The fundamental connectivity patterns of cell-cell communication networks that enable pathological dynamics to emerge remain unknown. Here, we studied epileptic circuits using a newly developed computational pipeline that leveraged single-cell calcium imaging of larval zebrafish and chronically epileptic mice, biologically constrained effective connectivity modeling, and higher-order motif-focused network analysis. We uncovered a novel functional cell type that preferentially emerged in the preseizure state, the superhub, that was unusually richly connected to the rest of the network through feedforward motifs, critically enhancing downstream excitation. Perturbation simulations indicated that disconnecting superhubs was significantly more effective in stabilizing epileptic circuits than disconnecting hub cells that were defined traditionally by connection count. In the dentate gyrus of chronically epileptic mice, superhubs were predominately modeled adult-born granule cells. Collectively, these results predict a new maximally selective and minimally invasive cellular target for seizure control.

    View details for DOI 10.1016/j.neuron.2021.06.007

    View details for PubMedID 34197732

  • GABA-glutamate supramammillary neurons control theta and gamma oscillations in the dentate gyrus during paradoxical (REM) sleep. Brain structure & function Billwiller, F., Castillo, L., Elseedy, H., Ivanov, A. I., Scapula, J., Ghestem, A., Carponcy, J., Libourel, P. A., Bras, H., Abdelmeguid, N. E., Krook-Magnuson, E., Soltesz, I., Bernard, C., Luppi, P., Esclapez, M. 2020

    Abstract

    Several studies suggest that neurons from the lateral region of the SuM (SuML) innervating the dorsal dentate gyrus (DG) display a dual GABAergic and glutamatergic transmission and are specifically activated during paradoxical (REM) sleep (PS). The objective of the present study is to characterize the anatomical, neurochemical and electrophysiological properties of the SuML-DG projection neurons and to determine how they control DG oscillations and neuronal activation during PS and other vigilance states. For this purpose, we combine structural connectivity techniques using neurotropic viral vectors (rabies virus, AAV), neurochemical anatomy (immunohistochemistry, in situ hybridization) and imaging (light, electron and confocal microscopy) with in vitro (patch clamp) and in vivo (LFP, EEG) optogenetic and electrophysiological recordings performed in transgenic VGLUT2-cre male mice. At the cellular level, we show that the SuML-DG neurons co-release GABA and glutamate on dentate granule cells and increase the activity of a subset of DG granule cells. At the network level, we show that activation of the SuML-DG pathway increases theta power and frequency during PS as well as gamma power during PS and waking in the DG. At the behavioral level, we show that the activation of this pathway does not change animal behavior during PS, induces awakening during slow wave sleep and increases motor activity during waking. These results suggest that the SuML-DG pathway is capable of supporting the increase of theta and gamma power in the DG observed during PS and plays an important modulatory role of DG network activity during this state.

    View details for DOI 10.1007/s00429-020-02146-y

    View details for PubMedID 32970253

  • In vivo assessment of mechanisms underlying the neurovascular basis of postictal amnesia. Scientific reports Farrell, J. S., Colangeli, R., Dudok, B., Wolff, M. D., Nguyen, S. L., Jackson, J., Dickson, C. T., Soltesz, I., Teskey, G. C. 2020; 10 (1): 14992

    Abstract

    Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.

    View details for DOI 10.1038/s41598-020-71935-6

    View details for PubMedID 32929133

  • Connecting Pathological Cellular Mechanisms to Large-Scale Seizure Structures. Trends in neurosciences Nguyen, Q., Moolchand, P., Soltesz, I. 2020

    Abstract

    Epilepsy is a neurological disorder characterized by recurrent seizures, where abnormal electrical activity begins in a local brain area and propagates before terminating. In a recent study, Liou and colleagues used multiscale computational modeling to gain mechanistic insights into clinical seizure dynamics based on cellular-level biophysical properties.

    View details for DOI 10.1016/j.tins.2020.04.006

    View details for PubMedID 32376035

  • Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy. Radiation research Dey, D., Parihar, V. K., Szabo, G. G., Klein, P. M., Tran, J., Moayyad, J., Ahmed, F., Nguyen, Q., Murry, A., Merriott, D., Nguyen, B., Goldman, J., Angulo, M. C., Piomelli, D., Soltesz, I., Baulch, J. E., Limoli, C. L. 2020

    Abstract

    Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by 50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.

    View details for DOI 10.1667/RR15540.1

    View details for PubMedID 32134362

  • Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy. Epilepsia Kim, H. K., Gschwind, T., Nguyen, T. M., Bui, A. D., Felong, S., Ampig, K., Suh, D., Ciernia, A. V., Wood, M. A., Soltesz, I. 2020

    Abstract

    OBJECTIVE: To determine if closed-loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well-established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory.METHODS: Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin-expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed-loop light intervention of seizures. Animals that responded to closed-loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed-loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory.RESULTS: Animals that received closed-loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult.SIGNIFICANCE: Many currently available treatments for epilepsy target seizures but not the associated comorbidities, thereforethere is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.

    View details for DOI 10.1111/epi.16445

    View details for PubMedID 32072628

  • Transcriptional readout of neuronal activity via an engineered Ca2+-activated protease. Proceedings of the National Academy of Sciences of the United States of America Sanchez, M. I., Nguyen, Q. A., Wang, W. n., Soltesz, I. n., Ting, A. Y. 2020

    Abstract

    Molecular integrators, in contrast to real-time indicators, convert transient cellular events into stable signals that can be exploited for imaging, selection, molecular characterization, or cellular manipulation. Many integrators, however, are designed as complex multicomponent circuits that have limited robustness, especially at high, low, or nonstoichiometric protein expression levels. Here, we report a simplified design of the calcium and light dual integrator FLARE. Single-chain FLARE (scFLARE) is a single polypeptide chain that incorporates a transcription factor, a LOV domain-caged protease cleavage site, and a calcium-activated TEV protease that we designed through structure-guided mutagenesis and screening. We show that scFLARE has greater dynamic range and robustness than first-generation FLARE and can be used in culture as well as in vivo to record patterns of neuronal activation with 10-min temporal resolution.

    View details for DOI 10.1073/pnas.2006521117

    View details for PubMedID 33323488

  • Mitigation of helium irradiation-induced brain injury by microglia depletion. Journal of neuroinflammation Allen, B. D., Syage, A. R., Maroso, M. n., Baddour, A. A., Luong, V. n., Minasyan, H. n., Giedzinski, E. n., West, B. L., Soltesz, I. n., Limoli, C. L., Baulch, J. E., Acharya, M. M. 2020; 17 (1): 159

    Abstract

    Cosmic radiation exposures have been found to elicit cognitive impairments involving a wide-range of underlying neuropathology including elevated oxidative stress, neural stem cell loss, and compromised neuronal architecture. Cognitive impairments have also been associated with sustained microglia activation following low dose exposure to helium ions. Space-relevant charged particles elicit neuroinflammation that persists long-term post-irradiation. Here, we investigated the potential neurocognitive benefits of microglia depletion following low dose whole body exposure to helium ions.Adult mice were administered a dietary inhibitor (PLX5622) of colony stimulating factor-1 receptor (CSF1R) to deplete microglia 2 weeks after whole body helium irradiation (4He, 30 cGy, 400 MeV/n). Cohorts of mice maintained on a normal and PLX5622 diet were tested for cognitive function using seven independent behavioral tasks, microglial activation, hippocampal neuronal morphology, spine density, and electrophysiology properties 4-6 weeks later.PLX5622 treatment caused a rapid and near complete elimination of microglia in the brain within 3 days of treatment. Irradiated animals on normal diet exhibited a range of behavioral deficits involving the medial pre-frontal cortex and hippocampus and increased microglial activation. Animals on PLX5622 diet exhibited no radiation-induced cognitive deficits, and expression of resting and activated microglia were almost completely abolished, without any effects on the oligodendrocyte progenitors, throughout the brain. While PLX5622 treatment was found to attenuate radiation-induced increases in post-synaptic density protein 95 (PSD-95) puncta and to preserve mushroom type spine densities, other morphologic features of neurons and electrophysiologic measures of intrinsic excitability were relatively unaffected.Our data suggest that microglia play a critical role in cosmic radiation-induced cognitive deficits in mice and, that approaches targeting microglial function are poised to provide considerable benefit to the brain exposed to charged particles.

    View details for DOI 10.1186/s12974-020-01790-9

    View details for PubMedID 32429943

  • Deep brain optogenetics without intracranial surgery. Nature biotechnology Chen, R. n., Gore, F. n., Nguyen, Q. A., Ramakrishnan, C. n., Patel, S. n., Kim, S. H., Raffiee, M. n., Kim, Y. S., Hsueh, B. n., Krook-Magnusson, E. n., Soltesz, I. n., Deisseroth, K. n. 2020

    Abstract

    Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7 mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics.

    View details for DOI 10.1038/s41587-020-0679-9

    View details for PubMedID 33020604

  • Regulation of gamma-frequency oscillation by feedforward inhibition: A computational modeling study HIPPOCAMPUS Renno-Costa, C., Teixeira, D., Soltesz, I. 2019; 29 (10): 957–70

    View details for DOI 10.1002/hipo.23093

    View details for Web of Science ID 000485902400005

  • Resolving the Micro-Macro Disconnect to Address Core Features of Seizure Networks NEURON Farrell, J. S., Quynh-Anh Nguyen, Soltesz, I. 2019; 101 (6): 1016–28
  • Ripple-related firing of identified deep CA1 pyramidal cells in chronic temporal lobe epilepsy in mice. Epilepsia open Marchionni, I. n., Oberoi, M. n., Soltesz, I. n., Alexander, A. n. 2019; 4 (2): 254–63

    Abstract

    Temporal lobe epilepsy (TLE) is often associated with memory deficits. Reactivation of memory traces in the hippocampus occurs during sharp-wave ripples (SWRs; 140-250 Hz). To better understand the mechanisms underlying high-frequency oscillations and cognitive comorbidities in epilepsy, we evaluated how rigorously identified deep CA1 pyramidal cells (dPCs) discharge during SWRs in control and TLE mice.We used the unilateral intraamygdala kainate model of TLE in video-electroencephalography (EEG) verified chronically epileptic adult mice. Local field potential and single-cell recordings were performed using juxtacellular recordings from awake control and TLE mice resting on a spherical treadmill, followed by post hoc identification of the recorded cells.Hippocampal SWRs in TLE mice occurred with increased intraripple frequency compared to control mice. The frequency of SWR events was decreased, whereas the overall frequency of SWRs, interictal epileptiform discharges, and high-frequency ripples (250-500 Hz) together was not altered. CA1 dPCs in TLE mice showed significantly increased firing during ripples as well as between the ripple events. The strength of ripple modulation of dPC discharges increased in TLE without alteration of the preferred phase of firing during the ripple waves.These juxtacellular electrophysiology data obtained from identified CA1 dPCs from chronically epileptic mice are in general agreement with recent findings indicating distortion of normal firing patterns during offline SWRs as a mechanism underlying deficits in memory consolidation in epilepsy. Because the primary seizure focus in our experiments was in the amygdala and we recorded from the CA1 region, these results are also in agreement with the presence of altered high-frequency oscillations in areas of secondary seizure spread.

    View details for DOI 10.1002/epi4.12310

    View details for PubMedID 31168492

    View details for PubMedCentralID PMC6546014

  • New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose-Rate, Neutron Radiation. eNeuro Acharya, M. M., Baulch, J. E., Klein, P. M., Baddour, A. A., Apodaca, L. A., Kramár, E. A., Alikhani, L. n., Garcia, C. n., Angulo, M. C., Batra, R. S., Fallgren, C. M., Borak, T. B., Stark, C. E., Wood, M. A., Britten, R. A., Soltesz, I. n., Limoli, C. L. 2019; 6 (4)

    Abstract

    As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function.

    View details for DOI 10.1523/ENEURO.0094-19.2019

    View details for PubMedID 31383727

  • Data-Driven Modeling of Normal and Pathological Oscillations in the Hippocampus MULTISCALE MODELS OF BRAIN DISORDERS Raikov, I., Soltesz, I., Cutsuridis 2019; 13: 185–92
  • Plants come to mind: Phytocannabinoids, endocannabinoids, and the control of seizures. Addiction (Abingdon, England) Farrell, J. S., Soltesz, I. 2018

    View details for PubMedID 30589476

  • Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus CEREBRAL CORTEX Zimmermann, T., Maroso, M., Beer, A., Baddenhausen, S., Ludewig, S., Fan, W., Vennin, C., Loch, S., Berninger, B., Hofmann, C., Korte, M., Soltesz, I., Lutz, B., Leschik, J. 2018; 28 (12): 4454–71
  • Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus. Cerebral cortex (New York, N.Y. : 1991) Zimmermann, T., Maroso, M., Beer, A., Baddenhausen, S., Ludewig, S., Fan, W., Vennin, C., Loch, S., Berninger, B., Hofmann, C., Korte, M., Soltesz, I., Lutz, B., Leschik, J. 2018

    Abstract

    Neural stem cells (NSCs) in the adult mouse hippocampus occur in a specific neurogenic niche, where a multitude of extracellular signaling molecules converges to regulate NSC proliferation as well as fate and functional integration. However, the underlying mechanisms how NSCs react to extrinsic signals and convert them to intracellular responses still remains elusive. NSCs contain a functional endocannabinoid system, including the cannabinoid type-1 receptor (CB1). To decipher whether CB1 regulates adult neurogenesis directly or indirectly in vivo, we performed NSC-specific conditional inactivation of CB1 by using triple-transgenic mice. Here, we show that lack of CB1 in NSCs is sufficient to decrease proliferation of the stem cell pool, which consequently leads to a reduction in the number of newborn neurons. Furthermore, neuronal differentiation was compromised at the level of dendritic maturation pointing towards a postsynaptic role of CB1 in vivo. Deteriorated neurogenesis in NSC-specific CB1 knock-outs additionally resulted in reduced long-term potentiation in the hippocampal formation. The observed cellular and physiological alterations led to decreased short-term spatial memory and increased depression-like behavior. These results demonstrate that CB1 expressed in NSCs and their progeny controls neurogenesis in adult mice to regulate the NSC stem cell pool, dendritic morphology, activity-dependent plasticity, and behavior.

    View details for PubMedID 30307491

  • Proceedings of the Epilepsy Foundation's 2017 Cannabinoids in Epilepsy Therapy Workshop Huizenga, M. N., Fureman, B. E., Soltesz, I., Stella, N. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2018: 237–42

    View details for PubMedID 29908905

  • Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice EXPERIMENTAL NEUROLOGY Parihar, V. K., Maroso, M., Syage, A., Allen, B. D., Angulo, M. C., Soltesz, I., Limoli, C. L. 2018; 305: 44–55

    Abstract

    Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1 year after exposure. Cosmic-radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like behavior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spontaneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation exposure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly protracted post-irradiation intervals.

    View details for PubMedID 29540322

  • CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus NATURE NEUROSCIENCE Soltesz, I., Losonczy, A. 2018; 21 (4): 484–93

    Abstract

    Hippocampal network operations supporting spatial navigation and declarative memory are traditionally interpreted in a framework where each hippocampal area, such as the dentate gyrus, CA3, and CA1, consists of homogeneous populations of functionally equivalent principal neurons. However, heterogeneity within hippocampal principal cell populations, in particular within pyramidal cells at the main CA1 output node, is increasingly recognized and includes developmental, molecular, anatomical, and functional differences. Here we review recent progress in the delineation of hippocampal principal cell subpopulations by focusing on radially defined subpopulations of CA1 pyramidal cells, and we consider how functional segregation of information streams, in parallel channels with nonuniform properties, could represent a general organizational principle of the hippocampus supporting diverse behaviors.

    View details for PubMedID 29593317

    View details for PubMedCentralID PMC5909691

  • Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory. Science (New York, N.Y.) Bui, A. D., Nguyen, T. M., Limouse, C., Kim, H. K., Szabo, G. G., Felong, S., Maroso, M., Soltesz, I. 2018; 359 (6377): 787-790

    Abstract

    Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.

    View details for DOI 10.1126/science.aan4074

    View details for PubMedID 29449490

  • Single Bursts of Individual Granule Cells Functionally Rearrange Feedforward Inhibition. The Journal of neuroscience : the official journal of the Society for Neuroscience Neubrandt, M., Oláh, V. J., Brunner, J., Marosi, E. L., Soltesz, I., Szabadics, J. 2018; 38 (7): 1711-1724

    Abstract

    The sparse single-spike activity of dentate gyrus granule cells (DG GCs) is punctuated by occasional brief bursts of 3-7 action potentials. It is well-known that such presynaptic bursts in individual mossy fibers (MFs; axons of granule cells) are often able to discharge postsynaptic CA3 pyramidal cells due to powerful short-term facilitation. However, what happens in the CA3 network after the passage of a brief MF burst, before the arrival of the next burst or solitary spike, is not understood. Because MFs innervate significantly more CA3 interneurons than pyramidal cells, we focused on unitary MF responses in identified interneurons in the seconds-long postburst period, using paired recordings in rat hippocampal slices. Single bursts as short as 5 spikes in <30 ms in individual presynaptic MFs caused a sustained, large increase (tripling) in the amplitude of the unitary MF-EPSCs for several seconds in ivy, axo-axonic/chandelier and basket interneurons. The postburst unitary MF-EPSCs in these feedforward interneurons reached amplitudes that were even larger than the MF-EPSCs during the bursts in the same cells. In contrast, no comparable postburst enhancement of MF-EPSCs could be observed in pyramidal cells or nonfeedforward interneurons. The robust postburst increase in MF-EPSCs in feedforward interneurons was associated with significant shortening of the unitary synaptic delay and large downstream increases in disynaptic IPSCs in pyramidal cells. These results reveal a new cell type-specific plasticity that enables even solitary brief bursts in single GCs to powerfully enhance inhibition at the DG-CA3 interface in the seconds-long time-scales of interburst intervals.SIGNIFICANCE STATEMENT The hippocampal formation is a brain region that plays key roles in spatial navigation and learning and memory. The first stage of information processing occurs in the dentate gyrus, where principal cells are remarkably quiet, discharging low-frequency single action potentials interspersed with occasional brief bursts of spikes. Such bursts, in particular, have attracted a lot of attention because they appear to be critical for efficient coding, storage, and recall of information. We show that single bursts of a few spikes in individual granule cells result in seconds-long potentiation of excitatory inputs to downstream interneurons. Thus, while it has been known that bursts powerfully discharge ("detonate") hippocampal excitatory cells, this study clarifies that they also regulate inhibition during the interburst intervals.

    View details for DOI 10.1523/JNEUROSCI.1595-17.2018

    View details for PubMedID 29335356

    View details for PubMedCentralID PMC5815453

  • Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory Science Bui, A., et al 2018: 787–90

    Abstract

    Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.

    View details for DOI 10.1126/science.aan4074

  • Plants come to mind: Phytocannabinoids, endocannabinoids, and the control of seizures Addiction Farrell, J. S., Soltesz, I. 2018: 1343–45

    View details for DOI 10.1111/add.14540

    View details for PubMedCentralID PMC6597308

  • Optogenetics: Lighting a Path from the Laboratory to the Clinic OPTOGENETICS: A ROADMAP Kim, H. K., Alexander, A. L., Soltesz, I., Stroh, A. 2018; 133: 277–300
  • Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice Exp Neurol Parihar, V., et al 2018
  • Single Bursts of Individual Granule Cells Functionally Rearrange Feedforward Inhibition Journal of Neuroscience Neubrandt, M., et al 2018: 1711–24

    Abstract

    The sparse single-spike activity of dentate gyrus granule cells (DG GCs) is punctuated by occasional brief bursts of 3-7 action potentials. It is well-known that such presynaptic bursts in individual mossy fibers (MFs; axons of granule cells) are often able to discharge postsynaptic CA3 pyramidal cells due to powerful short-term facilitation. However, what happens in the CA3 network after the passage of a brief MF burst, before the arrival of the next burst or solitary spike, is not understood. Because MFs innervate significantly more CA3 interneurons than pyramidal cells, we focused on unitary MF responses in identified interneurons in the seconds-long postburst period, using paired recordings in rat hippocampal slices. Single bursts as short as 5 spikes in <30 ms in individual presynaptic MFs caused a sustained, large increase (tripling) in the amplitude of the unitary MF-EPSCs for several seconds in ivy, axo-axonic/chandelier and basket interneurons. The postburst unitary MF-EPSCs in these feedforward interneurons reached amplitudes that were even larger than the MF-EPSCs during the bursts in the same cells. In contrast, no comparable postburst enhancement of MF-EPSCs could be observed in pyramidal cells or nonfeedforward interneurons. The robust postburst increase in MF-EPSCs in feedforward interneurons was associated with significant shortening of the unitary synaptic delay and large downstream increases in disynaptic IPSCs in pyramidal cells. These results reveal a new cell type-specific plasticity that enables even solitary brief bursts in single GCs to powerfully enhance inhibition at the DG-CA3 interface in the seconds-long time-scales of interburst intervals.SIGNIFICANCE STATEMENT The hippocampal formation is a brain region that plays key roles in spatial navigation and learning and memory. The first stage of information processing occurs in the dentate gyrus, where principal cells are remarkably quiet, discharging low-frequency single action potentials interspersed with occasional brief bursts of spikes. Such bursts, in particular, have attracted a lot of attention because they appear to be critical for efficient coding, storage, and recall of information. We show that single bursts of a few spikes in individual granule cells result in seconds-long potentiation of excitatory inputs to downstream interneurons. Thus, while it has been known that bursts powerfully discharge ("detonate") hippocampal excitatory cells, this study clarifies that they also regulate inhibition during the interburst intervals.

    View details for DOI 10.1523/JNEUROSCI.1595-17.2018

    View details for PubMedCentralID PMC5815453

  • Extended Interneuronal Network of the Dentate Gyrus. Cell reports Szabo, G. G., Du, X., Oijala, M., Varga, C., Parent, J. M., Soltesz, I. 2017; 20 (6): 1262-1268

    Abstract

    Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG) to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

    View details for DOI 10.1016/j.celrep.2017.07.042

    View details for PubMedID 28793251

    View details for PubMedCentralID PMC5576513

  • Seizing Control: From Current Treatments to Optogenetic Interventions in Epilepsy NEUROSCIENTIST Bui, A. D., Alexander, A., Soltesz, I. 2017; 23 (1): 68-81

    Abstract

    The unpredictability and severity of seizures contribute to the debilitating nature of epilepsy. These factors also render the condition particularly challenging to treat, as an ideal treatment would need to detect and halt the pathological bursts of hyperactivity without disrupting normal brain activity. Optogenetic techniques offer promising tools to study and perhaps eventually treat this episodic disorder by controlling specific brain circuits in epileptic animals with great temporal precision. Here, we briefly review the current treatment options for patients with epilepsy. We then describe the many ways optogenetics has allowed us to untangle the microcircuits involved in seizure activity, and how it has, in some cases, changed our perception of previous theories of seizure generation. Control of seizures with light is no longer a dream, and has been achieved in numerous different animal models of epilepsy. Beyond its application as a seizure suppressor, we highlight another facet of optogenetics in epilepsy, namely the ability to create "on-demand" seizures, as a tool to systematically probe the dynamics of networks during seizure initiation and propagation. Finally, we look into the future to discuss the possibilities and challenges of translating optogenetic techniques to clinical use.

    View details for DOI 10.1177/1073858415619600

    View details for Web of Science ID 000396916900010

    View details for PubMedCentralID PMC4919242

  • Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy Brain Neumann, A., et al 2017
  • Hippocampal Dentate Mossy Cells Improve Their CV and Trk into the Limelight. Neuron Milstein, A. D., Soltesz, I. n. 2017; 95 (4): 732–34

    Abstract

    The impact of dentate mossy cells on hippocampal activity remained uncertain despite a long history of investigation. In this issue of Neuron, Hashimotodani et al. (2017) discover a presynaptically expressed form of long-term potentiation at mossy cell outputs, shedding light on their mysterious function.

    View details for PubMedID 28817795

  • Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy. Brain : a journal of neurology Neumann, A. R., Raedt, R. n., Steenland, H. W., Sprengers, M. n., Bzymek, K. n., Navratilova, Z. n., Mesina, L. n., Xie, J. n., Lapointe, V. n., Kloosterman, F. n., Vonck, K. n., Boon, P. A., Soltesz, I. n., McNaughton, B. L., Luczak, A. n. 2017; 140 (9): 2355–69

    Abstract

    See Lenck-Santini (doi:10.1093/awx205) for a scientific commentary on this article. Epileptic seizures represent altered neuronal network dynamics, but the temporal evolution and cellular substrates of the neuronal activity patterns associated with spontaneous seizures are not fully understood. We used simultaneous recordings from multiple neurons in the hippocampus and neocortex of rats with chronic temporal lobe epilepsy to demonstrate that subsets of cells discharge in a highly stereotypical sequential pattern during ictal events, and that these stereotypical patterns were reproducible across consecutive seizures. In contrast to the canonical view that principal cell discharges dominate ictal events, the ictal sequences were predominantly composed of fast-spiking, putative inhibitory neurons, which displayed unusually strong coupling to local field potential even before seizures. The temporal evolution of activity was characterized by unique dynamics where the most correlated neuronal pairs before seizure onset displayed the largest increases in correlation strength during the seizures. These results demonstrate the selective involvement of fast spiking interneurons in structured temporal sequences during spontaneous ictal events in hippocampal and neocortical circuits in experimental models of chronic temporal lobe epilepsy.

    View details for PubMedID 29050390

    View details for PubMedCentralID PMC6248724

  • Network Models of Epilepsy-Related Pathological Structural and Functional Alterations in the Dentate Gyrus REWIRING BRAIN: A COMPUTATIONAL APPROACH TO STRUCTURAL PLASTICITY IN THE ADULT BRAIN Raikov, I., Plitt, M., Soltesz, I., VanOoyen, A., ButzOstendorf, M. 2017: 485–503
  • Extended Interneuronal Network of the Dentate Gyrus Cell Rep Szabo, G., et al 2017: 1262–68

    Abstract

    Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG) to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

    View details for DOI 10.1016/j.celrep.2017.07.042

    View details for PubMedCentralID PMC5576513

  • Hippocampal Dentate Mossy Cells Improve Their CV and Trk into the Limelight Neuron Milstein, A., Soltesz, I. 2017
  • Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit. eLife Bezaire, M. J., Raikov, I., Burk, K., Vyas, D., Soltesz, I. 2016; 5

    Abstract

    The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the rodent CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase-locked gamma oscillations and phase-preferential discharges of distinct interneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations.

    View details for DOI 10.7554/eLife.18566

    View details for PubMedID 28009257

    View details for PubMedCentralID PMC5313080

  • Neurophysiology of space travel: energetic solar particles cause cell type-specific plasticity of neurotransmission. Brain structure & function Lee, S., Dudok, B., Parihar, V. K., Jung, K., Zöldi, M., Kang, Y., Maroso, M., Alexander, A. L., Nelson, G. A., Piomelli, D., Katona, I., Limoli, C. L., Soltesz, I. 2016: -?

    Abstract

    In the not too distant future, humankind will embark on one of its greatest adventures, the travel to distant planets. However, deep space travel is associated with an inevitable exposure to radiation fields. Space-relevant doses of protons elicit persistent disruptions in cognition and neuronal structure. However, whether space-relevant irradiation alters neurotransmission is unknown. Within the hippocampus, a brain region crucial for cognition, perisomatic inhibitory control of pyramidal cells (PCs) is supplied by two distinct cell types, the cannabinoid type 1 receptor (CB1)-expressing basket cells (CB1BCs) and parvalbumin (PV)-expressing interneurons (PVINs). Mice subjected to low-dose proton irradiation were analyzed using electrophysiological, biochemical and imaging techniques months after exposure. In irradiated mice, GABA release from CB1BCs onto PCs was dramatically increased. This effect was abolished by CB1 blockade, indicating that irradiation decreased CB1-dependent tonic inhibition of GABA release. These alterations in GABA release were accompanied by decreased levels of the major CB1 ligand 2-arachidonoylglycerol. In contrast, GABA release from PVINs was unchanged, and the excitatory connectivity from PCs to the interneurons also underwent cell type-specific alterations. These results demonstrate that energetic charged particles at space-relevant low doses elicit surprisingly selective long-term plasticity of synaptic microcircuits in the hippocampus. The magnitude and persistent nature of these alterations in synaptic function are consistent with the observed perturbations in cognitive performance after irradiation, while the high specificity of these changes indicates that it may be possible to develop targeted therapeutic interventions to decrease the risk of adverse events during interplanetary travel.

    View details for PubMedID 27905022

  • Target-selectivity of parvalbumin-positive interneurons in layer II of medial entorhinal cortex in normal and epileptic animals. Hippocampus Armstrong, C., Wang, J., Yeun Lee, S., Broderick, J., Bezaire, M. J., Lee, S., Soltesz, I. 2016; 26 (6): 779-793

    Abstract

    The medial entorhinal cortex layer II (MEClayerII ) is a brain region critical for spatial navigation and memory, and it also demonstrates a number of changes in patients with, and animal models of, temporal lobe epilepsy (TLE). Prior studies of GABAergic microcircuitry in MEClayerII revealed that cholecystokinin-containing basket cells (CCKBCs) select their targets on the basis of the long-range projection pattern of the postsynaptic principal cell. Specifically, CCKBCs largely avoid reelin-containing principal cells that form the perforant path to the ipsilateral dentate gyrus and preferentially innervate non-perforant path forming calbindin-containing principal cells. We investigated whether parvalbumin containing basket cells (PVBCs), the other major perisomatic targeting GABAergic cell population, demonstrate similar postsynaptic target selectivity as well. In addition, we tested the hypothesis that the functional or anatomic arrangement of circuit selectivity is disrupted in MEClayerII in chronic TLE, using the repeated low-dose kainate model in rats. In control animals, we found that PVBCs innervated both principal cell populations, but also had significant selectivity for calbindin-containing principal cells in MEClayerII . However, the magnitude of this preference was smaller than for CCKBCs. In addition, axonal tracing and paired recordings showed that individual PVBCs were capable of contacting both calbindin and reelin-containing principal cells. In chronically epileptic animals, we found that the intrinsic properties of the two principal cell populations, the GABAergic perisomatic bouton numbers, and selectivity of the CCKBCs and PVBCs remained remarkably constant in MEClayerII . However, miniature IPSC frequency was decreased in epilepsy, and paired recordings revealed the presence of direct excitatory connections between principal cells in the MEClayerII in epilepsy, which is unusual in normal adult MEClayerII . Taken together, these findings advance our knowledge about the organization of perisomatic inhibition both in control and in epileptic animals. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hipo.22559

    View details for PubMedID 26663222

  • Target-Selectivity of Parvalbumin-Positive Interneurons in Layer II of Medial Entorhinal Cortex in Normal and Epileptic Animals HIPPOCAMPUS Armstrong, C., Wang, J., Lee, S. Y., Broderick, J., Bezaire, M. J., Lee, S., Soltesz, I. 2016; 26 (6): 779-793

    Abstract

    The medial entorhinal cortex layer II (MEClayerII ) is a brain region critical for spatial navigation and memory, and it also demonstrates a number of changes in patients with, and animal models of, temporal lobe epilepsy (TLE). Prior studies of GABAergic microcircuitry in MEClayerII revealed that cholecystokinin-containing basket cells (CCKBCs) select their targets on the basis of the long-range projection pattern of the postsynaptic principal cell. Specifically, CCKBCs largely avoid reelin-containing principal cells that form the perforant path to the ipsilateral dentate gyrus and preferentially innervate non-perforant path forming calbindin-containing principal cells. We investigated whether parvalbumin containing basket cells (PVBCs), the other major perisomatic targeting GABAergic cell population, demonstrate similar postsynaptic target selectivity as well. In addition, we tested the hypothesis that the functional or anatomic arrangement of circuit selectivity is disrupted in MEClayerII in chronic TLE, using the repeated low-dose kainate model in rats. In control animals, we found that PVBCs innervated both principal cell populations, but also had significant selectivity for calbindin-containing principal cells in MEClayerII . However, the magnitude of this preference was smaller than for CCKBCs. In addition, axonal tracing and paired recordings showed that individual PVBCs were capable of contacting both calbindin and reelin-containing principal cells. In chronically epileptic animals, we found that the intrinsic properties of the two principal cell populations, the GABAergic perisomatic bouton numbers, and selectivity of the CCKBCs and PVBCs remained remarkably constant in MEClayerII . However, miniature IPSC frequency was decreased in epilepsy, and paired recordings revealed the presence of direct excitatory connections between principal cells in the MEClayerII in epilepsy, which is unusual in normal adult MEClayerII . Taken together, these findings advance our knowledge about the organization of perisomatic inhibition both in control and in epileptic animals. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hipo.22559

    View details for Web of Science ID 000383272000009

    View details for PubMedCentralID PMC4866882

  • Hippogate: a break-in from entorhinal cortex. Nature neuroscience Alexander, A., Soltesz, I. 2016; 19 (4): 530-532

    View details for DOI 10.1038/nn.4253

    View details for PubMedID 26878673

  • Cannabinoid Control of Learning and Memory through HCN Channels NEURON Maroso, M., Szabo, G. G., Kim, H. K., Alexander, A., Bui, A. D., Lee, S., Lutz, B., Soltesz, I. 2016; 89 (5): 1059-1073

    Abstract

    The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.

    View details for DOI 10.1016/j.neuron.2016.01.023

    View details for PubMedID 26898775

  • Organization and control of epileptic circuits in temporal lobe epilepsy. Progress in brain research Alexander, A., Maroso, M., Soltesz, I. 2016; 226: 127-154

    Abstract

    When studying the pathological mechanisms of epilepsy, there are a seemingly endless number of approaches from the ultrastructural level-receptor expression by EM-to the behavioral level-comorbid depression in behaving animals. Epilepsy is characterized as a disorder of recurrent seizures, which are defined as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain" (Fisher et al., 2005). Such abnormal activity typically does not occur in a single isolated neuron; rather, it results from pathological activity in large groups-or circuits-of neurons. Here we choose to focus on two aspects of aberrant circuits in temporal lobe epilepsy: their organization and potential mechanisms to control these pathological circuits. We also look at two scales: microcircuits, ie, the relationship between individual neurons or small groups of similar neurons, and macrocircuits, ie, the organization of large-scale brain regions. We begin by summarizing the large body of literature that describes the stereotypical anatomical changes in the temporal lobe-ie, the anatomical basis of alterations in microcircuitry. We then offer a brief introduction to graph theory and describe how this type of mathematical analysis, in combination with computational neuroscience techniques and using parameters obtained from experimental data, can be used to postulate how microcircuit alterations may lead to seizures. We then zoom out and look at the changes which are seen over large whole-brain networks in patients and animal models, and finally we look to the future.

    View details for DOI 10.1016/bs.pbr.2016.04.007

    View details for PubMedID 27323941

  • Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention JOURNAL OF NEUROSCIENCE Ewell, L. A., Liang, L., Armstrong, C., Soltesz, I., Leutgeb, S., Leutgeb, J. K. 2015; 35 (47): 15635-15648

    Abstract

    Neural dynamics preceding seizures are of interest because they may shed light on mechanisms of seizure generation and could be predictive. In healthy animals, hippocampal network activity is shaped by behavioral brain state and, in epilepsy, seizures selectively emerge during specific brain states. To determine the degree to which changes in network dynamics before seizure are pathological or reflect ongoing fluctuations in brain state, dorsal hippocampal neurons were recorded during spontaneous seizures in a rat model of temporal lobe epilepsy. Seizures emerged from all brain states, but with a greater likelihood after REM sleep, potentially due to an observed increase in baseline excitability during periods of REM compared with other brains states also characterized by sustained theta oscillations. When comparing the firing patterns of the same neurons across brain states associated with and without seizures, activity dynamics before seizures followed patterns typical of the ongoing brain state, or brain state transitions, and did not differ until the onset of the electrographic seizure. Next, we tested whether disparate activity patterns during distinct brain states would influence the effectiveness of optogenetic curtailment of hippocampal seizures in a mouse model of temporal lobe epilepsy. Optogenetic curtailment was significantly more effective for seizures preceded by non-theta states compared with seizures that emerged from theta states. Our results indicate that consideration of behavioral brain state preceding a seizure is important for the appropriate interpretation of network dynamics leading up to a seizure and for designing effective seizure intervention.Hippocampal single-unit activity is strongly shaped by behavioral brain state, yet this relationship has been largely ignored when studying activity dynamics before spontaneous seizures in medial temporal lobe epilepsy. In light of the increased attention on using single-unit activity for the prediction of seizure onset and closed-loop seizure intervention, we show a need for monitoring brain state to interpret correctly whether changes in neural activity before seizure onset is pathological or normal. Moreover, we also find that the brain state preceding a seizure determines the success of therapeutic interventions to curtail seizure duration. Together, these findings suggest that seizure prediction and intervention will be more successful if tailored for the specific brain states from which seizures emerge.

    View details for DOI 10.1523/JNEUROSCI.5112-14.2015

    View details for PubMedID 26609157

    View details for PubMedCentralID PMC4659826

  • Pass-Through Code of Synaptic Integration. Neuron Szabo, G. G., Soltesz, I. 2015; 87 (6): 1124-1126

    Abstract

    How do the components of neuronal circuits collaborate to select combinations of synaptic inputs from multiple pathways? In this issue of Neuron, Milstein et al. (2015) uncover mechanisms of synaptic facilitation and dendritic inhibition that cooperate to provide filtering for co-active inputs of distinct origins.

    View details for DOI 10.1016/j.neuron.2015.09.006

    View details for PubMedID 26402596

  • Optogenetics: 10 years after ChR2 in neurons-views from the community NATURE NEUROSCIENCE Adamantidis, A., Arber, S., Bains, J. S., Bamberg, E., Bonci, A., Buzsaki, G., Cardin, J. A., Costa, R. M., Dan, Y., Goda, Y., Graybiel, A. M., Haeusser, M., Hegemann, P., Huguenard, J. R., Insel, T. R., Janak, P. H., Johnston, D., Josselyn, S. A., Koch, C., Kreitzer, A. C., Luescher, C., Malenka, R. C., Miesenboeck, G., Nagel, G., Roska, B., Schnitzer, M. J., Shenoy, K. V., Soltesz, I., Sternson, S. M., Tsien, R. W., Tsien, R. Y., Turrigiano, G. G., Tye, K. M., Wilson, R. I. 2015; 18 (9): 1202–12

    View details for PubMedID 26308981

  • Regulation of fast-spiking basket cell synapses by the chloride channel ClC-2 NATURE NEUROSCIENCE Foldy, C., Lee, S., Morgan, R. J., Soltesz, I. 2010; 13 (9): 1047-1049

    Abstract

    Parvalbumin-expressing, fast-spiking basket cells are important for the generation of synchronous, rhythmic population activities in the hippocampus. We found that GABAA receptor-mediated synaptic inputs from murine parvalbumin-expressing basket cells were selectively modulated by the membrane voltage- and intracellular chloride-dependent chloride channel ClC-2. Our data reveal a previously unknown cell type-specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons.

    View details for DOI 10.1038/nn.2609

    View details for Web of Science ID 000281332600006

    View details for PubMedID 20676104

    View details for PubMedCentralID PMC2928876