Publications by authors named "Tiago Branco"

45 Publications

Genetic atypical hemolytic uremic syndrome in children: a 20-year experience from a tertiary center.

J Bras Nefrol 2021 May 12. Epub 2021 May 12.

Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do Norte, Unidade de Nefrologia Pediátrica, Porto, Portugal.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, which primarily affects preschool-aged children. This study's aim was to describe the clinical profile, management, and long-term outcome of the genetic aHUS patients admitted to a tertiary care pediatric nephrology center during 20 years.

Methods: We performed a retrospective analysis of the clinical records of all aHUS patients younger than 18 years with identified genetic mutations. Data on clinical features, genetic study, therapeutic interventions, and long-term outcomes were reviewed.

Results: Five cases of aHUS with an identified genetic mutation were included; all were inaugural cases with the youngest being 4 months old. Complement factor H gene mutation was identified in four patients. Therapeutic plasma exchange was performed for acute management in 4 patients, one of whom also needed acute renal replacement therapy (peritoneal dialysis). All patients went on complete remission, 2 had more than one relapse but only 1 of these progressed to chronic kidney disease during the follow-up period (median (25th-75th percentile), 136 (43.5-200.5) months).

Conclusion: In children, the prognosis of renal function seems to be strongly dependent on the genetic background, thus being crucial to perform genetic study in all aHUS cases. In our cohort, 2 patients presented genetic mutations not previously described. Recent innovations on the genetic field leading to the identification of new mutations has lead to a better understanding of aHUS pathogenesis, but further studies, focusing on the genotype-phenotype correlation, with longer follow-up periods, are needed.
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http://dx.doi.org/10.1590/2175-8239-JBN-2020-0199DOI Listing
May 2021

Visualizing anatomically registered data with brainrender.

Elife 2021 Mar 19;10. Epub 2021 Mar 19.

UCL Sainsbury Wellcome Centre, London, United Kingdom.

Three-dimensional (3D) digital brain atlases and high-throughput brain-wide imaging techniques generate large multidimensional datasets that can be registered to a common reference frame. Generating insights from such datasets depends critically on visualization and interactive data exploration, but this a challenging task. Currently available software is dedicated to single atlases, model species or data types, and generating 3D renderings that merge anatomically registered data from diverse sources requires extensive development and programming skills. Here, we present brainrender: an open-source Python package for interactive visualization of multidimensional datasets registered to brain atlases. Brainrender facilitates the creation of complex renderings with different data types in the same visualization and enables seamless use of different atlas sources. High-quality visualizations can be used interactively and exported as high-resolution figures and animated videos. By facilitating the visualization of anatomically registered data, brainrender should accelerate the analysis, interpretation, and dissemination of brain-wide multidimensional data.
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http://dx.doi.org/10.7554/eLife.65751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079143PMC
March 2021

Bird Fancier's Lung Diagnosis in Times of COVID-19.

Arch Bronconeumol 2021 Jan 22;57 Suppl 1:90-91. Epub 2020 Oct 22.

Department of Medicine 2, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal; Faculty of Medicine of the University of Lisbon, Lisbon.

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http://dx.doi.org/10.1016/j.arbres.2020.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577872PMC
January 2021

COVID-19 treatment in sub-Saharan Africa: If the best is not available, the available becomes the best.

Travel Med Infect Dis 2020 Sep - Oct;37:101878. Epub 2020 Sep 11.

Masanga Medical Research Unit (MMRU), Masanga, Tonkolili District, Sierra Leone; Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Amsterdam University Medical Centers, Amsterdam Infection & Immunity, Amsterdam Public Health, University of Amsterdam, Location AMC, Meibergdreef 9, 1100 DD Amsterdam, Amsterdam, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.tmaid.2020.101878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485546PMC
October 2020

BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT OF HEPATOCELLULAR CARCINOMA.

Arq Gastroenterol 2020 9;57(suppl 1):1-20. Epub 2020 Mar 9.

Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.
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http://dx.doi.org/10.1590/S0004-2803.202000000-20DOI Listing
May 2020

The Neural Basis of Escape Behavior in Vertebrates.

Annu Rev Neurosci 2020 07 7;43:417-439. Epub 2020 Apr 7.

Department of Psychology, The University of Sheffield, Sheffield S1 2LT, United Kingdom; email:

Escape is one of the most studied animal behaviors, and there is a rich normative theory that links threat properties to evasive actions and their timing. The behavioral principles of escape are evolutionarily conserved and rely on elementary computational steps such as classifying sensory stimuli and executing appropriate movements. These are common building blocks of general adaptive behaviors. Here we consider the computational challenges required for escape behaviors to be implemented, discuss possible algorithmic solutions, and review some of the underlying neural circuits and mechanisms. We outline shared neural principles that can be implemented by evolutionarily ancient neural systems to generate escape behavior, to which cortical encephalization has been added to allow for increased sophistication and flexibility in responding to threat.
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http://dx.doi.org/10.1146/annurev-neuro-100219-122527DOI Listing
July 2020

Artificial Intelligence in Acute Kidney Injury Risk Prediction.

J Clin Med 2020 Mar 3;9(3). Epub 2020 Mar 3.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Acute kidney injury (AKI) is a frequent complication in hospitalized patients, which is associated with worse short and long-term outcomes. It is crucial to develop methods to identify patients at risk for AKI and to diagnose subclinical AKI in order to improve patient outcomes. The advances in clinical informatics and the increasing availability of electronic medical records have allowed for the development of artificial intelligence predictive models of risk estimation in AKI. In this review, we discussed the progress of AKI risk prediction from risk scores to electronic alerts to machine learning methods.
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http://dx.doi.org/10.3390/jcm9030678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141311PMC
March 2020

The role of the periaqueductal gray in escape behavior.

Curr Opin Neurobiol 2020 02 19;60:115-121. Epub 2019 Dec 19.

UCL Sainsbury Wellcome Centre for Neural Circuits and Behaviour, London W1T 4JG, UK. Electronic address:

Escape behavior is a defensive action deployed by animals in response to imminent threats. In mammalian species, a variety of different brain circuits are known to participate in this crucial survival behavior. One of these circuits is the periaqueductal gray, a midbrain structure that can command a variety of instinctive behaviors. Recent experiments using modern systems neuroscience techniques have begun to elucidate the specific role of the periaqueductal gray in controlling escape. These have shown that periaqueductal gray neurons are crucial units for gating and commanding the initiation of escape, specifically activated in situations of imminent, escapable threat. In addition, it is becoming clear that the periaqueductal gray integrates brain-wide information that can modulate escape initiation to generate flexible defensive behaviors.
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http://dx.doi.org/10.1016/j.conb.2019.11.014DOI Listing
February 2020

Cognitive Control of Escape Behaviour.

Trends Cogn Sci 2019 04 6;23(4):334-348. Epub 2019 Mar 6.

Sainsbury Wellcome Centre for Neural Circuits and Behaviour, UCL, London, UK. Electronic address:

When faced with potential predators, animals instinctively decide whether there is a threat they should escape from, and also when, how, and where to take evasive action. While escape is often viewed in classical ethology as an action that is released upon presentation of specific stimuli, successful and adaptive escape behaviour relies on integrating information from sensory systems, stored knowledge, and internal states. From a neuroscience perspective, escape is an incredibly rich model that provides opportunities for investigating processes such as perceptual and value-based decision-making, or action selection, in an ethological setting. We review recent research from laboratory and field studies that explore, at the behavioural and mechanistic levels, how elements from multiple information streams are integrated to generate flexible escape behaviour.
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http://dx.doi.org/10.1016/j.tics.2019.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438863PMC
April 2019

Global and Multiplexed Dendritic Computations under In Vivo-like Conditions.

Neuron 2018 11;100(3):579-592.e5

MRC Laboratory of Molecular Biology, Cambridge, UK; Sainsbury Wellcome Centre, University College London, London, UK.

Dendrites integrate inputs nonlinearly, but it is unclear how these nonlinearities contribute to the overall input-output transformation of single neurons. We developed statistically principled methods using a hierarchical cascade of linear-nonlinear subunits (hLN) to model the dynamically evolving somatic response of neurons receiving complex, in vivo-like spatiotemporal synaptic input patterns. We used the hLN to predict the somatic membrane potential of an in vivo-validated detailed biophysical model of a L2/3 pyramidal cell. Linear input integration with a single global dendritic nonlinearity achieved above 90% prediction accuracy. A novel hLN motif, input multiplexing into parallel processing channels, could improve predictions as much as conventionally used additional layers of local nonlinearities. We obtained similar results in two other cell types. This approach provides a data-driven characterization of a key component of cortical circuit computations: the input-output transformation of neurons during in vivo-like conditions.
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http://dx.doi.org/10.1016/j.neuron.2018.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226578PMC
November 2018

Membrane binding, internalization, and sorting of alpha-synuclein in the cell.

Acta Neuropathol Commun 2018 08 14;6(1):79. Epub 2018 Aug 14.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, 37073, Göttingen, Germany.

Alpha-synuclein (aSyn) plays a crucial role in Parkinson's disease (PD) and other synucleinopathies, since it misfolds and accumulates in typical proteinaceous inclusions. While the function of aSyn is thought to be related to vesicle binding and trafficking, the precise molecular mechanisms linking aSyn with synucleinopathies are still obscure. aSyn can spread in a prion-like manner between interconnected neurons, contributing to the propagation of the pathology and to the progressive nature of synucleinopathies. Here, we investigated the interaction of aSyn with membranes and trafficking machinery pathways using cellular models of PD that are amenable to detailed molecular analyses. We found that different species of aSyn can enter cells and form high molecular weight species, and that membrane binding properties are important for the internalization of aSyn. Once internalized, aSyn accumulates in intracellular inclusions. Interestingly, we found that internalization is blocked in the presence of dynamin inhibitors (blocked membrane scission), suggesting the involvement of the endocytic pathway in the internalization of aSyn. By screening a pool of small Rab-GTPase proteins (Rabs) which regulate membrane trafficking, we found that internalized aSyn partially colocalized with Rab5A and Rab7. Initially, aSyn accumulated in Rab4A-labelled vesicles and, at later stages, it reached the autophagy-lysosomal pathway (ALP) where it gets degraded. In total, our study emphasizes the importance of membrane binding, not only as part of the normal function but also as an important step in the internalization and subsequent accumulation of aSyn. Importantly, we identified a fundamental role for Rab proteins in the modulation of aSyn processing, clearance and spreading, suggesting that targeting Rab proteins may hold important therapeutic value in PD and other synucleinopathies.
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http://dx.doi.org/10.1186/s40478-018-0578-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090819PMC
August 2018

A Behavioral Assay for Investigating the Role of Spatial Memory During Instinctive Defense in Mice.

J Vis Exp 2018 07 21(137). Epub 2018 Jul 21.

UCL Sainsbury Wellcome Centre for Neural Circuits and Behaviour; MRC Laboratory of Molecular Biology;

Evolution has selected a repertoire of defensive behaviors that are essential for survival across all animal species. These behaviors are often stereotyped actions elicited in response to innately aversive sensory stimuli, but their success requires enough flexibility for adapting to different spatial environments, which can change rapidly. Here, we describe a behavioral assay to evaluate the influence of learned spatial knowledge on defensive behaviors in mice. We have adapted the widely used Barnes maze spatial memory assay to investigate how mice navigate to a shelter during escape responses to innately aversive sensory stimuli in a novel environment, and how they adapt to acute changes in the environment. This new assay is an ethological paradigm that does not require training and exploits the natural exploration patterns and navigation strategies in mice. We propose that the set of protocols described here are a powerful means of studying goal-directed behaviors and stimulus-triggered navigation, which should be of interest to both the fields of instinctive behaviors and spatial memory.
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http://dx.doi.org/10.3791/56988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126525PMC
July 2018

A Distance-Dependent Distribution of Presynaptic Boutons Tunes Frequency-Dependent Dendritic Integration.

Neuron 2018 07 5;99(2):275-282.e3. Epub 2018 Jul 5.

Centre for Developmental Neurobiology, Kings College London, New Hunts House, Guys Hospital Campus, London, SE1 1UL, UK; MRC Centre for Neurodevelopmental Disorders, Kings College London, New Hunts House, Guys Hospital Campus, London, SE1 1UL, UK. Electronic address:

How presynaptic inputs and neurotransmitter release dynamics are distributed along a dendritic tree is not well established. Here, we show that presynaptic boutons that form onto basal dendrites of CA1 pyramidal neurons display a decrease in active zone (AZ) size with distance from the soma, resulting in a distance-dependent increase in short-term facilitation. Our findings suggest that the spatial distribution of short-term facilitation serves to compensate for the electrotonic attenuation of subthreshold distal inputs during repeated stimulation and fine-tunes the preferred input frequency of dendritic domains.
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http://dx.doi.org/10.1016/j.neuron.2018.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078905PMC
July 2018

A synaptic threshold mechanism for computing escape decisions.

Nature 2018 06 20;558(7711):590-594. Epub 2018 Jun 20.

MRC Laboratory of Molecular Biology, Cambridge, UK.

Escaping from imminent danger is an instinctive behaviour that is fundamental for survival, and requires the classification of sensory stimuli as harmless or threatening. The absence of threat enables animals to forage for essential resources, but as the level of threat and potential for harm increases, they have to decide whether or not to seek safety . Despite previous work on instinctive defensive behaviours in rodents, little is known about how the brain computes the threat level for initiating  escape. Here we show that the probability and vigour of escape in mice scale with the saliency of innate threats, and are well described by a model that computes the distance between the threat level and an escape threshold. Calcium imaging and optogenetics in the midbrain of freely behaving mice show that the activity of excitatory neurons in the deep layers of the medial superior colliculus (mSC) represents the saliency of the threat stimulus and is predictive of escape, whereas glutamatergic neurons of the dorsal periaqueductal grey (dPAG) encode exclusively the choice to escape and control escape vigour. We demonstrate a feed-forward monosynaptic excitatory connection from mSC to dPAG neurons, which is weak and unreliable-yet required for escape behaviour-and provides a synaptic threshold for dPAG activation and the initiation of escape. This threshold can be overcome by high mSC network activity because of short-term synaptic facilitation and recurrent excitation within the mSC, which amplifies and sustains synaptic drive to the dPAG. Therefore, dPAG glutamatergic neurons compute escape decisions and escape vigour using a synaptic mechanism to  threshold threat information received from the mSC, and provide a biophysical model of how the brain performs a critical behavioural computation.
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http://dx.doi.org/10.1038/s41586-018-0244-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235113PMC
June 2018

Active dendritic integration as a mechanism for robust and precise grid cell firing.

Nat Neurosci 2017 Aug 19;20(8):1114-1121. Epub 2017 Jun 19.

Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

Understanding how active dendrites are exploited for behaviorally relevant computations is a fundamental challenge in neuroscience. Grid cells in medial entorhinal cortex are an attractive model system for addressing this question, as the computation they perform is clear: they convert synaptic inputs into spatially modulated, periodic firing. Whether active dendrites contribute to the generation of the dual temporal and rate codes characteristic of grid cell output is unknown. We show that dendrites of medial entorhinal cortex neurons are highly excitable and exhibit a supralinear input-output function in vitro, while in vivo recordings reveal membrane potential signatures consistent with recruitment of active dendritic conductances. By incorporating these nonlinear dynamics into grid cell models, we show that they can sharpen the precision of the temporal code and enhance the robustness of the rate code, thereby supporting a stable, accurate representation of space under varying environmental conditions. Our results suggest that active dendrites may therefore constitute a key cellular mechanism for ensuring reliable spatial navigation.
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http://dx.doi.org/10.1038/nn.4582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358004PMC
August 2017

Rapid Spatial Learning Controls Instinctive Defensive Behavior in Mice.

Curr Biol 2017 May 13;27(9):1342-1349. Epub 2017 Apr 13.

MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; UCL Sainsbury Wellcome Centre for Neural Circuits and Behaviour, Howland Street, London W1T 4JG, UK. Electronic address:

Instinctive defensive behaviors are essential for animal survival. Across the animal kingdom, there are sensory stimuli that innately represent threat and trigger stereotyped behaviors such as escape or freezing [1-4]. While innate behaviors are considered to be hard-wired stimulus-responses [5], they act within dynamic environments, and factors such as the properties of the threat [6-9] and its perceived intensity [1, 10, 11], access to food sources [12-14], and expectations from past experience [15, 16] have been shown to influence defensive behaviors, suggesting that their expression can be modulated. However, despite recent work [2, 4, 17-21], little is known about how flexible mouse innate defensive behaviors are and how quickly they can be modified by experience. To address this, we have investigated the dependence of escape behavior on learned knowledge about the spatial environment and how the behavior is updated when the environment changes acutely. Using behavioral assays with innately threatening visual and auditory stimuli, we show that the primary goal of escape in mice is to reach a previously memorized shelter location. Memory of the escape target can be formed in a single shelter visit lasting less than 20 s, and changes in the spatial environment lead to a rapid update of the defensive action, including changing the defensive strategy from escape to freezing. Our results show that although there are innate links between specific sensory features and defensive behavior, instinctive defensive actions are surprisingly flexible and can be rapidly updated by experience to adapt to changing spatial environments.
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http://dx.doi.org/10.1016/j.cub.2017.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434248PMC
May 2017

Validation of questionnaire on the Spiritual Needs Assessment for Patients (SNAP) questionnaire in Brazilian Portuguese.

Ecancermedicalscience 2016 22;10:694. Epub 2016 Nov 22.

Instituto do Câncer do Estado de São Paulo, 01246-000, Brazil; Faculty of Medicine of São Paulo University, 01246-903, Brazil.

Objectives: Spirituality is related to the care and the quality of life of cancer patients. Thus, it is very important to assess their needs. The objective of this study was the translation and cultural adjustment of the Spiritual Needs Assessment for Patients (SNAP) questionnaire to the Brazilian Portuguese language.

Methodology: The translation and cultural adjustment of the SNAP questionnaire involved six stages: backtranslation, revision of backtranslation, translation to the original language and adjustments, pre-test on ten patients, and test and retest with 30 patients after three weeks. Adult patients, with a solid tumour and literate with a minimum of four years schooling were included. For analysis and consistency we used the calculation of the Cronbach alpha coefficient and the Pearson linear correlation.

Results: The final questionnaire had some language and content adjustments compared to the original version in English. The correlation analysis of each item with the total score of the questionnaire showed coefficients above 0.99. The calculation of the Cronbach alpha coefficient was 0.9. The calculation of the Pearson linear correlation with the test and retest of the questionnaire was equal to 0.95.

Conclusion: The SNAP questionnaire translated into Brazilian Portuguese is adequately reliable and consistent. This instrument allows adequate access to spiritual needs and can help patient care.
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http://dx.doi.org/10.3332/ecancer.2016.694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215246PMC
November 2016

Prefrontal cortical control of a brainstem social behavior circuit.

Nat Neurosci 2017 02 9;20(2):260-270. Epub 2017 Jan 9.

Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.

The prefrontal cortex helps adjust an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas, and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior.
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http://dx.doi.org/10.1038/nn.4470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580810PMC
February 2017

Near-Perfect Synaptic Integration by Nav1.7 in Hypothalamic Neurons Regulates Body Weight.

Cell 2016 Jun;165(7):1749-1761

Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA. Electronic address:

Neurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration. Scn9a deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions.
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http://dx.doi.org/10.1016/j.cell.2016.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912688PMC
June 2016

Dendritic nonlinearities are tuned for efficient spike-based computations in cortical circuits.

Elife 2015 Dec 24;4. Epub 2015 Dec 24.

Computational and Biological Learning Lab, Department of Engineering, University of Cambridge, Cambridge, United Kingdom.

Cortical neurons integrate thousands of synaptic inputs in their dendrites in highly nonlinear ways. It is unknown how these dendritic nonlinearities in individual cells contribute to computations at the level of neural circuits. Here, we show that dendritic nonlinearities are critical for the efficient integration of synaptic inputs in circuits performing analog computations with spiking neurons. We developed a theory that formalizes how a neuron's dendritic nonlinearity that is optimal for integrating synaptic inputs depends on the statistics of its presynaptic activity patterns. Based on their in vivo preynaptic population statistics (firing rates, membrane potential fluctuations, and correlations due to ensemble dynamics), our theory accurately predicted the responses of two different types of cortical pyramidal cells to patterned stimulation by two-photon glutamate uncaging. These results reveal a new computational principle underlying dendritic integration in cortical neurons by suggesting a functional link between cellular and systems--level properties of cortical circuits.
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http://dx.doi.org/10.7554/eLife.10056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912838PMC
December 2015

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition.

Proc Natl Acad Sci U S A 2015 Oct 2;112(42):13099-104. Epub 2015 Oct 2.

Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom

Classical feed-forward inhibition involves an excitation-inhibition sequence that enhances the temporal precision of neuronal responses by narrowing the window for synaptic integration. In the input layer of the cerebellum, feed-forward inhibition is thought to preserve the temporal fidelity of granule cell spikes during mossy fiber stimulation. Although this classical feed-forward inhibitory circuit has been demonstrated in vitro, the extent to which inhibition shapes granule cell sensory responses in vivo remains unresolved. Here we combined whole-cell patch-clamp recordings in vivo and dynamic clamp recordings in vitro to directly assess the impact of Golgi cell inhibition on sensory information transmission in the granule cell layer of the cerebellum. We show that the majority of granule cells in Crus II of the cerebrocerebellum receive sensory-evoked phasic and spillover inhibition prior to mossy fiber excitation. This preceding inhibition reduces granule cell excitability and sensory-evoked spike precision, but enhances sensory response reproducibility across the granule cell population. Our findings suggest that neighboring granule cells and Golgi cells can receive segregated and functionally distinct mossy fiber inputs, enabling Golgi cells to regulate the size and reproducibility of sensory responses.
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http://dx.doi.org/10.1073/pnas.1510249112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620892PMC
October 2015

Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss.

Elife 2015 Sep 2;4. Epub 2015 Sep 2.

Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.

Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. Agouti related protein (AGRP)-expressing neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed Proopiomelanocortin (POMC)-expressing neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders.
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http://dx.doi.org/10.7554/eLife.09800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595745PMC
September 2015

Ultrafast tissue staining with chemical tags.

Proc Natl Acad Sci U S A 2014 Sep 25;111(36):E3805-14. Epub 2014 Aug 25.

Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom

Genetically encoded fluorescent proteins and immunostaining are widely used to detect cellular and subcellular structures in fixed biological samples. However, for thick or whole-mount tissue, each approach suffers from limitations, including limited spectral flexibility and lower signal or slow speed, poor penetration, and high background labeling, respectively. We have overcome these limitations by using transgenically expressed chemical tags for rapid, even, high-signal and low-background labeling of thick biological tissues. We first construct a platform of widely applicable transgenic Drosophila reporter lines, demonstrating that chemical labeling can accelerate staining of whole-mount fly brains by a factor of 100. Using viral vectors to deliver chemical tags into the mouse brain, we then demonstrate that this labeling strategy works well in mice. Thus this tag-based approach drastically improves the speed and specificity of labeling genetically marked cells in intact and/or thick biological samples.
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http://dx.doi.org/10.1073/pnas.1411087111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246963PMC
September 2014

Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo.

Nature 2013 Nov 27;503(7474):115-20. Epub 2013 Oct 27.

1] Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK [2] Department of Cell Biology and Physiology and Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.

Neuronal dendrites are electrically excitable: they can generate regenerative events such as dendritic spikes in response to sufficiently strong synaptic input. Although such events have been observed in many neuronal types, it is not well understood how active dendrites contribute to the tuning of neuronal output in vivo. Here we show that dendritic spikes increase the selectivity of neuronal responses to the orientation of a visual stimulus (orientation tuning). We performed direct patch-clamp recordings from the dendrites of pyramidal neurons in the primary visual cortex of lightly anaesthetized and awake mice, during sensory processing. Visual stimulation triggered regenerative local dendritic spikes that were distinct from back-propagating action potentials. These events were orientation tuned and were suppressed by either hyperpolarization of membrane potential or intracellular blockade of NMDA (N-methyl-d-aspartate) receptors. Both of these manipulations also decreased the selectivity of subthreshold orientation tuning measured at the soma, thus linking dendritic regenerative events to somatic orientation tuning. Together, our results suggest that dendritic spikes that are triggered by visual input contribute to a fundamental cortical computation: enhancing orientation selectivity in the visual cortex. Thus, dendritic excitability is an essential component of behaviourally relevant computations in neurons.
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http://dx.doi.org/10.1038/nature12600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319606PMC
November 2013

A preferentially segregated recycling vesicle pool of limited size supports neurotransmission in native central synapses.

Neuron 2012 Nov;76(3):579-89

School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.

At small central synapses, efficient turnover of vesicles is crucial for stimulus-driven transmission, but how the structure of this recycling pool relates to its functional role remains unclear. Here we characterize the organizational principles of functional vesicles at native hippocampal synapses with nanoscale resolution using fluorescent dye labeling and electron microscopy. We show that the recycling pool broadly scales with the magnitude of the total vesicle pool, but its average size is small (∼45 vesicles), highly variable, and regulated by CDK5/calcineurin activity. Spatial analysis demonstrates that recycling vesicles are preferentially arranged near the active zone and this segregation is abolished by actin stabilization, slowing the rate of activity-driven exocytosis. Our approach reveals a similarly biased recycling pool distribution at synapses in visual cortex activated by sensory stimulation in vivo. We suggest that in small native central synapses, efficient release of a limited pool of vesicles relies on their favored spatial positioning within the terminal.
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http://dx.doi.org/10.1016/j.neuron.2012.08.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526798PMC
November 2012

Tonic inhibition enhances fidelity of sensory information transmission in the cerebellar cortex.

J Neurosci 2012 Aug;32(32):11132-43

Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.

Tonic inhibition is a key regulator of neuronal excitability and network function in the brain, but its role in sensory information processing remains poorly understood. The cerebellum is a favorable model system for addressing this question as granule cells, which form the input layer of the cerebellar cortex, permit high-resolution patch-clamp recordings in vivo, and are the only neurons in the cerebellar cortex that express the α6δ-containing GABA(A) receptors mediating tonic inhibition. We investigated how tonic inhibition regulates sensory information transmission in the rat cerebellum by using a combination of intracellular recordings from granule cells and molecular layer interneurons in vivo, selective pharmacology, and in vitro dynamic clamp experiments. We show that blocking tonic inhibition significantly increases the spontaneous firing rate of granule cells while only moderately increasing sensory-evoked spike output. In contrast, enhancing tonic inhibition reduces the spike probability in response to sensory stimulation with minimal effect on the spontaneous spike rate. Both manipulations result in a reduction in the signal-to-noise ratio of sensory transmission in granule cells and of parallel fiber synaptic input to downstream molecular layer interneurons. These results suggest that under basal conditions the level of tonic inhibition in vivo enhances the fidelity of sensory information transmission through the input layer of the cerebellar cortex.
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http://dx.doi.org/10.1523/JNEUROSCI.0460-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363100PMC
August 2012

Recruitment of resting vesicles into recycling pools supports NMDA receptor-dependent synaptic potentiation in cultured hippocampal neurons.

J Physiol 2012 Apr 23;590(7):1585-97. Epub 2012 Jan 23.

School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.

Most presynaptic terminals in the central nervous system are characterized by two functionally distinct vesicle populations: a recycling pool, which supports action potential-driven neurotransmitter release via vesicle exocytosis, and a resting pool. The relative proportions of these two pools are highly variable between individual synapses, prompting speculation on their specific relationship, and on the possible functions of the resting pool.Using fluorescence imaging of FM-styryl dyes and synaptophysinI-pHluorin(sypHy) as well as correlative electronmicroscopy approaches, we show here that Hebbian plasticity-dependent changes in synaptic strength in rat hippocampal neurons can increase the recycling pool fraction at the expense of the resting pool in individual synaptic terminals. This recruitment process depends on NMDA-receptor activation, nitric oxide signalling and calcineurin and is accompanied by an increase in the probability of neurotransmitter release at individual terminals. Blockade of actin-mediated intersynaptic vesicle exchange does not prevent recycling pool expansion demonstrating that vesicle recruitment is intrasynaptic.We propose that the conversion of resting pool vesicles to the functionally recycling pool provides a rapid mechanism to implement long-lasting changes in presynaptic efficacy.
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http://dx.doi.org/10.1113/jphysiol.2011.226688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413500PMC
April 2012

Extrasynaptic vesicle recycling in mature hippocampal neurons.

Nat Commun 2011 Nov 8;2:531. Epub 2011 Nov 8.

School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.

Fast neuronal signalling relies on highly regulated vesicle fusion and recycling at specialized presynaptic terminals. Recently, examples of non-classical neurotransmission have also been reported, where fusion of vesicles can occur at sites remote from conventional synapses. This has potentially broad biological implications, but the underlying mechanisms are not well established. Here we show that a complete vesicle recycling pathway can occur at discrete axonal sites in mature hippocampal neurons and that extrasynaptic fusion is a robust feature of native tissue. We demonstrate that laterally mobile vesicle clusters trafficking between synaptic terminals become transiently stabilized by evoked action potentials and undergo complete but delayed Ca(2+)-dependent fusion along axons. This fusion is associated with dynamic actin accumulation and, subsequently, vesicles can be locally recycled, re-acidified and re-used. Immunofluorescence and ultrastructural work demonstrates that extrasynaptic fusion sites can have apposed postsynaptic specializations, suggesting that mobile vesicle recycling may underlie highly dynamic neuron-neuron communication.
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http://dx.doi.org/10.1038/ncomms1534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492933PMC
November 2011

Eppendorf winner. The language of dendrites.

Authors:
Tiago Branco

Science 2011 Nov;334(6056):615-6

University College London, London, WC1E 6BT UK.

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http://dx.doi.org/10.1126/science.1215079DOI Listing
November 2011

Synaptic integration gradients in single cortical pyramidal cell dendrites.

Neuron 2011 Mar;69(5):885-92

Wolfson Institute for Biomedical Research, University College London, London, UK.

Cortical pyramidal neurons receive thousands of synaptic inputs arriving at different dendritic locations with varying degrees of temporal synchrony. It is not known if different locations along single cortical dendrites integrate excitatory inputs in different ways. Here we have used two-photon glutamate uncaging and compartmental modeling to reveal a gradient of nonlinear synaptic integration in basal and apical oblique dendrites of cortical pyramidal neurons. Excitatory inputs to the proximal dendrite sum linearly and require precise temporal coincidence for effective summation, whereas distal inputs are amplified with high gain and integrated over broader time windows. This allows distal inputs to overcome their electrotonic disadvantage, and become surprisingly more effective than proximal inputs at influencing action potential output. Thus, single dendritic branches can already exhibit nonuniform synaptic integration, with the computational strategy shifting from temporal coding to rate coding along the dendrite.
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http://dx.doi.org/10.1016/j.neuron.2011.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420135PMC
March 2011