Publications by authors named "Alcino Silva"

180 Publications

Postnatal immune activation causes social deficits in a mouse model of tuberous sclerosis: Role of microglia and clinical implications.

Sci Adv 2021 Sep 17;7(38):eabf2073. Epub 2021 Sep 17.

Departments of Neurobiology, Psychology, and Psychiatry, Integrative Center for Learning and Memory, and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.

[Figure: see text].
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http://dx.doi.org/10.1126/sciadv.abf2073DOI Listing
September 2021

Experiment Selection in Meta-Analytic Piecemeal Causal Discovery.

IEEE Access 2021 1;9:97929-97941. Epub 2021 Jul 1.

Departments of Radiological Sciences, Bioinformatics, and Bioengineering, University of California at Los Angeles (UCLA), Los Angeles, CA 90095, USA.

Scientists try to design experiments that will yield maximal information. For instance, given the available evidence and a limitation on the number of variables that can be observed simultaneously, it may be more informative to intervene on variable and observe the response of variable than to intervene on and observe ; in other situations, the opposite may be true. Scientists must often make these decisions without primary data. To address this problem, in previous work, we created software for annotating aggregate statistics in the literature and deriving consistent causal explanations, expressed as causal graphs. This meta-analytic pipeline is useful not only for synthesizing evidence but also for planning experiments: one can use it strategically to select experiments that could further eliminate causal graphs from consideration. In this paper, we introduce interpretable policies for selecting experiments in the context of piecemeal causal discovery, a common setting in biological sciences in which each experiment can measure not an entire system but rather a strict subset of its variables. The limits of this piecemeal approach are only beginning to be fully characterized, with crucial theoretical work published recently. With simulations, we show that our experiment-selection policies identify causal structures more efficiently than random experiment selection. Unlike methods that require primary data, our meta-analytic approach offers a flexible alternative for those seeking to incorporate qualitative domain knowledge into their search for causal mechanisms. We also present a method that categorizes hypotheses with respect to their utility for identifying a system's causal structure. Although this categorization is usually infeasible to perform manually, it is critical for conducting research efficiently.
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http://dx.doi.org/10.1109/access.2021.3093524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442252PMC
July 2021

Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats.

Elife 2021 09 1;10. Epub 2021 Sep 1.

Department of Psychology, University of California, Los Angeles, Los Angeles, United States.

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd-cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human functional magnetic resonance imaging data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats.
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http://dx.doi.org/10.7554/eLife.69178DOI Listing
September 2021

Dimensions and mechanisms of memory organization.

Neuron 2021 09 8;109(17):2649-2662. Epub 2021 Jul 8.

Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Memory formation is dynamic in nature, and acquisition of new information is often influenced by previous experiences. Memories sharing certain attributes are known to interact so that retrieval of one increases the likelihood of retrieving the other, raising the possibility that related memories are organized into associative mnemonic structures of interconnected representations. Although the formation and retrieval of single memories have been studied extensively, very little is known about the brain mechanisms that organize and link related memories. Here we review studies that suggest the existence of mnemonic structures in humans and animal models. These studies suggest three main dimensions of experience that can serve to organize related memories: time, space, and perceptual/conceptual similarities. We propose potential molecular, cellular, and systems mechanisms that might support organization of memories according to these dimensions.
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http://dx.doi.org/10.1016/j.neuron.2021.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416710PMC
September 2021

Pharmacological blockers of CCR5 and CXCR4 improve recovery after traumatic brain injury.

Exp Neurol 2021 04 14;338:113604. Epub 2021 Jan 14.

Department of Pharmacology, the Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address:

CCR5 and CXCR4 are structurally related chemokine receptors that belong to the superfamily of G-protein coupled receptors through which the HIV virus enters and infects cells. Both receptors are also related to HIV-associated neurocognitive disorders that include difficulties in concentration and memory, impaired executive functions, psychomotor slowing, depression and irritability, which are also hallmarks of the long-term sequelae of TBI. Moreover, A growing body of evidence attributes negative influences to CCR5 activation on cognition, particularly after stroke and traumatic brain injury (TBI). Here we investigated the effect of their blockage on motor and cognitive functions, on brain tissue loss and preservation and on some of the biochemical pathways involved. We examined the effect of maraviroc, a CCR5 antagonist used in HIV patients as a viral entry inhibitor, and of plerixafor (AMD3100), a CXCR4 antagonist used in cancer patients as an immune-modulator, on mice subjected to closed head injury (CHI). Mice were treated with maraviroc or plerixafor after CHI for the following 4 or 5 days, respectively. Neurobehavior was assessed according to the Neurological Severity Score; cognitive tests were performed by using the Y-maze, Barnes maze and the novel object recognition test; anxiety was evaluated with the open field test. The mice were sacrificed and brain tissues were collected for Western blot, pathological and immunohistochemical analyses. Both drugs enhanced tissue preservation in the cortex, hippocampus, periventricular areas, corpus callosum and striatum, and reduced astrogliosis)GFAP expression). They also increased the levels of synaptic cognition-related signaling molecules such as phosphorylated NR1 and CREB, and the synaptic plasticity protein PSD95. Both treatments also enhanced the expression of CCR5 and CXCR4 on different brain cell types. In summary, the beneficial effects of blocking CCR5 and CXCR4 after CHI suggest that the drugs used in this study, both FDA approved and in clinical use, should be considered for translational research in TBI patients.
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http://dx.doi.org/10.1016/j.expneurol.2021.113604DOI Listing
April 2021

Chemokine Receptors CC Chemokine Receptor 5 and C-X-C Motif Chemokine Receptor 4 Are New Therapeutic Targets for Brain Recovery after Traumatic Brain Injury.

J Neurotrauma 2021 Jul 25;38(14):2003-2017. Epub 2021 Jan 25.

Department of Pharmacology, the Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.

Recently, chemokine receptor CC chemokine receptor 5 (CCR5) was found to be a negative modulator of learning and memory. Its inhibition improved outcome after stroke and traumatic brain injury (TBI). To better understand its role after TBI and establish therapeutic strategies, we investigated the effect of reduced CCR5 signaling as a neuroprotective strategy and of the temporal changes of CCR5 expression after TBI in different brain cell types. To silence CCR5 expression, short hairpin RNA (shRNA) or shRNA (control) was injected into the cornu ammonis (CA) 1 and CA3 regions of the hippocampus 2 weeks before induction of closed-head injury in mice. Animals were then monitored for 32 days and euthanized at different time points to assess lesion area, inflammatory components of the glial response (immunohistochemistry; IHC), cytokine levels (enzyme-linked immunosorbent array), and extracellular signal-regulated kinase (ERK) phosphorylation (western blot). Fluorescence-activated cell sorting (FACS) analysis was performed to study post-injury temporal changes of CCR5 and C-X-C motif chemokine receptor 4 (CXCR4) expression in cortical and hippocampal cell populations (neurons, astrocytes, and microglia). Phosphorylation of the N-methyl-d-aspartate subunit 1 (NR1) subunit of N-methyl-d-aspartate (western blot) and cAMP-response-element-binding protein (CREB; IHC) were also assessed. The shRNA mice displayed reduced lesion area, dynamic alterations in levels of inflammation-related CCR5 ligands and cytokines, and higher levels of phosphorylated ERK. The 5 shRNA also reduced astrocytosis in the lesioned and sublesioned cortex. FACS analysis revealed increased cortical CCR5 and CXCR4 expression in CD11b-positive cells, astrocytes, and neurons, which was most evident in cells expressing both receptors, at 3 and 11 days post-injury. The lowest levels of phosphorylated NR1 and phosphorylated CREB were found at day 3 post-injury, suggesting that this is the critical time point for therapeutic intervention.
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http://dx.doi.org/10.1089/neu.2020.7015DOI Listing
July 2021

Breakdown of spatial coding and interneuron synchronization in epileptic mice.

Nat Neurosci 2020 02 6;23(2):229-238. Epub 2020 Jan 6.

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Temporal lobe epilepsy causes severe cognitive deficits, but the circuit mechanisms remain unknown. Interneuron death and reorganization during epileptogenesis may disrupt the synchrony of hippocampal inhibition. To test this, we simultaneously recorded from the CA1 and dentate gyrus in pilocarpine-treated epileptic mice with silicon probes during head-fixed virtual navigation. We found desynchronized interneuron firing between the CA1 and dentate gyrus in epileptic mice. Since hippocampal interneurons control information processing, we tested whether CA1 spatial coding was altered in this desynchronized circuit, using a novel wire-free miniscope. We found that CA1 place cells in epileptic mice were unstable and completely remapped across a week. This spatial instability emerged around 6 weeks after status epilepticus, well after the onset of chronic seizures and interneuron death. Finally, CA1 network modeling showed that desynchronized inputs can impair the precision and stability of CA1 place cells. Together, these results demonstrate that temporally precise intrahippocampal communication is critical for spatial processing.
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http://dx.doi.org/10.1038/s41593-019-0559-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259114PMC
February 2020

Human Memories Can Be Linked by Temporal Proximity.

Front Hum Neurosci 2019 13;13:315. Epub 2019 Sep 13.

Department of Cognitive Sciences, University of California, Irvine, Irvine, CA, United States.

Real-world memories involve the integration of multiple events across time, yet the mechanisms underlying this integration is unknown. Recent rodent studies show that distinct memories encoded within a few hours, but not several days, share a common neural ensemble, and a common fate whereby later fear conditioning can transfer from one memory to the other. Here, we tested if distinct memories could be linked by temporal proximity in humans. 74 young adults encoded two memories (A and B) close (3-h) or far apart (7-day) in time. One day after encoding the second memory (B), Memory A was updated by pairing it with electric shock (i.e., fear conditioning). We tested whether the memory and fear associated with Memory B would be stronger in the 3-h, compared with the 7-day condition. Results were generally consistent with rodent studies, where we found heightened Memory B fear expression when the two memories were encoded close, but not far apart, in time. Furthermore, there was less forgetting of Memory B in the 3-h compared to 7-day condition. Our results suggest that temporally proximal memories may be linked, such that updating one experience updates the other.
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http://dx.doi.org/10.3389/fnhum.2019.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753892PMC
September 2019

Getting the full picture.

Elife 2019 03 26;8. Epub 2019 Mar 26.

Department of Neurobiology, University of California Los Angeles, Los Angeles, United States.

A combination of old and new techniques has revealed new details about the behavior of individual neurons across the sleep-wake-cycle.
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http://dx.doi.org/10.7554/eLife.46279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435316PMC
March 2019

Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory.

Sci Signal 2019 03 5;12(571). Epub 2019 Mar 5.

Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.

Mutations in RAS signaling pathway components cause diverse neurodevelopmental disorders, collectively called RASopathies. Previous studies have suggested that dysregulation in RAS-extracellular signal-regulated kinase (ERK) activation is restricted to distinct cell types in different RASopathies. Some cases of Noonan syndrome (NS) are associated with gain-of-function mutations in the phosphatase SHP2 (encoded by ); however, SHP2 is abundant in multiple cell types, so it is unclear which cell type(s) contribute to NS phenotypes. Here, we found that expressing the NS-associated mutant SHP2 in excitatory, but not inhibitory, hippocampal neurons increased ERK signaling and impaired both long-term potentiation (LTP) and spatial memory in mice, although endogenous SHP2 was expressed in both neuronal types. Transcriptomic analyses revealed that the genes encoding SHP2-interacting proteins that are critical for ERK activation, such as GAB1 and GRB2, were enriched in excitatory neurons. Accordingly, expressing a dominant-negative mutant of GAB1, which reduced its interaction with SHP2, selectively in excitatory neurons, reversed SHP2-mediated deficits. Moreover, ectopic expression of GAB1 and GRB2 together with SHP2 in inhibitory neurons resulted in ERK activation. These results demonstrate that RAS-ERK signaling networks are notably different between excitatory and inhibitory neurons, accounting for the cell type-specific pathophysiology of NS and perhaps other RASopathies.
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http://dx.doi.org/10.1126/scisignal.aau5755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800025PMC
March 2019

CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury.

Cell 2019 02;176(5):1143-1157.e13

Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA. Electronic address:

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.
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http://dx.doi.org/10.1016/j.cell.2019.01.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259116PMC
February 2019

All the light that we can see: a new era in miniaturized microscopy.

Nat Methods 2019 Jan;16(1):11-13

Department of Neurology, Integrative Center for Learning and Memory, Brain Research Institute, University of California, Los Angeles, CA, USA.

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http://dx.doi.org/10.1038/s41592-018-0266-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320687PMC
January 2019

The mouse as a model for neuropsychiatric drug development.

Curr Biol 2018 09;28(17):R909-R914

Departments of Neurobiology, Psychiatry & Biobehavioral Sciences and Psychology, Integrative Center for Learning and Memory, Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Much has been written about the validity of mice as a preclinical model for brain disorders. Critics cite numerous examples of apparently effective treatments in mouse models that failed in human clinical trials, raising the possibility that the two species' neurobiological differences could explain the high translational failure rate in psychiatry and neurology (neuropsychiatry). However, every stage of translation is plagued by complex problems unrelated to neurobiological conservation. Therefore, although these case studies are intriguing, they cannot alone determine whether these differences observed account for translation failures. Our analysis of the literature indicates that most neuropsychiatric treatments used in humans are at least partially effective in mouse models, suggesting that neurobiological differences are unlikely to be the main cause of neuropsychiatric translation failures.
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http://dx.doi.org/10.1016/j.cub.2018.07.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163022PMC
September 2018

Miniaturized two-photon microscope: seeing clearer and deeper into the brain.

Authors:
Alcino J Silva

Light Sci Appl 2017 Aug 25;6(8):e17104. Epub 2017 Aug 25.

Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, Integrative Center for Learning and Memory, University of California Los Angeles, Los Angeles, CA 90095, USA.

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http://dx.doi.org/10.1038/lsa.2017.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062320PMC
August 2017

ResearchMaps.org for integrating and planning research.

PLoS One 2018 3;13(5):e0195271. Epub 2018 May 3.

Department of Neurobiology, University of California Los Angeles, Los Angeles, California, United States of America.

To plan experiments, a biologist needs to evaluate a growing set of empirical findings and hypothetical assertions from diverse fields that use increasingly complex techniques. To address this problem, we operationalized principles (e.g., convergence and consistency) that biologists use to test causal relations and evaluate experimental evidence. With the framework we derived, we then created a free, open-source web application that allows biologists to create research maps, graph-based representations of empirical evidence and hypothetical assertions found in research articles, reviews, and other sources. With our ResearchMaps web application, biologists can systematically reason through the research that is most important to them, as well as evaluate and plan experiments with a breadth and precision that are unlikely without such a tool.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933701PMC
August 2018

Enhancement of Brain d-Serine Mediates Recovery of Cognitive Function after Traumatic Brain Injury.

J Neurotrauma 2018 07 30;35(14):1667-1680. Epub 2018 Apr 30.

2 Department of Pharmacology, Institute for Drug Research, Hebrew University , Jerusalem, Israel .

Cognitive deficits, especially memory loss, are common and devastating neuropsychiatric sequelae of traumatic brain injury (TBI). The deficits may persist for years and may be accompanied by increased risk of developing early- onset dementia. Past attempts to reverse the neuropathological effects of brain injury with glutamate-N-methyl-d-aspartate (NMDA) antagonists failed to show any benefits or worsened the outcome, suggesting that activation, rather than blockage, of the NMDA receptor (NMDAR) may be useful in the subacute period after TBI and stroke. Activation of the NMDAR requires occupation of the glycine-modulatory site by co-agonists to achieve its synaptic functions. Glycine and d-serine are endogenous ligands/co-agonists of synaptic NMDARs in many areas of the mature brain. The aim of the present study was to evaluate the effect of 6-chlorobenzo(d)isoxazol-3-ol (CBIO), an inhibitor of D-amino acid oxidase (DAAO), which degrades d-serine, on cognitive outcome in a mouse model of TBI. Because treating TBI animals with CBIO elevates the endogenous levels of d-serine, we compared this novel treatment with treatment by exogenous d-serine alone and combined with CBIO. The results show that a single treatment (24 h post-injury) with CBIO in the mouse model of closed head injury significantly improves cognitive and motor function, and decreases lesion volume and the inflammatory response. Moreover, the compound proved to be neuroprotective, as the hippocampal volume and the number of neurons in hippocampal regions increased. Treatment with CBIO boosted the NR1 and phospho- NR1 subunits of the NMDAR and affected the CREB, phospho-CREB, and brain-derived neurotropic factor (BDNF) pathways. These findings render CBIO a promising, novel treatment for cognitive impairment following TBI.
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http://dx.doi.org/10.1089/neu.2017.5561DOI Listing
July 2018

Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability.

Cell 2018 03;173(1):166-180.e14

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Center for Neuroengineering, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA; Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 22208, USA. Electronic address:

Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain.
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http://dx.doi.org/10.1016/j.cell.2018.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005365PMC
March 2018

Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA).

Mol Autism 2018 22;9:12. Epub 2018 Feb 22.

3Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Greater Manchester Mental Health NHS Foundation Trust, Room 3.311, Jean McFarlane Building, Oxford Road, Manchester, M13 9PL UK.

Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes.

Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression).

Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA ((12) = - 2.12,  = .055), GABA/Glx ratio ((12) = - 2.78,  = .016), and reduced grey nuclei Glx (ANCOVA < 0.05, Mann-Whitney < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney  < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney  < 0.01). Machine-learning classification of imaging outcomes achieved 79% ( < .05) accuracy differentiating groups at endpoint against chance level (64%,  = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome.

Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network.

Trial Registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu).
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http://dx.doi.org/10.1186/s13229-018-0190-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824534PMC
October 2018

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability.

Nat Neurosci 2018 03 12;21(3):309-314. Epub 2018 Feb 12.

Department of Biology, Brandeis University, Waltham, MA, USA.

The modification of synaptic strength produced by long-term potentiation (LTP) is widely thought to underlie memory storage. Indeed, given that hippocampal pyramidal neurons have >10,000 independently modifiable synapses, the potential for information storage by synaptic modification is enormous. However, recent work suggests that CREB-mediated global changes in neuronal excitability also play a critical role in memory formation. Because these global changes have a modest capacity for information storage compared with that of synaptic plasticity, their importance for memory function has been unclear. Here we review the newly emerging evidence for CREB-dependent control of excitability and discuss two possible mechanisms. First, the CREB-dependent transient change in neuronal excitability performs a memory-allocation function ensuring that memory is stored in ways that facilitate effective linking of events with temporal proximity (hours). Second, these changes may promote cell-assembly formation during the memory-consolidation phase. It has been unclear whether such global excitability changes and local synaptic mechanisms are complementary. Here we argue that the two mechanisms can work together to promote useful memory function.
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http://dx.doi.org/10.1038/s41593-018-0076-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915620PMC
March 2018

Hotspots of dendritic spine turnover facilitate clustered spine addition and learning and memory.

Nat Commun 2018 01 29;9(1):422. Epub 2018 Jan 29.

Department of Neurobiology; Integrative Center for Learning and Memory; Brain Research Institute, University of California, Los Angeles, CA, 90095, USA.

Modeling studies suggest that clustered structural plasticity of dendritic spines is an efficient mechanism of information storage in cortical circuits. However, why new clustered spines occur in specific locations and how their formation relates to learning and memory (L&M) remain unclear. Using in vivo two-photon microscopy, we track spine dynamics in retrosplenial cortex before, during, and after two forms of episodic-like learning and find that spine turnover before learning predicts future L&M performance, as well as the localization and rates of spine clustering. Consistent with the idea that these measures are causally related, a genetic manipulation that enhances spine turnover also enhances both L&M and spine clustering. Biophysically inspired modeling suggests turnover increases clustering, network sparsity, and memory capacity. These results support a hotspot model where spine turnover is the driver for localization of clustered spine formation, which serves to modulate network function, thus influencing storage capacity and L&M.
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http://dx.doi.org/10.1038/s41467-017-02751-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789055PMC
January 2018

Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes.

Mol Autism 2017 19;8:47. Epub 2017 Sep 19.

CiBIT, Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.

Background: Excitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased γ-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent.

Methods: In current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the mouse.

Results: Cortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism.

Conclusions: Our data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found.
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http://dx.doi.org/10.1186/s13229-017-0166-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605987PMC
May 2018

Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study.

Biol Psychiatry Cogn Neurosci Neuroimaging 2017 Mar;2(2):170-179

Semel Institute for Neuroscience and Human Behavior, University of California-Los Angeles.

Background: Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits.

Methods: Youth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes.

Results: Behaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1.

Conclusions: Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1.
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http://dx.doi.org/10.1016/j.bpsc.2016.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518467PMC
March 2017

Spatial working memory in neurofibromatosis 1: Altered neural activity and functional connectivity.

Neuroimage Clin 2017 27;15:801-811. Epub 2017 Jun 27.

Department of Psychology, University of California, Los Angeles, United States; Department of Psychiatry & Biobehavioral Sciences, University of California, Los Angeles, United States; Integrative Center for Learning and Memory, University of California, Los Angeles, United States. Electronic address:

Background: Neurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1.

Methods: BOLD images were acquired from 23 adults with NF1 (age  = 32.69; 61% male) and 25 matched healthy controls (age  = 33.08; 64% male) during an in-scanner visuo-spatial WM task. Whole brain functional and psycho-physiological interaction analyses were utilized to investigate neural activity and functional connectivity, respectively, during visuo-spatial WM performance. Participants also completed behavioral measures of spatial reasoning and verbal WM.

Results: Relative to healthy controls, participants with NF1 showed reduced recruitment of key components of WM circuitry, the left dorsolateral prefrontal cortex and right parietal cortex. In addition, healthy controls exhibited greater simultaneous deactivation between the posterior cingulate cortex (PCC) and temporal regions than NF1 patients. In contrast, NF1 patients showed greater PCC and bilateral parietal connectivity with visual cortices as well as between the PCC and the cerebellum. In NF1 participants, increased functional coupling of the PCC with frontal and parietal regions was associated with better spatial reasoning and WM performance, respectively; these relationships were not observed in controls.

Conclusions: Dysfunctional engagement of WM circuitry, and aberrant functional connectivity of 'task-negative' regions in NF1 patients may underlie spatial WM difficulties characteristic of the disorder.
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http://dx.doi.org/10.1016/j.nicl.2017.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501884PMC
June 2018

Viruses vector control proposal: genus Aedes emphasis.

Braz J Infect Dis 2017 Jul - Aug;21(4):457-463. Epub 2017 May 31.

Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address:

The dengue fever is a major public health problem in the world. In Brazil, in 2015, there were 1,534,932 cases, being 20,320 cases of severe form, and 811 deaths related to this disease. The distribution of Aedes aegypti, the vector, is extensive. Recently, Zika and Chikungunya viruses had arisen, sharing the same vector as dengue and became a huge public health issue. Without specific treatment, it is urgently required as an effective vector control. This article is focused on reviewing vector control strategies, their effectiveness, viability and economical impact. Among all, the Sterile Insect Technique is highlighted as the best option to be adopted in Brazil, once it is largely effectively used in the USA and Mexico for plagues related to agribusiness.
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http://dx.doi.org/10.1016/j.bjid.2017.03.020DOI Listing
August 2017

RESPECT TO HISTORY: VON PRESSER SYNDROME.

Arq Bras Cir Dig 2017 Jan-Mar;30(1):1-2

Professor Emérito da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil. Ex-Presidente do Colégio Brasileiro de Cirurgia Digestiva.

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http://dx.doi.org/10.1590/0102-6720201700010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424675PMC
January 2019

Noonan syndrome-associated SHP2 mutation differentially modulates the expression of postsynaptic receptors according to developmental maturation.

Neurosci Lett 2017 05 31;649:41-47. Epub 2017 Mar 31.

Dept of Medicine and Microbiology, College of Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea. Electronic address:

Glutamate is the major excitatory neurotransmitter in the central nervous system, and related signaling involves both AMPA and NMDA subtype receptors. The expression of glutamate receptors is dynamically regulated during development. Recent studies showed that the dysregulation of glutamate receptor expression and function is associated with neurodevelopmental disorders including intellectual disability. Previously, a Noonan syndrome (NS)-associated SHP2 mutation (SHP2) was shown to increase the synaptic delivery of AMPA receptor, subsequently impairing synaptic plasticity and learning in adult mice. However, how the mutant SHP2 affects glutamate receptor expression during development is not known. Here, we found that the SHP2 differentially regulates the expression of AMPA and NMDA receptors depending on the stage of neuronal maturation. In cultured neurons (immature stage; DIV 6), overexpression of SHP2 significantly increased the average size and the number of NMDA receptor-containing particles, but not those with AMPA receptors. In early matured neurons (DIV 12), SHP2 significantly increased only the average size of AMPA receptor particles, and subsequently increased their number in matured neurons (DIV 18). Importantly, all the changes described above for SHP2 neurons were reversed by inhibiting MAPK. These data demonstrate that the increased activation of MAPK signaling pathway by SHP2 could deregulate the surface expression of synaptic receptors during neuronal development, which likely contributes to cognitive impairments in NS patients.
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http://dx.doi.org/10.1016/j.neulet.2017.03.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844293PMC
May 2017

Computer-Aided Experiment Planning toward Causal Discovery in Neuroscience.

Front Neuroinform 2017 13;11:12. Epub 2017 Feb 13.

Medical Imaging Informatics Group, Department of Radiological Sciences, University of California, Los Angeles Los Angeles, CA, USA.

Computers help neuroscientists to analyze experimental results by automating the application of statistics; however, computer-aided experiment planning is far less common, due to a lack of similar quantitative formalisms for systematically assessing evidence and uncertainty. While ontologies and other Semantic Web resources help neuroscientists to assimilate required domain knowledge, experiment planning requires not only ontological but also epistemological (e.g., methodological) information regarding how knowledge was obtained. Here, we outline how epistemological principles and graphical representations of causality can be used to formalize experiment planning toward causal discovery. We outline two complementary approaches to experiment planning: one that quantifies evidence per the principles of convergence and consistency, and another that quantifies uncertainty using logical representations of constraints on causal structure. These approaches operationalize experiment planning as the search for an experiment that either maximizes evidence or minimizes uncertainty. Despite work in laboratory automation, humans must still plan experiments and will likely continue to do so for some time. There is thus a great need for experiment-planning frameworks that are not only amenable to machine computation but also useful as aids in human reasoning.
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http://dx.doi.org/10.3389/fninf.2017.00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304468PMC
February 2017

CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory.

Elife 2016 12 20;5. Epub 2016 Dec 20.

Departments of Neurobiology, Psychology, Psychiatry, Integrative Center for Learning and Memory and Brain Research Institute, University of California, Los Angeles, Los Angeles, United States.

Although the role of CCR5 in immunity and in HIV infection has been studied widely, its role in neuronal plasticity, learning and memory is not understood. Here, we report that decreasing the function of CCR5 increases MAPK/CREB signaling, long-term potentiation (LTP), and hippocampus-dependent memory in mice, while neuronal CCR5 overexpression caused memory deficits. Decreasing CCR5 function in mouse barrel cortex also resulted in enhanced spike timing dependent plasticity and consequently, dramatically accelerated experience-dependent plasticity. These results suggest that CCR5 is a powerful suppressor for plasticity and memory, and CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits. Consistent with this hypothesis, the HIV V3 peptide caused LTP, signaling and memory deficits that were prevented by Ccr5 knockout or knockdown. Overall, our results demonstrate that CCR5 plays an important role in neuroplasticity, learning and memory, and indicate that CCR5 has a role in the cognitive deficits caused by HIV.
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http://dx.doi.org/10.7554/eLife.20985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5213777PMC
December 2016

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1.

Neurology 2016 Dec 9;87(24):2575-2584. Epub 2016 Nov 9.

From the Murdoch Children's Research Institute (J.M.P., S.J.C.H., K.N.N.), Royal Children's Hospital; Department of Paediatrics (J.M.P., K.N.N.), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne; Children's Hospital Education Research Institute (B.B.), Children's Hospital at Westmead; Discipline of Paediatrics and Child Health (B.B.), University of Sydney, Australia; Department of Neurology (N.J.U., C.R.-C.), Boston Children's Hospital, MA; Department of Preventative Medicine (A.C.), School of Public Health (G.C.), Department of Psychology (J.D.A.), and Department of Genetics (B.K.), University of Alabama at Birmingham; Department of Neurology (T.R., S.H.O.), Children's Hospital of Los Angeles, CA; Center for Neuroscience and Behavioral Medicine (K.S.W., G.A.G., R.J.P., M.T.A.), Children's National Health System, Washington, DC; Pediatric Oncology Branch Center for Cancer Research (P.L.W.), National Cancer Institute, Bethesda, MD; Division of Neurology (J.T., S.J.H.), University of Chicago Medicine Comer Children's Hospital, IL; Human Genetics (E.S.) and Division of Neurology (A.W.B.), Cincinnati Children's Hospital Medical Center, OH; Department of Genetics (D.V.), University of Utah, Salt Lake City; Department of Pediatrics (L.K.), University of Texas Southwestern Medical Center, Dallas; Division of Oncology (M.F., C.L.A.), Children's Hospital of Philadelphia, PA; Department of Neurology (D.H.G., J.I.), Washington University School of Medicine in St Louis, MO; Gonda Neuroscience and Genetics Center (A.J.S.), University of California Los Angeles; Primary Children's Hospital (N.L.C.), Salt Lake City, UT; and University of Texas MD Anderson Cancer Center (P.L.S.), Houston.

Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1).

Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population.

Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo.

Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population.

Clinicaltrialsgov Identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493).

Classification Of Evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.
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http://dx.doi.org/10.1212/WNL.0000000000003435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207004PMC
December 2016
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