Alcino J. Silva

Last updated
Alcino J. Silva
Alcino Silva.jpg
Silva in 2008
Born
Alcino Jose Silva

(1961-04-09) April 9, 1961 (age 62)
Marco de Canaveses Municipality, Portugal
Alma mater Rutgers University
University of Utah
Massachusetts Institute of Technology
Known for Molecular cellular cognition of memory
Spouse(s)Tawnie Silva (2 children: Elenna Silva and Alexander Silva)
AwardsMedalha Marco Canavezes, Senior Roche Award for Translational Neuroscience, Order of Prince Henry, American Association for the Advancement of Science, UCLA Distinguished Professor
Scientific career
Fields Neuroscience, psychiatry, psychology
Institutions UCLA
Doctoral advisor Raymond White
Susumu Tonegawa (post doctoral)

Alcino J. Silva (born April 9, 1961) is a Portuguese-American neuroscientist who was the recipient of the 2008 Order of Prince Henry and elected as a fellow of the American Association for the Advancement of Science in 2013 for his contributions to the molecular cellular cognition of memory, a field he pioneered with the publication of two articles in Science in 1992. [1] [2]

Contents

Silva is a Distinguished Professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA, director of the Integrated Center for Learning and Memory at UCLA, and the Founding President of the Molecular and Cellular Cognition Society.

He is former scientific director of the Division of Intramural Research Programs at the National Institute of Mental Health, [3] having also served as member of the Board of Regents of the University of Minho, Portugal.

Early years

Silva was born in Portugal in 1961, but spent his early years in Luanda, Angola. He left Africa when he was 12 and in Portugal he went through the Carnation Revolution of 1974. He arrived in the United States in 1978, attended Rutgers University, where he studied biology and philosophy and worked in the Drosophila laboratory of William Sofer. After that he pursued graduate studies in human genetics at the University of Utah. There, he worked with Raymond White, one of the pioneers of modern human genetics.

His graduate work showed that epigenetic patterns of DNA methylation can be polymorphic and that they are inherited in a Mendelian fashion. [4] During his graduate studies he became intrigued by the inner processes of science, and organized yearly graduate symposia where leading scientists shared their insights on this subject. It was in Utah that he realized that he could combine his passion for biology with his interest in epistemology. [5] It was also in Utah, while working with Mario Capecchi, that he had the idea of bringing the newly developed mouse gene targeting approaches [6] to studies of memory. Capecchi shared the Nobel prize with Martin Evans and Oliver Smithies for the development of gene targeting strategies in mice. [7]

Post-doctoral work and early research at MIT

While at a meeting in Cold Spring Harbor Laboratory, Silva heard from Peter Mombaerts (now at the Max Planck Institute for Biophysics) that Susumu Tonegawa at MIT was interested in Neuroscience (Tonegawa had taken a Neuroscience course at CSHL in 1987), and that his lab was trying to set up gene targeting to study the immunology T-cell receptors they had cloned. [8] So, he wrote to Tonegawa and proposed to target genes expressed postnatally in the cerebellum to study cerebellar memory. At the time the Tonegawa laboratory at MIT was focused exclusively in immunology. Susumu Tomegawa was awarded a Nobel Prize in 1987 for his discovery of the genetic mechanism that produces antibody diversity. [9] Silva joined the Tonegawa laboratory in early fall of 1988.

After attending a Society for Neuroscience symposium (Toronto, 1988), organized by John Lisman on mechanisms of hippocampal plasticity, Silva decided to study hippocampal-dependent memory formation. The compelling properties of calcium calmodulin kinase II, one of the topics discussed in that symposium, and a model by John Lisman proposing a key role for that kinase in hippocampal learning and memory, [10] persuaded Silva to refocus his project in the Tonegawa laboratory on the role of the alpha calcium calmodulin kinase II in hippocampal synaptic plasticity and learning & memory. [1] [2] The two articles he published in Science as a post-doctural fellow in Susumu Tonegawa's laboratory were the first to combine molecular genetic techniques with electrophysiological analyses and behavioral studies. [11] This interdisciplinary integration of molecular, electrophysiological and behavioral approaches, fostered by transgenic techniques, has become a mainstay of neuroscience studies.

The Cold Spring Harbor Laboratory years

After spending three years in the Tonegawa laboratory, Silva set up his own laboratory at Cold Spring Harbor Laboratory in Long Island, New York, a research institute then run by James Watson, best known as the co-discoverer of the structure of DNA in 1953 with Francis Crick. Initially, the Silva laboratory focused its studies on molecular and cellular mechanisms of hippocampal learning and memory. For example, Rousudan Bourtchuladze led a project in the Silva laboratory that uncovered a role for the transcription factor CREB in the stability of hippocampal long term potentiation and long-term memory. [12] This was the first report of a genetic manipulation that affected the stability of synaptic plasticity and specifically long-. but not short-term memory. [13] Other notable studies of memory mechanisms in the early years of the Silva laboratory in Cold Spring Harbor included the discovery that hippocampal pre-synaptic short-term plasticity mechanisms have a role in hippocampal learning and memory. [14] This early work with hippocampal mutations that affected long term potentiation and learning & memory became the basis for a large literature that now has definitively implicated stable changes in synaptic plasticity in the hippocampal CA1 region in hippocampal dependent learning and memory. [15]

Move to UCLA

In 1998, the Silva laboratory moved to the Department of Neurobiology at the UCLA School of Medicine. There, the laboratory bridged their growing involvement in animal models of cognitive disorders with clinical studies. Additionally, UCLA's large and highly collaborative neuroscience community was an ideal environment for the interdisciplinary studies that characterized work in the Silva laboratory. The Silva laboratory became more involved in studying molecular and cellular mechanisms responsible for cognitive deficits in genetic neurodevelopmental disorders. In the late nineties, cognitive deficits associated with this class of disorders were thought to be caused by genetic disruptions of brain development [16] [17] Animal model studies of Neurofibromatosis type I (NF1) in the Silva lab suggested that the learning and memory deficits associated with NF1 mutations are caused by changes in synaptic plasticity mechanisms in adults. Accordingly, a project led by Rui M. Costa in the Silva Lab demonstrated that the electrophysiological, and more importantly the behavioral deficits, caused by NF1 mutations could be reversed in adults by manipulations that corrected the molecular signaling deficits associated with these mutations. [18] This discovery, and a series of later studies in many laboratories worldwide, have demonstrated the surprising efficacy of adult interventions in reversing cognitive phenotypes in animal models of neurodevelopmental disorders. [16] Following the NF1 studies published in 2002 by the Silva laboratory, [18] other findings that reported adult rescue of neurodevelopment disorders include, for example, animal studies of Lhermitte-Duclos disease [19] and Rubinstein-Taybi syndrome in 2003, [20] Fragile X syndrome in 2005, [21] Down syndrome in 2007, [22] Rett syndrome [23] and Angelman syndrome in 2007, [24] and Tuberous Sclerosis in 2008. [25]

Development of treatments for cognitive deficits in neurofibromatosis type I and tuberous sclerosis

Weidong Li and Steven Kushner led a team in the Silva lab that developed a treatment for the cognitive deficits associated with an animal model of Neurofibromatosis type I (NF1). [26] They discovered that Lovastatin, a statin that crosses the blood–brain barrier, at a dose that does not affect control mice, rescues the Ras/MAPK signaling, synaptic plasticity and behavioral deficits of mice with a NF1 mutation. [27] Statins decrease the levels of isoprenyls, lipid groups that are required for the isoprenylation and activity of Ras, [28] a signaling molecule normally regulated by the protein encoded by the NF1 gene. The work in the Silva lab showed that the NF1 mutation leads to increases in the levels of active Ras in the brain, and that statins reverse this increase without affecting Ras signaling in controls. These results have led to a number of small promising, but inconclusive, clinical trials, [29] [30] [31] and to two large ongoing clinical studies in the US and Europe. [32] [33] A team led by Dan Ehninger in the Silva lab also showed that rapamycin, an FDA approved inhibitor of mTOR, can reverse the late-LTP deficits and learning impairments they discovered in an animal model of Tuberous Sclerosis (Tsc2 heterozygous mice). [34] TSC is highly associated with autism, but the Tsc2 heterozygous mice did not show any autism-like behavioral abnormalities, such as social interaction deficits. Artificially activating the immune system of pregnant mice, however, does reveal social interaction deficits in Tsc2 heterozygous progeny, suggesting that the autism-like symptoms in TSC require not only Tsc mutations, but also another factor, such as immune activation during pregnancy. [35] Importantly, analyses of human TSC data suggested a similar interaction between the TSC mutation and immuno-activation during pregnancy. [35] Recently, Miou Zhou and colleagues at the Silva lab found that rapamycin is also capable of both preventing and reversing behavioral deficits caused by mutation of a schizophrenia-causing gene (DISC 1) in neurons that are born and develop in adult mice (i.e., adult neurogenesis). [36] Surprisingly, rapamycin reverses behavioral deficits despite its inability to reverse structural deficits discovered in neurons with Disc 1 knock down. All together, these findings make a compelling case that adult treatments may be effective at reversing behavioral cognitive and psychiatric symptoms associated with neurodevelopmental disorders such as NF1, TSC and schizophrenia. [37]

Mechanisms of remote memory

Until recently, research on molecular, cellular and system mechanisms of memory focused almost exclusively on the early stages (minutes, hours following training) of memory formation. Paul Frankland and colleagues in the Silva laboratory explored the molecular and cellular underpinnings of remote memory consolidation. They discovered one of the first molecular manipulations that disrupts specifically remote memory. [38] [39] Strikingly, the remote memory mutation they described disrupts synaptic plasticity in neocortex, but not in the hippocampus, a result consistent with models proposing that the hippocampus can only support memory for a short time, and that remote memory depends on neocortical storage sites. [38] Frankland and colleagues in the Silva lab also used a combination of genetic, imaging and reversible lesion approaches to search for regions in the neocortex that are involved in remote memory. [40] [41] These studies indicated that unlike the hippocampus, prefrontal cortical regions, such as the anterior cingulate, have a critical role in remote, but not in recent memory retrieval. [39] Altogether, these studies opened the door to unraveling the molecular and cellular mechanisms that are responsible for the long-term storage of information in the brain. Once again, studies in the Silva Laboratory revealed the critical role of synaptic plasticity in learning and memory, this time in cortical memory storage [42]

Discovery of neuronal memory allocation

A team led by Sheena Josselyn in the Silva Lab discovered that there are molecular and cellular mechanisms that regulate which neurons in a circuit encode a given memory (neuronal memory allocation). [43] They found that the transcription factor CREB modulates the probability that individual amygdala neurons become involved in storing a specific emotional memory: higher levels of CREB increase this probability while lower levels of CREB have the opposite effect. [44] Later, Yu Zhou and colleagues in the Silva lab discovered that CREB modulates memory allocation by regulating neuronal excitability. [45] These studies suggested that the mechanisms that consolidate one memory, for a limited period of time, may be involved in determining the allocation of the next memory, so that the two memories are associated or linked. [46]

In 2016, Denise Cai, a postdoctoral fellow in Silva's laboratory, led a team of scientists at UCLA and UCSD that discovered that mechanisms of memory allocation can be used to link memories across time. [43] [47] They showed that one memory triggers the activation of CREB and subsequent enhancements in excitability in a subset of neurons of a neuronetwork, so that a subsequent memory, even many hours later, can be directed or allocated to some of the same neurons that encoded the first memory. Later on, recall of the first memory triggers the activation of those neurons and therefore the reactivation and retrieval of the second memory. These results represent the first molecular, cellular and circuit mechanism underlying the linking of memories across time. These authors also showed that memory linking mechanisms are affected in the aging brain, and that manipulating excitability in a subset of neurons reverses these deficits. Impairments in CREB and neuronal excitability in aging likely underlie these abnormalities in memory linking. It is possible that problems with memory linking may underlie well-known source memory problems (source amnesia) associated with aging. In July 2018, Scientific American highlighted the Silva laboratory's discovery of Memory Allocation and Linking as one of "13 Discoveries that Could Change Everything." [48]

In 2022 Yang Shen, Miou Zhou and colleagues in the Silva lab discovered that the delayed expression of the receptor CCR5 closes the window of time in which two memories can be linked. [49] CCR5 activation results in a decrease in neuronal excitability, and this leads to a loss in the overlap between the memory ensembles in the hippocampus (CA1) that encode both memories, and consequently to a loss of memory linking. Without this memory ensemble overlap, the recall of one memory no longer triggers the recall of the other. Remarkably, these authors also found that increases in CCR5 underlie the age-related decline in memory linking that the Silva lab had discovered in 2016. [43] [47] Indeed, Maraviroc, an FDA approved CCR5 inhibitor, as well as a CCR5 genetic mutation, can reverse this age-related decline in memory linking. These results suggest the exciting possibility that drugs like Maraviroc may be useful for treating age-related decline in forms of memory that are related to memory linking, including source and relational memory. This discovery was extensively covered by the science and public press, including by a News and Views article in the Journal Nature.

ResearchMaps for integrating and planning research

The growth of the scientific literature in the last 20 years has been unprecedented. [50] For example, the library of medicine now includes more than two million Neuroscience articles. Anthony Landreth and Alcino Silva have developed a strategy to derive maps (simplified abstraction) of published articles in Neuroscience that they think could be used to integrate and summarize with more clarity and objectivity what we know, what we are uncertain about and what we do not know in neuroscience. [51] [52] [53] They propose that these maps of research findings would also be invaluable during experiment planning: Understanding more objectively the implications of the millions of neuroscience papers already published would allow neuroscientists to more clearly define what to do next. Landreth and Silva propose that quantitative maps of research findings will be to experiment planning in neuroscience what statistics is to experiment analyses: a tool that will help neuroscientists judge the likelihood that a series of planned experiments will contribute to the research record. As a first step towards the generation of these maps, Landreth and Silva developed a way to classify the millions of experiments in neuroscience into a small number of categories that are critical for the generation of these maps. To generate these maps, Landreth and Silva also developed a set of algorithms that formalize strategies neuroscientists use to determine the strength of evidence in their fields. These algorithms are used to represent the experiments in networks of causally connected phenomena (i.e., research maps). Pranay Doshi and colleagues in the Silva Lab developed a free app that helps researchers generate these maps. [54] Data from individual research articles is entered into a relational database, and the app can generate maps not only for experimental findings in single research articles, but also for combinations of findings associated with different articles. The user can query the app and make specific maps that can then be used for experiment planning.

Awards

Selected publications

Related Research Articles

<span class="mw-page-title-main">Dendritic spine</span> Small protrusion on a dendrite that receives input from a single axon

A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head, and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons. It has also been suggested that changes in the activity of neurons have a positive effect on spine morphology.

<span class="mw-page-title-main">Long-term potentiation</span> Persistent strengthening of synapses based on recent patterns of activity

In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.

In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

<span class="mw-page-title-main">Fear conditioning</span> Behavioral paradigm in which organisms learn to predict aversive events

Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus is associated with a particular neutral context or neutral stimulus, resulting in the expression of fear responses to the originally neutral stimulus or context. This can be done by pairing the neutral stimulus with an aversive stimulus. Eventually, the neutral stimulus alone can elicit the state of fear. In the vocabulary of classical conditioning, the neutral stimulus or context is the "conditional stimulus" (CS), the aversive stimulus is the "unconditional stimulus" (US), and the fear is the "conditional response" (CR).

An engram is a unit of cognitive information imprinted in a physical substance, theorized to be the means by which memories are stored as biophysical or biochemical changes in the brain or other biological tissue, in response to external stimuli.

<span class="mw-page-title-main">Adult neurogenesis</span> Generating of neurons from neural stem cells in adults

Adult neurogenesis is the process in which neurons are generated from neural stem cells in the adult. This process differs from prenatal neurogenesis.

<span class="mw-page-title-main">Place cell</span> Place-activated hippocampus cells found in some mammals

A place cell is a kind of pyramidal neuron in the hippocampus that becomes active when an animal enters a particular place in its environment, which is known as the place field. Place cells are thought to act collectively as a cognitive representation of a specific location in space, known as a cognitive map. Place cells work with other types of neurons in the hippocampus and surrounding regions to perform this kind of spatial processing. They have been found in a variety of animals, including rodents, bats, monkeys and humans.

<span class="mw-page-title-main">Susumu Tonegawa</span> Japanese scientist (born 1939)

Susumu Tonegawa is a Japanese scientist who was the sole recipient of the Nobel Prize for Physiology or Medicine in 1987 for his discovery of V(D)J recombination, the genetic mechanism which produces antibody diversity. Although he won the Nobel Prize for his work in immunology, Tonegawa is a molecular biologist by training and he again changed fields following his Nobel Prize win; he now studies neuroscience, examining the molecular, cellular and neuronal basis of memory formation and retrieval.

<span class="mw-page-title-main">Neurofibromin 1</span> Mammalian protein found in Homo sapiens

neurofibromatosis 1 (NF1) is a gene in humans that is located on chromosome 17. NF1 codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations in NF1 can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

Ca<sup>2+</sup>/calmodulin-dependent protein kinase II

Ca2+
/calmodulin-dependent protein kinase II is a serine/threonine-specific protein kinase that is regulated by the Ca2+
/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca2+
 homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation.

Molecular cellular cognition (MCC) is a branch of neuroscience that involves the study of cognitive processes with approaches that integrate molecular, cellular and behavioral mechanisms. Key goals of MCC studies include the derivation of molecular and cellular explanations of cognitive processes, as well as finding mechanisms and treatments for cognitive disorders.

Tobias Bonhoeffer is a German-American neurobiologist. He is director of the department Synapses – Circuits – Plasticity and current managing director at the Max Planck Institute for Biological Intelligence. His father, the neurobiologist Friedrich Bonhoeffer, was director at the Max Planck Institute for Developmental Biology in Tübingen.

<span class="mw-page-title-main">Environmental enrichment</span> Brain stimulation through physical and social surroundings

Environmental enrichment is the stimulation of the brain by its physical and social surroundings. Brains in richer, more stimulating environments have higher rates of synaptogenesis and more complex dendrite arbors, leading to increased brain activity. This effect takes place primarily during neurodevelopment, but also during adulthood to a lesser degree. With extra synapses there is also increased synapse activity, leading to an increased size and number of glial energy-support cells. Environmental enrichment also enhances capillary vasculation, providing the neurons and glial cells with extra energy. The neuropil expands, thickening the cortex. Research on rodent brains suggests that environmental enrichment may also lead to an increased rate of neurogenesis.

<span class="mw-page-title-main">Eric J. Nestler</span> Neuroscientist of addiction and depression

Eric J. Nestler is the Nash Family Professor of Neuroscience, Director of the Friedman Brain Institute, and Dean for Academic Affairs at the Icahn School of Medicine at Mount Sinai and Chief Scientific Officer of the Mount Sinai Health System. His research is focused on a molecular approach to drug addiction and depression.

The cellular transcription factor CREB helps learning and the stabilization and retrieval of fear-based, long-term memories. This is done mainly through its expression in the hippocampus and the amygdala. Studies supporting the role of CREB in cognition include those that knock out the gene, reduce its expression, or overexpress it.

Memory allocation is a process that determines which specific synapses and neurons in a neural network will store a given memory. Although multiple neurons can receive a stimulus, only a subset of the neurons will induce the necessary plasticity for memory encoding. The selection of this subset of neurons is termed neuronal allocation. Similarly, multiple synapses can be activated by a given set of inputs, but specific mechanisms determine which synapses actually go on to encode the memory, and this process is referred to as synaptic allocation. Memory allocation was first discovered in the lateral amygdala by Sheena Josselyn and colleagues in Alcino J. Silva's laboratory.

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to play an important role in learning and memory.

<span class="mw-page-title-main">Deficiency of RbAp48 protein and memory loss</span>

Memory is commonly referred to as the ability to encode, store, retain and subsequently recall information and past experiences in the human brain. This process involves many proteins, one of which is the Histone-binding protein RbAp48, encoded by the RBBP4 gene in humans.

Hippocampal replay is a phenomenon observed in rats, mice, cats, rabbits, songbirds and monkeys. During sleep or awake rest, replay refers to the re-occurrence of a sequence of cell activations that also occurred during activity, but the replay has a much faster time scale. It may be in the same order, or in reverse. Cases were also found where a sequence of activations occurs before the actual activity, but it is still the same sequence. This is called preplay.

Attila Losonczy is a Hungarian neuroscientist, Professor of Neuroscience at Columbia University Medical Center. Losonczy's main area of research is on the relationship between neural networks and behavior, specifically with regard to learning in the hippocampus.

References

  1. 1 2 Silva AJ, Paylor R, Wehner JM, Tonegawa S (1992). "Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice". Science. 257 (5067): 206–11. Bibcode:1992Sci...257..206S. doi:10.1126/science.1321493. PMID   1321493.
  2. 1 2 Silva AJ, Stevens CF, Tonegawa S, Wang Y (1992). "Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice". Science. 257 (5067): 201–6. Bibcode:1992Sci...257..201S. doi:10.1126/science.1378648. PMID   1378648.
  3. ↑ "New Division Directors Come on Board at NIMH". Archived from the original on 2013-05-02.
  4. ↑ Silva, A.J.; White, R. (1988). "Inheritance of allelic blueprints for methylation patterns". Cell. 54 (2): 145–52. doi:10.1016/0092-8674(88)90546-6. PMID   2898978. S2CID   2115543.
  5. ↑ Silva, A.J. and R. White, Thesis for a Ph.D. in the Department of Human Genetics, University of Utah: The genetics of human methylation. UMI, Bell and Howell Information Company, #3058. 1989.
  6. ↑ Thomas, K. R.; Capecchi, M. R. (1987). "Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells". Cell. 51 (3): 503–512. doi:10.1016/0092-8674(87)90646-5. PMID   2822260. S2CID   31961262.
  7. ↑ "The Nobel Prize in Physiology or Medicine 2007". Nobelprize.org. Retrieved 2007-10-08.
  8. ↑ Mombaerts, P.; Clarke, A. R.; et al. (1992). "Mutations in T-cell antigen receptor genes alpha and ß block thymocyte development at different stages". Nature. 360 (6401): 225–231. doi:10.1038/360225a0. PMID   1359428. S2CID   4319983.
  9. ↑ "The MIT 150: 150 Ideas, Inventions, and Innovators that Helped Shape Our World". The Boston Globe. May 15, 2011. Retrieved August 8, 2011.
  10. ↑ Lisman, J. E.; Goldring, M. A. (1988). "Feasibility of long-term storage of graded information by the Ca2+/calmodulin-dependent protein kinase molecules of the postsynaptic density". Proc Natl Acad Sci U S A. 85 (14): 5320–5324. Bibcode:1988PNAS...85.5320L. doi: 10.1073/pnas.85.14.5320 . PMC   281742 . PMID   3393540.
  11. ↑ Grant, S.G. and A.J. Silva, Targeting learning. Trends Neurosci 1994; 17(2): p. 71-5.
  12. ↑ Bourtchuladze, R.; Frenguelli, B.; Blendy, J.; Cioffi, D.; Schutz, G.; Silva, A.J. (1994). "Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein". Cell. 79 (1): 59–68. doi:10.1016/0092-8674(94)90400-6. PMID   7923378. S2CID   17250247.
  13. ↑ Silva, A.J.; Kogan, J.H.; Frankland, P.W.; Kida, S. (1998). "CREB and memory". Annu Rev Neurosci. 21: 127–48. doi:10.1146/annurev.neuro.21.1.127. PMID   9530494. S2CID   15836689.
  14. ↑ Silva, A.J.; Rosahl, T.W.; Chapman, P.F.; Marowitz, Z.; Friedman, E.; Frankland, P.W.; Cestari, V.; Cioffi, D.; Sudhof, T.C.; Bourtchuladze, R. (1996). "Impaired learning in mice with abnormal short-lived plasticity". Curr Biol. 6 (11): 1509–18. doi: 10.1016/s0960-9822(96)00756-7 . PMID   8939606.
  15. ↑ Lee, Y-S; Silva, AJ (Feb 2009). "The molecular and cellular biology of enhanced cognition". Nat Rev Neurosci. 10 (2): 126–40. doi:10.1038/nrn2572. PMC   2664745 . PMID   19153576.
  16. 1 2 Ehninger, D., Li, W, Fox, K, Stryker, MP, and Silva, AJ. Reversing neurodevelopmental disorders in adults. Neuron 2008;60(6):950-60. PMC   2710296.
  17. ↑ Castren, E.; Elgersma, Y.; et al. (2012). "Treatment of neurodevelopmental disorders in adulthood". The Journal of Neuroscience. 32 (41): 14074–14079. doi:10.1523/jneurosci.3287-12.2012. PMC   3500763 . PMID   23055475.
  18. 1 2 Costa, R.M.; Federov, N.B.; Kogan, J.H.; Murphy, G.G.; Stern, J.; Ohno, M.; Kucherlapati, R.; Jacks, T.; Silva, A.J. (2002). "Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1". Nature. 415 (6871): 526–30. doi:10.1038/nature711. PMID   11793011. S2CID   4342613.
  19. ↑ Kwon, C. H.; Zhu, X.; Zhang, J.; Baker, S. J. (2003). "mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo". Proc Natl Acad Sci U S A. 100 (22): 12923–12928. Bibcode:2003PNAS..10012923K. doi: 10.1073/pnas.2132711100 . PMC   240720 . PMID   14534328.
  20. ↑ Bourtchouladze, R.; Lidge, R.; Catapano, R.; Stanley, J.; Gossweiler, S.; Romashko, D.; Scott, R.; Tully, T. (2003). "A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4". Proc Natl Acad Sci U S A. 100 (18): 10518–10522. Bibcode:2003PNAS..10010518B. doi: 10.1073/pnas.1834280100 . PMC   193593 . PMID   12930888.
  21. ↑ McBride, S. M.; Choi, C. H.; Wang, Y.; Liebelt, D.; Braunstein, E.; Ferreiro, D.; Sehgal, A.; Siwicki, K. K.; Dockendorff, T. C.; Nguyen, H. T.; et al. (2005). "Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome". Neuron. 45 (5): 753–764. doi: 10.1016/j.neuron.2005.01.038 . PMID   15748850.
  22. ↑ Fernandez, F.; Morishita, W.; Zuniga, E.; Nguyen, J.; Blank, M.; Malenka, R. C.; Garner, C. C. (2007). "Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome". Nat Neurosci. 10 (4): 411–413. doi:10.1038/nn1860. PMID   17322876. S2CID   29468421.
  23. ↑ Guy, J.; Gan, J.; Selfridge, J.; Cobb, S.; Bird, A. (2007). "Reversal of neurological defects in a mouse model of Rett syndrome". Science. 315 (5815): 1143–1147. Bibcode:2007Sci...315.1143G. doi:10.1126/science.1138389. PMC   7610836 . PMID   17289941. S2CID   25172134.
  24. ↑ Van Woerden, G. M.; Harris, K. D.; Hojjati, M. R.; Gustin, R. M.; Qiu, S.; de Avila Freire, R.; Jiang, Y. H.; Elgersma, Y.; Weeber, E. J. (2007). "Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation". Nat Neurosci. 10 (3): 280–282. doi:10.1038/nn1845. hdl: 1765/9252 . PMID   17259980. S2CID   17162315.
  25. ↑ Ehninger, D.; Han, S.; Shilyansky, C.; Zhou, Y.; Li, W.; Kwiatkowski, D. J.; Ramesh, V.; Silva, A. J. (2008). "Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis". Nat Med. 14 (8): 843–848. doi:10.1038/nm1788. PMC   2664098 . PMID   18568033.
  26. ↑ Li, W.; Cui, Y.; Kushner, S.A.; Brown, R.A.; Jentsch, J.D.; Frankland, P.W.; Cannon, T.D.; Silva, A.J. (2005). "The HMG-CoA reductase inhibitor lovastatin (U.S. Food and Drug Administration (FDA) approved) reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1". Curr Biol. 15 (21): 1961–7. doi: 10.1016/j.cub.2005.09.043 . PMID   16271875.
  27. ↑ Cui, Y; Costa, RM; Murphy, GG; Elgersma, Y; Zhu, Y; Gutmann, DH; Parada, LF; Mody, I; Silva, AJ (2008). "Neurofibromin regulation of ERK signaling modulates GABA release and learning". Cell. 135 (3): 549–560. doi:10.1016/j.cell.2008.09.060. PMC   2673196 . PMID   18984165.
  28. ↑ Sebti, SM; Tkalcevic, GT; Jani, JP (1991). "Lovastatin, a cholesterol biosynthesis inhibitor, inhibits the growth of human H-ras oncogene transformed cells in nude mice". Cancer Commun. 3 (5): 141–147. doi:10.3727/095535491820873371. PMID   2043425.
  29. ↑ Krab, L.C.; Aarsen, F.K.; Pluijm, S.M.; Bouman, M.J.; Lequin, M.; Catsman, C.E.; Arts, W.F.; Kushner, S.A.; Silva, A.J.; Moll, H.A.; Elgersma, Y. (2008). "Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial". JAMA. 300 (3): 287–94. doi:10.1001/jama.300.3.287. PMC   2664742 . PMID   18632543.
  30. ↑ Chabernaud, C; Mennes, M; Kardel, PG; Gaillard, WD; Kalbfleisch, ML; Vanmeter, JW; Packer, RJ; Milham, MP; Castellanos, FX; Acosta, MT (Apr 2012). "Lovastatin regulates brain spontaneous low-frequency brain activity in neurofibromatosis type 1". Neurosci. Lett. 515 (1): 28–33. doi:10.1016/j.neulet.2012.03.009. PMC   3363969 . PMID   22433254.
  31. ↑ Acosta, MT; Kardel, PG; Walsh, KS; Rosenbaum, KN; Gioia, GA; Packer, RJ (Oct 2011). "Lovastatin as treatment for neurocognitive deficits in neurofibromatosis type 1: phase I study". Pediatr Neurol. 45 (4): 241–5. doi:10.1016/j.pediatrneurol.2011.06.016. PMID   21907886.
  32. ↑ Acosta, MT; Bearden, CE; Castellanos, XF; Cutting, L; Elgersma, Y; Gioia, G; Gutmann, DH; Lee, YS; Legius, E; Muenke, M; North, K; Parada, LF; Ratner, N; Hunter-Schaedle, K; Silva, AJ (2012). "The Learning Disabilities Network (LeaDNet): Using neurofibromatosis type 1 (NF1) as a paradigm for translational research". American Journal of Medical Genetics. 158A (9): 2225–32. doi:10.1002/ajmg.a.35535. PMC   4074877 . PMID   22821737.
  33. ↑ Gutmann, DH; Parada, LF; Silva, AJ; Ratner, N (2012). "Neurofibromatosis type 1: modeling CNS dysfunction". J Neurosci. 32 (41): 14087–93. doi:10.1523/JNEUROSCI.3242-12.2012. PMC   3477849 . PMID   23055477.
  34. ↑ Ehninger, D.; Han, S.; Shilyansky, C.; Zhou, Y.; Li, W.; Kwiatkowski, D.J.; Ramesh, V.; Silva, A.J. (2008). "Reversal of learning deficits in a Tsc2(+/-) mouse model of tuberous sclerosis". Nat Med. 14 (8): 843–848. doi:10.1038/nm1788. PMC   2664098 . PMID   18568033.
  35. 1 2 Ehninger, D.; Sano, Y.; Dies, K.; Franz, D.; Geschwind, D.H.; Kaur, M.; Lee, Y.S.; Li, W.; Lowe, J.K.; Nakagawa, J.A.; Sahin, M.; Smith, K.; Whittemore, V.; Silva, A.J. (2012). "Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice". Molecular Psychiatry. 17 (1): 62–70. doi:10.1038/mp.2010.115. PMC   3118259 . PMID   21079609.
  36. ↑ Zhou, M; Li, W; Huang, S; Song, J; Kim, J Tian; Kang, E Sano; Liu, C; Balaji, J; Wu, S; Zhou, Y; Zhou, Y; Parivash, S; Ehninger, D; He, L. Song; Ming, G; Silva, AJ (2013). "mTOR Inhibition Ameliorates Cognitive and Affective Deficits Caused by Disc1 Knockdown Specifically in Adult-Born Dentate Granule Neurons". Neuron. 77 (4): 647–654. doi:10.1016/j.neuron.2012.12.033. PMC   3586374 . PMID   23439118.
  37. ↑ Ehninger, D.; Li, W; Fox, K; Stryker, MP; Silva, AJ. (2008). "Reversing neurodevelopmental disorders in adults". Neuron. 60 (6): 950–60. doi:10.1016/j.neuron.2008.12.007. PMC   2710296 . PMID   19109903.
  38. 1 2 Frankland, P.W.; O'Brien, C.; Ohno, M.; Kirkwood, A.; Silva, A.J. (2001). "Alpha-CaMKII-dependent plasticity in the cortex is required for permanent memory". Nature. 411 (6835): 309–13. Bibcode:2001Natur.411..309F. doi:10.1038/35077089. PMID   11357133. S2CID   4384100.
  39. 1 2 Frankland, P.W.; Bontempi, B.; Talton, L.E.; Kaczmarek, L.; Silva, A.J. (2004). "The involvement of the anterior cingulate cortex in remote contextual fear memory". Science. 304 (5672): 881–3. Bibcode:2004Sci...304..881F. doi:10.1126/science.1094804. PMID   15131309. S2CID   15893863.
  40. ↑ Bontempi, B.; Laurent-Demir, C.; et al. (1999). "Time-dependent reorganization of brain circuitry underlying long-term memory storage". Nature. 400 (6745): 671–675. Bibcode:1999Natur.400..671B. doi:10.1038/23270. PMID   10458162. S2CID   4400591.
  41. ↑ Frankland, P.; Bontempi, B.; et al. (2004). "The involvement of the anterior cingulate cortex in remote contextual fear memory". Science. 304 (5672): 881–3. Bibcode:2004Sci...304..881F. doi:10.1126/science.1094804. PMID   15131309. S2CID   15893863.
  42. ↑ Frankland, P. W.; Bontempi, B. (2005). "The organization of recent and remote memories". Nat Rev Neurosci. 6 (2): 119–130. doi:10.1038/nrn1607. PMID   15685217. S2CID   1115019.
  43. 1 2 3 Silva, A.J. (2017). "Memory's Intricate Web". Sci Am. 317 (1): 30–37. Bibcode:2017SciAm.317a..30S. doi:10.1038/scientificamerican0717-30. PMC   5915626 . PMID   28632232.
  44. ↑ Han, J.H.; Kushner, S.A.; Yiu, A.P.; Cole, C.J.; Matynia, A.; Brown, R.A.; Neve, R.L.; Guzowski, J.F.; Silva, A.J.; Josselyn, S.A. (2007). "Neuronal competition and selection during memory formation". Science. 316 (5823): 457–60. Bibcode:2007Sci...316..457H. doi:10.1126/science.1139438. PMID   17446403. S2CID   8460538.
  45. ↑ Zhou, Y; Won, J.; Karlsson, M.G. Zhou; Rogerson, T; Balaji, J.; Neve, R.; Poirazi, P.; Silva, A.J. (2009). "CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala". Nature Neuroscience. 12 (11): 1438–43. doi:10.1038/nn.2405. PMC   2783698 . PMID   19783993.
  46. ↑ Silva, A.J.; Zhou, Y; Rogerson, T; Shobe, J; Balaji, J. (2009). "Molecular and Cellular Approaches to Memory Allocation in Neural Circuits". Science. 326 (5951): 391–5. doi:10.1126/science.1174519. PMC   2844777 . PMID   19833959.
  47. 1 2 Cai DJ, Aharoni D, Shuman T, Shobe J, Biane J, Song W, Wei B, Veshkini M, La-Vu M, Lou J, Flores S, Kim I, Sano Y, Zhou M, Baumgaertel K, Lavi A, Kamata M, Tuszynski M, Mayford M, Golshani P, Silva AJ. A shared neural ensemble links distinct contextual memories encoded close in time. Nature 2016 May 23;534(7605):115-8
  48. ↑ Silva, AJ How one memory attaches to another. In Revolutions in Science: Discoveries that could change everything. Scientific American; July 2018, Volume 27, Issue 3s
  49. ↑ Shen, Y; Zhou, M; Cai, D; Almeida, Filho D; Fernandes, G; Cai, Y; Kim, N; Necula, D; Zhou, C; Liu, A; Kang, X; Kamata, M; Lavi, A; Huang, S; Silva, TK; Heo, WD; Silva, AJ (June 2022). "CCR5 closes the temporal window for memory linking". Nature . 606 (7912): 146–152. Bibcode:2022Natur.606..146S. doi:10.1038/s41586-022-04783-1. PMC   9197199 . PMID   35614219.
  50. ↑ Szalay, A; Gray, J (2006). "2020 Computing: Science in an exponential world". Nature. 440 (7083): 413–414. Bibcode:2006Natur.440..413S. doi:10.1038/440413a. hdl: 1885/46877 . PMID   16554783. S2CID   4360446.
  51. ↑ Silva, AJ; Müller, KR (Aug 2015). "The need for novel informatics tools for integrating and planning research in molecular and cellular cognition". Learn. Mem. 22 (9): 494–8. doi:10.1101/lm.029355.112. PMC   4561409 . PMID   26286658.
  52. ↑ Landreth, A; Silva, AJ (2013). "The need for research maps to navigate published work and inform experiment planning". Neuron. 79 (3): 411–5. doi: 10.1016/j.neuron.2013.07.024 . PMID   23931992.
  53. ↑ Bickle, J. and Silva, A. (2008). Intimology and the Search for the Molecular Mechanisms of Cognitive Functions. Bickle, J. (Eds.), Oxford Handbook of Philosophy and Neuroscience. Oxford: Oxford University Press
  54. ↑ "ResearchMaps". www.researchmaps.org. Retrieved 2022-02-23.
  55. ↑ "Alcino Silva". Arnold and Mabel Beckman Foundation. Retrieved 9 March 2017.
  56. ↑ "Senior Roche Award 2009 Press Release".
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.