Alcino Silva

Alcino Silva
University of California, Los Angeles | UCLA · Department of Neurobiology

Ph.D.

About

306
Publications
37,913
Reads
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Introduction
The goal of my lab (www.silvalab.org) is to derive explanations of cognitive processes that integrate molecular, cellular, circuit and behavioral mechanisms, as well as to leverage this information to treat cognitive disorders and accelerate recovery. We are also developing strategies (www.researchmaps.org) to optimize the process of integrating and planning experiments.
Additional affiliations
May 2015 - present
University of California, Los Angeles
Position
  • UCLA Distinguished Professor
May 1998 - May 2015
University of California, Los Angeles
Position
  • Professor (Full)
May 1998 - present
Integrative Center for Learning and Memory
Position
  • Managing Director
Description
  • UCLA’s Integrative Center for Learning and Memory (ICLM) includes a diverse, highly collaborative community of neuroscientists exploring some of the most fundamental questions of learning and memory

Publications

Publications (306)
Article
Full-text available
Systems neuroscience is focused on how ensemble properties in the brain, such as the activity of neuronal circuits, gives rise to internal brain states and behavior. Many of the studies in this field have traditionally involved electrophysiological recordings and computational approaches that attempt to decode how the brain transforms inputs into f...
Article
Full-text available
A kind of “ruthless reductionism” characterized the experimental practices of the first two decades of molecular and cellular cognition (MCC). More recently, new research tools have expanded experimental practices in this field, enabling researchers to image and manipulate individual molecular mechanisms in behaving organisms with an unprecedented...
Article
Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we sh...
Article
Full-text available
Real-world memories are formed in a particular context and are often not acquired or recalled in isolation1–5. Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not1–4. How the brain segrega...
Article
Background Tuberous Sclerosis Complex (TSC) is a genetic disorder associated with high rates of intellectual disability and autism. Mice with a heterozygous null mutation of the Tsc2 gene (Tsc2+/-), show deficits in hippocampal dependent tasks, as well as abnormal long-term potentiation (LTP) in the hippocampal CA1 region. Although previous studies...
Article
Most commonly used behavioral measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal's residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal's performance. Here, we describe novel measures of performance in the MWM that...
Preprint
Full-text available
We present a large field of view (FOV) open-source miniature microscope (MiniLFOV) designed to extend the capabilities of the UCLA Miniscope platform to large-scale, single cell resolution neural imaging in freely behaving large rodents and head-fixed mice. This system is capable of multiple imaging configurations, including deep brain imaging usin...
Preprint
Events occurring close in time are often linked in memory, providing an episodic timeline and a framework for those memories. Recent studies suggest that memories acquired close in time are encoded by overlapping neuronal ensembles, but whether dendritic plasticity plays a role in linking memories is unknown. Using activity-dependent labeling and m...
Preprint
Memories engage ensembles of neurons across different brain regions within a memory system. However, it is unclear whether the allocation of a memory to these ensembles is coordinated across brain regions. To address this question, we used CREB expression to bias memory allocation in one brain region, and rabies retrograde tracing to test memory al...
Preprint
Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on temporary increase in excitability that drive the overlap between dorsal CA1 (dCA1) hippocampal ensembles encoding the linked memories. Here, we show tha...
Preprint
Full-text available
Real world memories are formed in a particular context and are not acquired or recalled in isolation ¹⁻⁵ . Time is a key variable in the organization of memories, since events experienced close in time are more likely to be meaningfully associated, while those experienced with a longer interval are not ¹⁻⁴ . How does the brain segregate events that...
Preprint
Tuberous Sclerosis Complex (TSC) is a genetic disorder associated with high rates of intellectual disability and autism. Although previous studies focused on the role of neuronal deficits in the memory phenotypes of rodent models of TSC, the results presented here demonstrate a role for microglia in these deficits. Mice with a heterozygous null mut...
Article
Full-text available
There is growing evidence that prenatal immune activation contributes to neuropsychiatric disorders. Here, we show that early postnatal immune activation resulted in profound impairments in social behavior, including in social memory in adult male mice heterozygous for a gene responsible for tuberous sclerosis complex (Tsc2 +/−), a genetic disorder...
Preprint
Full-text available
Most commonly used behavioural measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal s residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal s performance. Here, we describe novel measures of performance in the MWM that...
Article
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 sl...
Article
Aim: Chemokine receptor CCR5 was recently found to be a negative modulator of learning and memory. Its inhibition improved outcome after stroke and TBI. To better understand its role after TBI, we investigated the effect of reduced CCR5 signaling as a neuroprotective strategy, and the temporal changes of CCR5 expression after TBI in different brai...
Article
Full-text available
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...
Article
Full-text available
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 t...
Article
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 w...
Article
We tested a newly described molecular memory sys-tem, CCR5 signaling, for its role in recovery afterstroke and traumatic brain injury (TBI). CCR5 isuniquely 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 dendri...
Article
One major challenge in neuroscience is to uncover how defined neural circuits in the brain encode, store, modify, and retrieve information. Meeting this challenge comprehensively requires tools capable of recording and manipulating the activity of intact neural networks in naturally behaving animals. Head-mounted miniature microscopes are emerging...
Article
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...
Preprint
Temporal lobe epilepsy causes significant cognitive deficits in both human patients and rodent models, yet the specific circuit mechanisms that alter cognitive processes remain unknown. There is dramatic and selective interneuron death and axonal reorganization within the hippocampus of both humans and animal models, but the functional consequences...
Presentation
Full-text available
Grant Funding: NRSA F31M102999, U.S. Army Department of Defense W81XWH-12-1-0081
Article
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 glo...
Article
Full-text available
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 dynami...
Chapter
The formation, stabilization, and editing of memory engrams has been a subject of active research in neuroscience. By comparison, little is known regarding the mechanisms that determine which synapses and neurons (synaptic and neuronal allocation, respectively) go on to encode a given memory. Memory allocation mechanisms are critical for controllin...
Article
Full-text available
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 neur...
Poster
Full-text available
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by a mutation of the neurofibromin gene on chromosome 17. It is associated with a range of both physical complications and cognitive deficits. Individuals with NF1 have cognitive dysfunction in the areas of attention, executive function, and visuospatial learning, which...
Article
Full-text available
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-Le...
Article
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 neurod...
Data
Full names and MGI accession # of the 148 mutant strains in the reverse genetic memory screen (*Jax stock#: 370200; **Jax stock#: 370202).DOI: http://dx.doi.org/10.7554/eLife.20985.003
Article
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...
Article
Full-text available
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 Tr...
Article
Full-text available
Memories are believed to be stored in distributed neuronal assemblies through activity-induced changes in synaptic and intrinsic properties. However, the specific mechanisms by which different memories become associated or linked remain a mystery. Here, we develop a simplified, biophysically inspired network model that incorporates multiple plastic...
Article
Full-text available
Recent findings suggest that memory allocation to specific neurons (i.e., neuronal allocation) in the amygdala is not random, but rather the transcription factor cAMP-response element binding protein (CREB) modulates this process, perhaps by regulating the transcription of channels that control neuronal excitability. Here, optogenetic studies in th...
Article
Neurofibromatosis type-1 (NF1) is a common neurogenetic disorder and an important cause of intellectual disability. Brain-behaviour associations can be examined in vivo using morphometric magnetic resonance (MRI) and diffusion tensor imaging (DTI) to study brain structure. Here we studied structural and behavioural phenotypes in heterozygous Nf1 mi...
Article
Recent studies suggest that a shared neural ensemble may link distinct memories encoded close in time(1-12). According to the memory allocation hypothesis(1,2), learning triggers a temporary increase in neuronal excitability(13-15) that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that re...
Article
Full-text available
On March 10 to March 12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda, Maryland, to assess progress and new opportunities for research in tuberous sclerosis complex with the goal of updating the 2003 Research Plan for Tuberous Sclerosis (http://www.ninds.nih.g...
Article
Full-text available
Objective: Lovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras-MAPK pathway and associated with learning disabilities. We conducted a randomized double-blind placebo-controlled trial to assess lovastatin's effects on cognition and beh...
Article
Full-text available
The sheer volume and complexity of publications in the biological sciences are straining traditional approaches to research planning. Nowhere is this problem more serious than in molecular and cellular cognition, since in this neuroscience field, researchers routinely use approaches and information from a variety of areas in neuroscience and other...
Article
Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relation...
Article
Full-text available
Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneu...
Article
"The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family N...
Article
It is generally accepted that complex memories are stored in distributed representations throughout the brain, however the mechanisms underlying these representations are not understood. Here, we review recent findings regarding the subcellular mechanisms implicated in memory formation, which provide evidence for a dendrite-centered theory of memor...
Article
The molecular and cellular mechanisms of memory storage have attracted a great deal of attention. By comparison, little is known about memory allocation, the process that determines which specific neurons in a neural network will store a given memory [1, 2]. Previous studies demonstrated that memory allocation is not random in the amygdala; these s...
Article
Full-text available
In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in...
Article
Full-text available
A period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant...
Article
Full-text available
The α isoform of the calcium/calmodulin-dependent protein kinase II (αCaMKII) has been implicated extensively in molecular and cellular mechanisms underlying spatial and contextual learning in a wide variety of species. Germline deletion of Camk2a leads to severe deficits in spatial and contextual learning in mice. However, the temporal and region-...
Article
Full-text available
The retrosplenial cortex (RSC) is part of a network of interconnected cortical, hippocampal, and thalamic structures harboring spatially modulated neurons. The RSC contains head direction cells and connects to the parahippocampal region and anterior thalamus. Manipulations of the RSC can affect spatial and contextual tasks. A considerable amount of...
Article
Full-text available
Molecular and electrophysiological studies find convergent evidence suggesting that plasticity within a dendritic tree is not randomly dispersed, but rather clustered into functional groups. Further, results from in silico neuronal modeling show that clustered plasticity is able to increase storage capacity 45 times compared to dispersed plasticity...
Article
Full-text available
There is now compelling evidence that the allocation of memory to specific neurons (neuronal allocation) and synapses (synaptic allocation) in a neurocircuit is not random and that instead specific mechanisms, such as increases in neuronal excitability and synaptic tagging and capture, determine the exact sites where memories are stored. We propose...