André A. Fenton's research while affiliated with New York University and other places
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Publications (234)
Hundreds of proteins determine the function of synapses, and synapses define the neuronal circuits that subserve myriad brain, cognitive, and behavioral functions. It is thus necessary to precisely manipulate specific proteins at specific sub-cellular locations and times to elucidate the roles of particular proteins and synapses in brain function....
Affordable novel strategies are needed to treat COVID-19 cases complicated by respiratory compromise in resource limited settings. We report a mixed-methods pre-post assessment of 1) the useability of CPAP/O2 helmet non-invasive ventilation (NIV) to treat COVID-19, at ~1% the cost of mechanical ventilation; 2) the effectiveness of a train-the-train...
Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery, but how this uncompetitive NMDA-receptor antagonist impairs cognition remains unknown. Using rats and mice, we report that, consistent with ionotropic actions, PCP discoordinated hippocampus CA1 action potential disch...
Affordable novel strategies are needed to treat COVID-19 cases complicated by respiratory compromise in resource limited settings. We report a mixed-methods pre-post assessment of 1) the useability of CPAP/O2 helmet non-invasive ventilation (NIV) to treat COVID-19, at ~1% the cost of mechanical ventilation; 2) the effectiveness of a train-the-train...
Background
ADHD is a common neurodevelopmental disorder with a pediatric prevalence of 5.2%.While medication treatment for ADHD is effective, it does not address all symptoms and a small but notable subgroup does not respond to medications. Adverse effects limit its use and some parents and participants resist use of medication. Thus, limitations o...
basis of modern computation is the formal description of a finite state machine, the Universal Turing Machine, based on manipulation of integers and logic symbols. In this contribution to the discourse on the computer-brain analogy, we discuss the extent to which analog computing, as performed by the mammalian brain, is like and unlike the digital...
We consider the possibility of applying game theory to analysis and modeling of neurobiological systems. Specifically, the basic properties and features of information asymmetric signal games are considered and discussed as having potential to explain diverse neurobiological phenomena at levels of biological function that include gene regulation, m...
Could learning that uses cognitive control to judiciously use relevant information while ignoring distractions generally improve brain function, beyond forming explicit memories? According to a neuroplasticity hypothesis for how some cognitive behavioral therapies are effective, cognitive control training (CCT) changes neural circuit information pr...
Academic success and how to achieve it takes diverse forms, depending on who's asked. We suggest that happiness, impact, and longevity can be achieved with professional effort and support that balances the toil and joys of one's chosen path.
Protein kinase Mζ (PKMζ) maintains long-term potentiation (LTP) and long-term memory through persistent increases in kinase expression. Early-life adversity is a precursor to adult mood and anxiety disorders, in part, through persistent disruption of emotional memory throughout life. Here we subjected 10- to 16-wk-old male bonnet macaques to advers...
Background
Acute respiratory failure, a major cause of death in COVID-19, is managed with high-flow oxygen therapy via invasive mechanical ventilation. In resource-limited settings like Nigeria, the shortage of ventilators and oxygen supply makes this option challenging. Evidence-based non-invasive alternatives to mechanical ventilation such as the...
Mouse hippocampus CA1 place-cell discharge typically encodes current location, but during slow gamma dominance (SGdom), when SG oscillations (30–50 Hz) dominate mid-frequency gamma oscillations (70–90 Hz) in CA1 local field potentials, CA1 discharge switches to represent distant recollected locations. We report that dentate spike type 2 (DSM) event...
Hippocampus CA1 place cells express a spatial neural code by discharging action potentials in cell-specific locations (′place fields′), but their discharge timing is also coordinated by multiple mechanisms, suggesting an alternative ′ensemble cofiring′ neural code, potentially distinct from place fields. We compare the importance of these distinct...
PKMζ is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other kinases that are transiently stimulated by second messengers, PKMζ is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKMζ expr...
The hippocampus carries out multiple functions: spatial cognition dorsally (DH) and regulation of emotionality‐driven behavior ventrally (VH). Previously, we showed that dendrites of DH and VH pyramidal neurons of female rats are still developing robustly during adolescence and are altered by the experience of food restriction and voluntary exercis...
In the hippocampus, a widely accepted model posits that the dentate gyrus improves learning and memory by enhancing discrimination between inputs. To test this model, we studied conditional knockout mice in which the vast majority of dentate granule cells (DGCs) fail to develop – including nearly all DGCs in the dorsal hippocampus – secondary to el...
In the hippocampus, a widely accepted model posits that the dentate gyrus improves learning and memory by enhancing discrimination between inputs. To test this model, we studied conditional knockout mice in which the vast majority of dentate granule cells (DGCs) fail to develop – including nearly all DGCs in the dorsal hippocampus – secondary to el...
Mouse hippocampus CA1 place-cell discharge typically encodes current location but during slow gamma dominance (SGdom), when slow gamma oscillations (30-60 Hz) dominate mid-frequency gamma oscillations (60-90 Hz) in CA1 local field potentials, CA1 discharge switches to represent distant recollected locations. We now report that dentate spike type 2...
PKMζ is an autonomously active, atypical PKC isoform crucial for maintaining synaptic long-term potentiation (LTP) and long-term memory. Unlike other PKCs that are transiently activated by short-lived second messengers, PKMζ is persistently activated by long-lasting increases in the amount of the autonomously active kinase during LTP and long-term...
The hippocampus plays a critical role in storing and retrieving spatial information. By targeting the dorsal hippocampus and manipulating specific candidate molecules using pharmacological and genetic manipulations, we have previously discovered that long-term active place avoidance memory requires transient activation of particular molecules in do...
Cognitive control tasks require using one class of information and ignoring another competing class of information. A central role of the medial prefrontal cortex (mPFC) in cognitive control is well established in the primate literature, and largely accepted in the rodent literature because mPFC damage causes deficits in tasks that may require cogn...
The neurobiology of psychological concepts like schema, and psychotherapeutic strategies of cognitive behavioral therapy (CBT) is poorly understood, partly because learning to process information confounds, and is rarely distinguished from acquiring content-specific memory. Learning to learn changes one's overall information-processing ability, whe...
The elucidation of the molecular mechanisms of long-term synaptic plasticity has been hindered by both the compensation that can occur after chronic loss of the core plasticity molecules and by ex vivo conditions that may not reproduce in vivo plasticity. Here we describe a novel method to rapidly suppress gene expression by antisense oligodeoxynuc...
In 1980, Nadel and Wilner extended Richard Hirsh's notion that the hippocampus creates environmental representations, called “contexts,” suggesting that the fundamental structure of context was the spatial representation proposed by O'Keefe and Nadel's landmark book, The Hippocampus as a Cognitive Map (1978). This book, in turn, derives from the di...
How experience causes long-lasting changes in the brain is a central question in neuroscience. The common view is that synaptic function is altered by experience to change brain circuit functions that underlie conditioned behavior. We examined hippocampus synaptic circuit function in vivo, in three groups of animals, to assess the impact of experie...
Single‐neuron gene expression studies may be especially important for understanding nervous system structure and function because of the neuron‐specific functionality and plasticity that defines functional neural circuits. Cellular dissociation is a prerequisite technical manipulation for single‐cell and single cell‐population studies, but the exte...
Afferents modulate newborn neurons
What is the role of adult neurogenesis in learning, memory, and mood? Luna et al. found that adult-born neurons either inhibited or excited the dentate gyrus, depending on whether synaptic inputs originated from the lateral or the medial entorhinal cortex (see the Perspective by Llorens-Martín). These opposing mec...
Gamma oscillations are readily observed in a variety of brain regions during both waking and sleeping states. Computational models of gamma oscillations typically involve simulations of large networks of synaptically coupled spiking units. These networks can exhibit strongly synchronized gamma behavior, whereby neurons fire in near synchrony on eve...
Single-neuron gene expression studies may be especially important for understanding nervous system structure and function because of the neuron-specific functionality and plasticity that defines functional neural circuits. Cellular dissociation is a prerequisite technical manipulation for single-cell and single cell-population studies, but the exte...
Abstract In “Criteria for identifying the molecular basis of the engram (CaMKII, PKMζ),” Lisman proposes that elucidating the mechanism of LTP maintenance is key to understanding memory storage. He suggests three criteria for a maintenance mechanism to evaluate data on CaMKII and PKMζ as memory storage molecules: necessity, occlusion, and erasure....
Head-direction cells preferentially discharge when the head points in a particular azimuthal direction, are hypothesized to collectively function as a single neural system for a unitary direction sense, and are believed to be essential for navigating extra-personal space by functioning like a compass. We tested these ideas by recording medial entor...
Rodents exhibit neophobia for novel tastes, demonstrated by an initial reluctance to drink novel-tasting, potentially-aversive solutions. Taste neophobia attenuates across days if the solution is not aversive, demonstrated by increased consumption as the solution becomes familiar. This attenuation of taste neophobia is context dependent, which has...
Patients with neuropsychiatric and neurological disorders often express limbic circuit abnormalities and deficits in information processing. While these disorders appear to have diverse etiologies, their common features suggest neurodevelopmental origins. Neurodevelopment is a prolonged process of diverse events including neurogenesis/apoptosis, ax...
Hippocampal neuronal nucleolar expression of fibrillarin is increased after training and retention test.
A) Table showing mean (and standard deviation) for each of 4 groups (n = 3/group) (trained and untrained with and without RT), as well as total for each condition. A two-way ANOVA found increased fibrillarin staining in response to training (F1,...
Abstract
The transition from short-term to long-term forms of synaptic plasticity requires protein synthesis and new gene expression. Most efforts to understand experience-induced changes in neuronal gene expression have focused on the transcription products of RNA polymerase II—primarily mRNAs and the proteins they encode. We recently showed that...
Supporting information methods.
Description of the methods used to produce the data presented in S1–S3 Figs.
(DOCX)
Intra-hippocampal treatment of CX-5461 48 h before training does not inhibit 24 h memory consolidation.
A) Timeline of the training protocol. Animals were injected with CX-5461 or vehicle 48 h before commencement of training. B) Comparison of learning and memory between APA trained mice who received intracranial injection of vehicle (black circles)...
Characterized rRNA variants are not differentially expressed 24 h after training.
Real-Time qPCR analysis demonstrates that none of the five known hippocampal rRNA variants are significantly upregulated 24 h after the third APA training trial, whether or not an animal received a retention test. [Significance analyzed by ANOVA. All p values > 0.14]....
Primary data.
The primary data points used to produce means and variance presented in figures and results.
(XLSX)
Activity-dependent changes in the effective connection strength of synapses are a fundamental feature of a nervous system. This so-called synaptic plasticity is thought to underlie storage of information in memory and has been hypothesized to be crucial for the effects of cognitive behavioral therapy. Synaptic plasticity stores information in a neu...
Discriminating similar memories and events depends on the dentate gyrus region of the hippocampus. This region is also distinctive because neurogenesis continues in adulthood. Whether both mature and immature granule cells play a role in memory discrimination, and whether the roles are distinct is actively investigated. Here we demonstrate that man...
The dentate gyrus (DG) is crucial for behaviorally discriminating similar spatial memories, predicting that DG place cells change ("remap") their relative spatial tuning ("place fields") for memory discrimination. This prediction was never tested, although DG place cells remap across similar environments without memory tasks. We confirm this prior...
The electroencephalography (EEG) has become increasingly valuable outside of its traditional use in neurology for neuropsychiatric diagnosis, neurological evaluation of traumatic brain injury, neurotherapy, gaming, neurofeedback, mindfulness and cognitive enhancement training. The trend to increase the number of EEG electrodes, the development of n...
Related to Fig 3; avoidance histograms during retention and conflict sessions, probability of behavioral states during SGdom and random events in pretraining sessions and SGdom event rates across training sessions.
(A) Locations of avoidances across six 60° sectors during the first and second halves of the memory retention and conflict sessions. Av...
Related to Fig 4; single-unit recordings and selection of the pyramidal cell data set.
(A) Example of single-unit isolation and the Open Ephys microdrive (left inset) and an implanted mouse (right inset). The inset table lists isolated units with their corresponding IsoIBG and IsoINN values used for selecting units with sufficient isolation quality...
Related to Fig 4; nonlocal place representations in putative pyramidal cell ensemble discharge during SG oscillations without concurrent MG oscillations and SWRs in WT and Fmr1-KO mice.
(A) Average voltage traces during isolated SG, MG, and SWR events. Percentage of (non-isolated) SG and MG events that coincide with SWR events. (B) Relationships be...
Related to S1 Video; raw LFP and wavelet spectrum examples of identified SGdom episodes.
(A) SG/MG ratio computed over a 55-s-long time period, with identified SGdom peaks (gray circles) and a selected subset of SGdom peaks used for LFP and wavelet spectrum extraction in the examples below (red circles). (B–D) LFP (top) and wavelet spectrum (bottom...
Author summary
Behavior is often used as proxy to study memory and cognitive deficits in animals like Fmr1-KO mice that model Fragile X Syndrome, the most prevalent single-gene cause of intellectual disability and autism. However, it is unclear what neural events define cognitive variables like recollection of memory and cognitive inflexibility. We...
Related to Fig 1; basic LFP properties during active avoidance.
(A) Power spectra with log frequency axis during periods of stillness and running throughout active avoidance training. Dotted lines indicate linear fits to the data. (B) Power spectra with linear frequency axis during periods of stillness and running throughout active avoidance traini...
Related to Fig 2; dynamical schematic representation of SGdom-identified recollection.
Real-time slow (30–50 Hz; low pitch) and mid-frequency (70–90 Hz; high pitch) gamma event replay represented as an audio track. Notice how both SG and MG events co-occur but that SG events can dominate. Top, left: polar coordinate of the mouse in a 55-s-long wind...
Related to Fig 1; oscillatory activity in mouse dorsal hippocampus CA1 LFPs.
(A) LFP signals obtained using 32-site linear silicon electrode array during an SWR. (B) CSD analysis of CA1 LFP to separate individual oscillatory components within CA1. (C) CSD power profiles averaged over theta cycles from s.p., s.r., and s.l.m electrodes. Notice the mi...
Related to Fig 1; selecting the threshold for oscillatory events and selecting the oscillation frequencies to represent slow and mid-frequency gamma.
(A) Example time-frequency representation of LFP before and after avoidance. Power in the mid-frequency gamma range during stillness prior to avoidance is typically attenuated, leading to a higher num...
Silence of FMR1 causes loss of fragile X mental retardation protein (FMRP) and dysregulated translation at synapses, resulting in the intellectual disability and autistic symptoms of fragile X syndrome (FXS). Synaptic dysfunction hypotheses for how intellectual disabilities like cognitive inflexibility arise in FXS predict impaired neural coding in...
Nonprotein coding dendritic BC1 RNA regulates translation of mRNAs in neurons. We examined two lines of BC1 knockout mice and report that loss of BC1 RNA exaggerates group I mGluR-stimulated LTD of the Schaffer collateral synapse, with one of the lines showing a much more enhanced DHPG-induced LTD than the other. When the animals were given the hip...
We used the psychotomimetic phencyclidine (PCP) to investigate the relationships among cognitive behavior, coordinated neural network function, and information processing within the hippocampus place cell system. We report in rats that PCP (5 mg/kg, i.p.) impairs a well learned, hippocampus-dependent place avoidance behavior in rats that requires c...
We used the psychotomimetic phencyclidine (PCP) to investigate the relationships between cognitive behavior, coordinated neural network function and information processing within the hippocampus place cell system. We report in rats that PCP (5mg/kg i.p.) impairs a well-learned hippocampus-dependent place avoidance behavior in rats that requires cog...
There is common agreement that many disorders of the central nervous system are 'complex', that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment. Most of these disorders, unfortunately, have no cure at the present time, and therapeutic strategies often have debilitat...
Silence of FMR1 causes loss of fragile X mental retardation protein (FMRP) and dysregulated translation at synapses, resulting in the intellectual disability and autistic symptoms of Fragile X Syndrome (FXS). Synaptic dysfunction hypotheses for how intellectual disabilities like cognitive inflexibility arise in FXS, predict impaired neural coding i...
Behavior is used to assess memory and cognitive deficits in animals like Fmr1-null mice that model Fragile-X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal CA1 hippocampus. During a shocked-place avoidance...
Experimental and theoretical studies demonstrate that neuronal gamma oscillations crucially depend on interneurons, but current models do not consider the diversity of known interneuron subtypes. Moreover, in CA1 of the hippocampus, experimental evidence indicates the presence of multiple gamma oscillators, two of which may be coordinated by differ...
Behavior is used to assess memory and identify memory deficits in animal models of mental dysfunction, but behavior is a proxy for the neural events that define cognitive variables like recollection. We sought to identify an electrophysiological signature of recollection in mouse dorsal CA1 hippocampus, using the active place avoidance task. We fir...
The greatest challenge in moving neuroscience research forward in the 21st century is recruiting, training, and retaining the brightest, rigorous, and most diverse scientists. The MBL research training courses Neurobiology and Neural Systems & Behavior, and the Summer Program in Neuroscience, Excellence, and Success provide a model for full immersi...
Background:
Correlated neuronal activity in the brain is hypothesized to contribute to information representation, and is important for gauging brain dynamics in health and disease. Due to high dimensional neural datasets, it is difficult to study temporal variations in correlation structure.
New method:
We developed a multiscale method, Populat...
Training in the active place avoidance task changes hippocampus synaptic function, the dynamics of hippocampus local field potentials, place cell discharge, and active place avoidance memory is maintained by persistent PKMζ activity. The extent to which these changes reflect memory processes and/or stress responses is unknown. We designed a study t...
A widely accepted notion for a process underlying memory formation is that learning changes the efficacy of synapses by the mechanism of synaptic plasticity. While there is compelling evidence of changes in synaptic efficacy observed after learning, demonstration of persistent synaptic changes accompanying memory has been elusive. We report that ac...
PKMζ is an autonomously active PKC isoform that persistently increases in LTP maintenance and although PKMζ is thought to sustain both LTP and long-term memory, the molecular mechanism for the persistent action of PKMζ during memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1...
Cognitive impairments are amongst the most debilitating deficits of schizophrenia and the best predictor of functional outcome. Schizophrenia is hypothesized to have a neurodevelopmental origin, making animal models of neurodevelopmental insult important for testing predictions that early insults will impair cognitive function. Rats exposed to meth...
The hippocampus (HPC) is a neural system that is crucial for high-order cognitive functions such as autobiographic memory, spatial navigation, and cognitive control. The HPC place cell (PC) network is hypothesized to form the cognitive map that enables these functions. Deficits of cognitive control--inability to use relevant information while ignor...
The hippocampus (HPC) is a neural system that is crucial for high-order cognitive functions such as autobiographic memory, spatial navigation, and cognitive control. The HPC place cell (PC) network is hypothesized to form the cognitive map that enables these functions. Deficits of cognitive control--inability to use relevant information while ignor...
PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null...
Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). Absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why absence of FMRP impairs...
The processes that organize different thoughts and memories, allowing the separation of currently relevant and irrelevant information, are collectively known as cognitive control. The neuronal mechanisms of these processes can be investigated by place cell ensemble recordings during behaviors and environmental manipulations that present cognitive c...
The hippocampus (HPC) is the model neural system facilitating high-order cognitive functions such as autobiographical memory, spatial navigation, and cognitive control. Though much focus has been placed on dedicated spatial tuning properties of individual place cells, the HPC also exhibits dynamic functional grouping of place cells that are tempora...
Fragile X syndrome (FXS) patients do not express the fragile X mental retardation protein (FMRP). Absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why absence of FMRP impairs memory discrimination and exagg...
Place cells in the hippocampus (HPC) are the foundation of the longstanding cognitive map theory of hippocampal function, and an integral part of the brain's GPS navigation system. Discrete spatial tuning curves of place fields are thought both to guide navigation and knowledge about location in space, and form a neural network that supports adapti...
