Biology subjects

Fenton, A. A.

Publications and source records attributed to Fenton, A. A..

16 recordsLinked to original sources

bioRxiv2026

Temporal Coding rather than Circuit Wiring allows Hippocampal CA3 Neurons to Dynamically Distinguish Different Cortical Inputs

Memory relies on associating and indexing multimodal information. How does this occur within single neurons? The hippocampus integrates multisensory information from medial (MEC) and lateral (LEC) entorhinal cortices to form environmental representations1-6, yet their synaptic dynamics, circuit organization, and integrative functions remain elusive. Contrary to canonical models emphasizing anatomical and functional segregation, our dual-color optogenetic7 circuit mapping revealed that both MEC and LEC inputs converge on virtually every CA3 pyramidal neuron and exhibit similar input-output functions and modulation via GABAergic microcircuitry. Divergence occurs in their frequency-dependent short-term plasticity. With increasing frequencies, facilitating LEC-evoked responses undergo synaptic depression, whereas MEC-evoked responses continue facilitating. In vivo, MEC-originating dentate spikes fire CA3 more than LEC, likely due to their distinct temporal relationship with oscillatory activity. Our findings support that hippocampal area CA3 processes region-specific information from MEC and LEC via temporal coding, rather than hard-wired circuit organization, at both single-neuron and network levels.

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bioRxiv2026

PKMζ-KIBRA interactions, molecular turnover, and memory

How can the molecules that strengthen synaptic connections maintain memory in the face of molecular turnover? Our previous work showed that persistent interaction between the postsynaptic scaffolding protein, KIBRA, and the autonomously active PKC isoform, PKM{zeta}, is crucial for maintaining synaptic long-term potentiation (LTP) and memory for at least a month. This duration is longer than the lifespans of individual KIBRA and PKM{zeta} molecules. Biophysical modeling of the interaction suggests oligomers of KIBRA-PKM{zeta} dimers, but not individual dimers or monomers, can overcome molecular turnover by continually incorporating newly synthesized KIBRA and PKM{zeta}, replacing those that have degraded. Here we used AlphaFold 3 to predict the structures of KIBRA-PKM{zeta} heterodimers and heterohexamers and to examine the sites of action of two structurally distinct inhibitors of KIBRA-PKM{zeta} interaction that disrupt established late-LTP and long-term memory. The structures predict that the peptide K-ZAP blocks formation of heterodimers, whereas the small molecule {zeta}-stat prevents PKM{zeta} of one heterodimer from binding a second KIBRA and PKM{zeta}, essential for forming larger oligomeric structures. We show that {zeta}-stat, like K-ZAP, disrupts 1-month-old spatial memory. Thus, continual formation of KIBRA-PKM{zeta} oligomers can be a core molecular mechanism driving the persistence of long-term memory in the face of molecular turnover.

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bioRxiv2025

PKMζ-PKC{iota}/{lambda} double-knockout reveals the atypical PKCs are crucial for hippocampal late-LTP and spatial long-term memory

PKM{zeta}, a persistently active atypical PKC (aPKC) isoform, is thought to maintain late-phase long-term potentiation (late-LTP) and long-term memory. However, PKM{zeta}-knockout mice still exhibit hippocampal LTP and spatial memory while lacking neocortical LTP, questioning whether this kinase is fundamental to enduring synaptic potentiation and memory. Tsokas et al. (2016) showed the other aPKC, PKC{iota}/{lambda}, likely compensates for PKM{zeta} during maintenance in the hippocampus of PKM{zeta}-null mice. In wild-type mice, PKC{iota}/{lambda} drives early-LTP and short-term memory, while PKM{zeta} compensates for PKC{iota}/{lambda} knockout by supporting both early- and late-phase processes. Here we show PKC{iota}/{lambda} persistently increases during maintenance in two mouse models: PKM{zeta}-conditional knockout (cKO) mice, and double-knockout mice carrying both conditional deletion of PKC{iota}/{lambda} and constitutive loss of PKM{zeta}. In the double-knockout mice, PKC{iota}/{lambda} was measured while the kinase was still present, prior to its inducible ablation, to characterize its compensatory upregulation in late-LTP before removal. To test whether this compensation was functional, we ablated PKC{iota}/{lambda} in the hippocampus of the double-knockout mice. The double-knockout eliminated late-LTP, whereas individual knockout of either aPKC alone showed normal-appearing LTP. Double-knockout also abolished spatial long-term memory without affecting short-term memory. Thus, when PKM{zeta} is absent, PKC{iota}/{lambda} persists to maintain hippocampal late-LTP and long-term memory.

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bioRxiv2025

Effective computations for hippocampal place cell phenomena in sparse untrained random networks

The mammalian brain processes experience-dependent spatial information through poorly-understood network mechanisms thought to depend on particular network connectivity patterns and activity-dependent synaptic plasticity. However, dedicated input connections that learn to shape information about place cannot easily explain many rodent hippocampal place cell phenomena. For example, representational drift notwithstanding, the discharge of each place cell maps to specific locations in a fixed environment, but the discharge of most cells remap to distinct independent locations across environments, despite the fact that most sub-second cofiring relationships amongst hippocampal neuron pairs persist across environments. Whereas some models of hippocampal spatial information processing rely on the dedicated input connections of a for-purpose connectome (ignoring remapping, representational drift, and maintained cofiring), other models use synaptic plasticity implemented by learning rules to alter random input connections, but struggle with either limited capacity, representational drift, and/or biological implausibility. Here, using a randomly tuned network with feedback inhibition, we examine whether the assumptions of a specific connectome and learning-implemented synaptic plasticity are necessary for diverse place cell phenomena. We find that the random network with non-plastic connections accounts for positional tuning, single place fields in small spaces and multiple place fields in large spaces, mixed selectivity, and remapping, amongst other place cell phenomena. This requires excitatory activity to be sparse and organized across stimuli by divisive normalization. Enabling synaptic plasticity only at the network connections (not at network inputs) accounts for additional place cell phenomena including overdispersion, representational drift, and memory tagging. We show by simulations and analytically that DivSparse, a random network with sparsifying inhibition can explain many features of place cell network activity, suggesting that simple biologically-plausible architectures can realize representations of spatial experience that are robust, flexible, and spontaneous.

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bioRxiv2025

Persistently increased expression of PKMzeta and unbiased gene expression profiles identify hippocampal molecular traces of a long-term active place avoidance memory and 'shadow' proteins

Long-term memory formation transiently activates Ca2+-calmodulin kinase II and atypical protein kinase C isoform iota/lambda, whereas persistent activation of the other atypical PKC, protein kinase M zeta (PKM{zeta}), together with its interacting partner, the scaffolding-protein KIBRA (Wwc1), are necessary for maintaining potentiated synapses and memory. Here, we use immediate-early gene (IEG) Arc activation during active place avoidance memory expression to tag memory-activated neurons with EYFP-ChR2. PKM{zeta} immunohistochemistry identified which hippocampal synaptic pathways are persistently altered. EYFP-PKM{zeta} colocalization persistently increases in the hippocampal trisynaptic pathway (dentate gyrus [DG][->]CA3[->]CA1) tracing a one-month-old PKM{zeta} engram. DG, CA3, and CA1 transcriptional profiling identifies that memory persistence correlates with upregulated immediate-early-genes Arc, Fos, and NPas4 in DG, but not with PKM{zeta} or most genes known to be crucial for LTP and memory. This rules out strong memory-related transcriptional regulation, but not regulation of mRNA translation or altered stability of "shadow proteins" like PKM{zeta} that, despite being crucial for memory maintenance, evade detection by unbiased transcriptome profiling. In contrast, our method Correlation Signal Co-cluster Reduction (C-SCoRe) incorporates weak linear and non-linear gene correlations and highlights network interaction changes predicting memory, and related IEG and Prkcz/Wwc1 expression. Manifold transcriptional relationships can reveal shadow molecular components of long-term memory.

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bioRxiv2023

On the results of causal optogenetic engram manipulations

Hippocampal neurons encoding memories discharge in sparsely-distributed patterns; they can be optogenetically tagged, then photostimulated to elicit conditioned behavior, potentially generating a synthetic memory trace, "engram". We investigated mouse hippocampal population responses to the photostimulation of memory-tagged neurons to determine if memory-associated discharge is mimicked in hippocampus, a network with non-linear and homeostatic interactions. Both memory-tagged and not-tagged CA1 cells adjusted firing during photostimulation without altering place cell firing fields. Cell-pair cofiring relationships also maintain during photostimulation, indicating a low-dimensional, dynamical structure-preserving, homeostatic network response instead of the photostimulated pattern. Photostimulating neurons that were tagged during place-avoidance memory elicits similar place-avoidance memory in control conditions. Thus artificial photostimulation elicits natural, stored, homeostatic neuronal network cofiring patterns to elicit memory, establishing mimicry evidence for the engram.

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bioRxiv2022

Phencyclidine disrupts neural coordination and cognitive control by dysregulating translation

BackgroundPhencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist impairs cognition remains unknown. MethodsThe effects of PCP were investigated i) on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice; ii) on synaptic responses in ex vivo mouse hippocampus slices; iii) in mice on a hippocampus-dependent active place avoidance task that requires cognitive control; and iv) on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects to the effects of inhibitors of protein synthesis, group-1-type metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. ResultsConsistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity, and impaired active place avoidance, despite learning the task before PCP. Consistent with metabotropic actions, PCP exaggerated protein-synthesis dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression (LTD). Pretreatment with anisomycin or the mGluR1/5-antagonist MPEP, both of which repress translation, prevented the PCP-induced discoordination, and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR-antagonist NVP-AAM077 unbalanced translation that engages the AKT, mTOR and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. ConclusionsPCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, leading to the neural discoordination that is central to the cognitive and sensorimotor impairments.

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bioRxiv2022

Do place cells dream of deceptive moves in a signaling game?

We consider the possibility of applying game theory to analysis and modeling of neurobiological systems. Specifically, the basic properties and features of information asymmetric signaling games are considered and discussed as having potential to explain diverse neurobiological phenomena at levels of biological function that include gene regulation, molecular and biochemical signaling, cellular and metabolic function, as well as the neuronal action potential discharge that can represent cognitive variables such as memory and purposeful behavior. We begin by arguing that there is a pressing need for conceptual frameworks that can permit analysis and integration of information and explanations across the many scales of diverse levels of biological function. Developing such integrative frameworks is crucial if we are to understand cognitive functions like learning, memory, and perception. The present work focuses on systems level neuroscience organized around the connected brain regions of the entorhinal cortex and hippocampus. These areas are intensely studied in rodent subjects as model neuronal systems that undergo activity-dependent synaptic plasticity to form and represent memories and spatial knowledge used for purposeful navigation. Examples of cognition-related spatial information in the observed neuronal discharge of hippocampal place cell populations and medial entorhinal head-direction cell populations are used to illustrate possible challenges to information maximization concepts. It may be natural to explain these observations using the ideas and features of information asymmetric signaling games.

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bioRxiv2021

A neuronal code for space in hippocampal coactivity dynamics independent of place fields

Hippocampus is comprised of [~]20% place cells, discharging in cell-specific locations ("place fields"), standardly interpreted as a dedicated neuronal code for space. However, place cell discharge is temporally unreliable across seconds and days, and place fields are multimodal, suggesting an alternative "ensemble cofiring" spatial code with manifold dynamics that does not require reliable spatial tuning. We evaluated these hypotheses using GCaMP6f and miniature microscopes to image mouse CA1 ensemble activity in two environments, across 3 weeks. Both place fields and ensemble coactivity relationships appear to "remap," being distinct between, and (weakly) similar within environments. Decoding location as well as environment from 1-s ensemble location-specific discharge is effective and improves with experience. Decoding the environment (but not location) from cell-pair coactivity relationships is also effective and improves with experience, even after removing place tuning. Discriminating environments from 1-s ensemble coactivity relies crucially on the cells with the most anti-cofiring cell-pair relationships because ensemble activity is internally-organized on a low-dimensional manifold of non-linear cofiring relationships that intermittently reregisters to environments according to the anti-cofiring subpopulation activity.

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bioRxiv2020

Dentate spikes and external control of hippocampal function

Mouse hippocampus CA1 place-cell discharge typically encodes current location but during slow gamma dominance (SGdom), when slow gamma 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) events initiated by MECII[->]DG inputs promote SGdom and change excitation-inhibition coordinated discharge in DG, CA3, and CA1, whereas type 1 (DSL) events initiated by LECII[->]DG inputs do not. Just before SGdom, LECII-originating slow gamma oscillations in dentate gyrus and CA3-originating slow gamma oscillations in CA1 phase and frequency synchronize at the DSM peak when discharge within DG and CA3 increases to promote excitation-inhibition cofiring within and across the DG[->]CA3[->]CA1 pathway. This optimizes discharge for the 5-10 ms DG-to-CA1 neuro-transmission that coincides with SGdom. DSM properties identify extrahippocampal control of SGdom, and a cortico-hippocampal mechanism that switches between memory-related modes of information processing.

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bioRxiv2020

Transcriptome analysis of hippocampal subfields identifies gene expression profiles associated with long-term active place avoidance memory

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 dorsal hippocampus. These molecules include amongst others, the persistent kinases Ca-calmodulin kinase II (CaMKII) and the atypical protein kinase C isoform PKC{iota} /{lambda} for acquisition of the conditioned behavior, whereas persistent activation of the other atypical PKC, protein kinase M zeta (PKM{zeta}) is necessary for maintaining the memory for at least a month. It nonetheless remains unclear what other molecules and their interactions maintain active place avoidance long-term memory, and the candidate molecule approach is both impractical and inadequate to identify new candidates since there are so many to survey. Here we use a complementary approach to identify candidates by transcriptional profiling of hippocampus subregions after formation of the long-term active place avoidance memory. Interestingly, 24-h after conditioning and soon after expressing memory retention, immediate early genes were upregulated in the dentate gyrus but not Ammons horn of the memory expressing group. In addition to determining what genes are differentially regulated during memory maintenance, we performed an integrative, unbiased survey of the genes with expression levels that covary with behavioral measures of active place avoidance memory persistence. Gene Ontology analysis of the most differentially expressed genes shows that active place avoidance memory is associated with activation of transcription and synaptic differentiation in dentate gyrus but not CA3 or CA1, whereas hypothesis-driven candidate molecule analyses identified insignificant changes in the expression of many LTP-associated molecules in the various hippocampal subfields, nor did they covary with active place avoidance memory expression, ruling out strong transcriptional regulation but not translational regulation, which was not investigated. These findings and the data set establish an unbiased resource to screen for molecules and evaluate hypotheses for the molecular components of a hippocampus-dependent, long-term active place avoidance memory.

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bioRxiv2020

PKMζ traces hippocampal LTP maintenance and spatial long-term memory

PKM{zeta} is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other protein kinases that are transiently stimulated by second messengers, PKM{zeta} is persistently activated through sustained increases in kinase protein expression. Therefore, visualizing increases in PKM{zeta} expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKM{zeta}-null mice, we examined the amount and distribution of PKM{zeta} in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKM{zeta} increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 h. During spatial memory storage, PKM{zeta} increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. The subset of CA1 pyramidal cells that are tagged by immediate early gene Arc-driven transcription of fluorescent proteins, whose expression increases during initial memory formation, also expresses the persistent increase of PKM{zeta} during memory storage. In the memory-tagged cells, the increased PKM{zeta} expression persists in dendritic compartments within stratum radiatum for 1 month, indicating the long-term storage of information in the CA3-to-CA1 pathway during remote spatial memory. We conclude that persistent increases in PKM{zeta} trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.

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bioRxiv2018

Optogenetic silencing of immature and mature neurons in dentate gyrus to assess their roles in memory discriminations

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 manipulating either mature or immature granule cells can impair discrimination of similar active place avoidance memories, but the manipulations have different effects. We also observe that prior experience modulates which memories are compromised by inactivation of immature neurons. These data demonstrate the importance of the dentate gyrus network of cells for memory discrimination.

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bioRxiv2017

Phencyclidine discoordinates hippocampal network activity but not place fields

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 cognitive control, even when PCP is injected directly into dorsal hippocampus. PCP increases 60-100 Hz medium gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive impairment caused by systemic PCP administration. PCP discoordinates theta-modulated medium and slow gamma oscillations in CA1 local field potentials (LFP) such that medium gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell firing fields are preserved under PCP but the drug discoordinates the sub-second temporal organization of discharge amongst place cells. This discoordination causes place cell ensemble representations of a familiar space to cease resembling pre-PCP representations, despite preserved place fields. These findings point to the cognitive impairments caused by PCP arising from neural discoordination. PCP disrupts the timing of discharge with respect to the sub-second timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from local inhibitory synaptic activity, these findings point to excitation-inhibition discoordination as the root of PCP-induced cognitive impairment.\n\nSIGNIFICANCE STATEMENTHippocampal neural discharge is temporally coordinated on timescales of theta and gamma oscillations in the local field potential, and the discharge of a subset of pyramidal neurons called \"place cells\" is spatially organized such that discharge is restricted to locations called a cells \"place field.\" Because this temporal coordination and spatial discharge organization is thought to represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt cognitive behavior and assess the importance of neural coordination and place fields for spatial cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal discharge, without disrupting firing fields. These findings dissociate place fields from spatial cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial cognition.

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bioRxiv2017

Normal CA1 place fields but discoordinated network discharge in a Fmr1-null mouse model of fragile X syndrome

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 the absence of FMRP. We tested the prediction by comparing hippocampus place cells in wild-type and FXS-model mice. Experience-driven CA1 synaptic function and synaptic plasticity changes are excessive in Fmr1-null mice, but CA1 place fields are normal. However, Fmr1-null discharge relationships to local field potential oscillations are abnormally weak, stereotyped, and homogeneous; also discharge coordination within Fmr1-null place cell networks is weaker and less reliable than wild-type. Rather than disruption of single-cell neural codes, these findings point to invariant tuning of single-cell responses and inadequate discharge coordination within neural ensembles as a pathophysiological basis of cognitive inflexibility in FXS.

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bioRxiv2017

Control of recollection by slow gamma dominating medium gamma in hippocampus CA1

Behavior is used to assess memory and cognitive deficits in animals like Fmrl-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 task, slow gamma (SG: 30-50 Hz) dominates mid-frequency gamma (MG: 70-90 Hz) oscillations 2-3 seconds before successful avoidance, but not failures. Wild-type but not Fmrl-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdominance) decrease in wild-type but not in cognitively inflexible Fmrl-null mice. During SGdominance, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, wild-type ensembles represent distant locations near the currently-correct shock zone but Fmrl-null ensembles represent the formerly-correct zone. These findings indicate that recollection occurs when CA1 slow gamma dominates mid-frequency gamma, and that accurate recollection of inappropriate memories explains Fmrl-null cognitive inflexibility.

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