Emily A. Aery Jones

All Publications

• One-shot entorhinal maps enable flexible navigation in novel environments. Nature Wen, J. H., Sorscher, B., Aery Jones, E. A., Ganguli, S., Giocomo, L. M. 2024

  Abstract

  Animals must navigate changing environments to find food, shelter or mates. In mammals, grid cells in the medial entorhinal cortex construct a neural spatial map of the external environment1-5. However, how grid cell firing patterns rapidly adapt to novel or changing environmental features on a timescale relevant to behaviour remains unknown. Here, by recording over 15,000 grid cells in mice navigating virtual environments, we tracked the real-time state of the grid cell network. This allowed us to observe and predict how altering environmental features influenced grid cell firing patterns on a nearly instantaneous timescale. We found evidence that visual landmarks provide inputs to fixed points in the grid cell network. This resulted in stable grid cell firing patterns in novel and altered environments after a single exposure. Fixed visual landmark inputs also influenced the grid cell network such that altering landmarks induced distortions in grid cell firing patterns. Such distortions could be predicted by a computational model with a fixed landmark to grid cell network architecture. Finally, a medial entorhinal cortex-dependent task revealed that although grid cell firing patterns are distorted by landmark changes, behaviour can adapt via a downstream region implementing behavioural timescale synaptic plasticity6. Overall, our findings reveal how the navigational system of the brain constructs spatial maps that balance rapidity and accuracy. Fixed connections between landmarks and grid cells enable the brain to quickly generate stable spatial maps, essential for navigation in novel or changing environments. Conversely, plasticity in regions downstream from grid cells allows the spatial maps of the brain to more accurately mirror the external spatial environment. More generally, these findings raise the possibility of a broader neural principle: by allocating fixed and plastic connectivity across different networks, the brain can solve problems requiring both rapidity and representational accuracy.

  View details for DOI 10.1038/s41586-024-08034-3

  View details for PubMedID 39385034

  View details for PubMedCentralID 3007674

• Entorhinal cortex represents task-relevant remote locations independent of CA1. bioRxiv : the preprint server for biology Aery Jones, E. A., Low, I. I., Cho, F. S., Giocomo, L. M. 2024

  Abstract

  Neurons can collectively represent the current sensory experience while an animal is exploring its environment or remote experiences while the animal is immobile. These remote representations can reflect learned associations and be required for learning. Neurons in the medial entorhinal cortex (MEC) reflect the animal's current location during movement, but little is known about what MEC neurons collectively represent during immobility. Here, we recorded thousands of neurons in superficial MEC and dorsal CA1 as mice learned to associate two pairs of rewarded locations. We found that during immobility, the MEC neural population frequently represented positions far from the animal's location, which we defined as 'non-local coding'. Cells with spatial firing fields at remote locations drove non-local coding, even as cells representing the current position remained active. While MEC non-local coding has been reported during sharp-wave ripples in downstream CA1, we observed non-local coding more often outside of ripples. In fact, CA1 activity was less coordinated with MEC during non-local coding. We further observed that non-local coding was pertinent to the task, as MEC preferentially represented remote task-relevant locations at appropriate times, while rarely representing task-irrelevant locations. Together, this work raises the possibility that MEC non-local coding could strengthen associations between locations independently from CA1.

  View details for DOI 10.1101/2024.07.23.604815

  View details for PubMedID 39091781

• Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimer's Disease Pathogenesis. bioRxiv : the preprint server for biology Tabuena, D. R., Jang, S., Grone, B., Yip, O., Aery Jones, E. A., Blumenfeld, J., Liang, Z., Koutsodendris, N., Rao, A., Ding, L., Zhang, A. R., Hao, Y., Xu, Q., Yoon, S. Y., De Leon, S., Huang, Y., Zilberter, M. 2024

  Abstract

  The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.

  View details for DOI 10.1101/2023.08.28.555153

  View details for PubMedID 37693533

• Waveform-based classification of dentate spikes. Scientific reports Santiago, R. M., Lopes-Dos-Santos, V., Aery Jones, E. A., Huang, Y., Dupret, D., Tort, A. B. 2024; 14 (1): 2989

  Abstract

  Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer's disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.

  View details for DOI 10.1038/s41598-024-53075-3

  View details for PubMedID 38316828

  View details for PubMedCentralID 497229

• Waveform-based classification of dentate spikes. bioRxiv : the preprint server for biology Santiago, R. M., Lopes-Dos-Santos, V., Jones, E. A., Huang, Y., Dupret, D., Tort, A. B. 2023

  Abstract

  Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer's disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.Author summary: The entorhinal cortex and the dentate gyrus are regions of the hippocampal formation that play a crucial role in learning and memory. Their synchronous activation generates fast and high-amplitude electrophysiological patterns in the dentate gyrus, called dentate spikes (DSs). However, the functional role of DSs is still poorly understood. A technical limitation for the study of DSs is that their classification is only possible through laminar profiles obtained by multicontact linear probes. In the present work, we propose a method to classify the different types of DSs through their waveforms, thus allowing their investigation in single-site recordings.

  View details for DOI 10.1101/2023.10.24.563826

  View details for PubMedID 37961150

• Ketamine evoked disruption of entorhinal and hippocampal spatial maps. Nature communications Masuda, F. K., Aery Jones, E. A., Sun, Y., Giocomo, L. M. 2023; 14 (1): 6285

  Abstract

  Ketamine, a rapid-acting anesthetic and acute antidepressant, carries undesirable spatial cognition side effects including out-of-body experiences and spatial memory impairments. The neural substrates that underlie these alterations in spatial cognition however, remain incompletely understood. Here, we used electrophysiology and calcium imaging to examine ketamine's impacts on the medial entorhinal cortex and hippocampus, which contain neurons that encode an animal's spatial position, as mice navigated virtual reality and real world environments. Ketamine acutely increased firing rates, degraded cell-pair temporal firing-rate relationships, and altered oscillations, leading to longer-term remapping of spatial representations. In the reciprocally connected hippocampus, the activity of neurons that encode the position of the animal was suppressed after ketamine administration. Together, these findings demonstrate ketamine-induced dysfunction of the MEC-hippocampal circuit at the single cell, local-circuit population, and network levels, connecting previously demonstrated physiological effects of ketamine on spatial cognition to alterations in the spatial navigation circuit.

  View details for DOI 10.1038/s41467-023-41750-4

  View details for PubMedID 37805575

  View details for PubMedCentralID PMC10560293

• Neural ensembles in navigation: From single cells to population codes. Current opinion in neurobiology Aery Jones, E. A., Giocomo, L. M. 2022; 78: 102665

  Abstract

  The brain can represent behaviorally relevant information through the firing of individual neurons as well as the coordinated firing of ensembles of neurons. Neurons in the hippocampus and associated cortical regions participate in a variety of types of ensembles to support navigation. These ensemble types include single cell codes, population codes, time-compressed sequences, behavioral sequences, and engrams. We present the physiological basis and behavioral relevance of ensemble firing. We discuss how these traditional definitions of ensembles can constrain or expand potential analyses due to the underlying assumptions and abstractions made. We highlight how coding can change at the ensemble level while underlying single cell codes remain intact. Finally, we present how ensemble definitions could be broadened to better understand the full complexity of the brain.

  View details for DOI 10.1016/j.conb.2022.102665

  View details for PubMedID 36542882

• Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1. Cell reports Aery Jones, E. A., Rao, A., Zilberter, M., Djukic, B., Bant, J. S., Gillespie, A. K., Koutsodendris, N., Nelson, M., Yoon, S. Y., Huang, K., Yuan, H., Gill, T. M., Huang, Y., Frank, L. M. 1800; 37 (13): 110159

  Abstract

  Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV+) and somatostatin-expressing (SST+), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons has the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.

  View details for DOI 10.1016/j.celrep.2021.110159

  View details for PubMedID 34965435

• Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease. Nature aging Taubes, A., Nova, P., Zalocusky, K. A., Kosti, I., Bicak, M., Zilberter, M. Y., Hao, Y., Yoon, S. Y., Oskotsky, T., Pineda, S., Chen, B., Jones, E. A., Choudhary, K., Grone, B., Balestra, M. E., Chaudhry, F., Paranjpe, I., De Freitas, J., Koutsodendris, N., Chen, N., Wang, C., Chang, W., An, A., Glicksberg, B. S., Sirota, M., Huang, Y. 2021; 1 (10): 932-947

  Abstract

  The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Abeta accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.

  View details for DOI 10.1038/s43587-021-00122-7

  View details for PubMedID 36172600

• In Vivo Chimeric Alzheimer's Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons. Cell reports Najm, R., Zalocusky, K. A., Zilberter, M., Yoon, S. Y., Hao, Y., Koutsodendris, N., Nelson, M., Rao, A., Taubes, A., Jones, E. A., Huang, Y. 2020; 32 (4): 107962

  Abstract

  Despite its clear impact on Alzheimer's disease (AD) risk, apolipoprotein (apo) E4's contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplant human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knockin mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single-nucleus RNA sequencing (snRNA-seq), we identify key transcriptional changes specific to human neuron subtypes in response to endogenous or exogenous apoE4. We also find that Aβ from transplanted human neurons forms plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype. These findings highlight the power of in vivo chimeric disease modeling for studying AD.

  View details for DOI 10.1016/j.celrep.2020.107962

  View details for PubMedID 32726626

  View details for PubMedCentralID PMC7430173

• Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer's disease. Molecular neurodegeneration Najm, R. n., Jones, E. A., Huang, Y. n. 2019; 14 (1): 24

  Abstract

  Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4's detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.

  View details for DOI 10.1186/s13024-019-0324-6

  View details for PubMedID 31186040

  View details for PubMedCentralID PMC6558779

• Early Hippocampal Sharp-Wave Ripple Deficits Predict Later Learning and Memory Impairments in an Alzheimer's Disease Mouse Model. Cell reports Jones, E. A., Gillespie, A. K., Yoon, S. Y., Frank, L. M., Huang, Y. n. 2019; 29 (8): 2123–33.e4

  Abstract

  Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs)-electrophysiological signatures of memory reactivation in the hippocampus-are a compelling candidate for this purpose. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knockin (apoE4-KI) mice-a model of the major genetic risk factor for AD-we find that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1-2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.

  View details for DOI 10.1016/j.celrep.2019.10.056

  View details for PubMedID 31747587

• Approaching Alzheimer's disease from a network level. Oncotarget Gillespie, A. K., Jones, E. A., Huang, Y. n. 2017; 8 (6): 9003–4

  View details for DOI 10.18632/oncotarget.14617

  View details for PubMedID 28099927

  View details for PubMedCentralID PMC5354704

• Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples. Neuron Gillespie, A. K., Jones, E. A., Lin, Y. H., Karlsson, M. P., Kay, K. n., Yoon, S. Y., Tong, L. M., Nova, P. n., Carr, J. S., Frank, L. M., Huang, Y. n. 2016; 90 (4): 740–51

  Abstract

  Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however, the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments. VIDEO ABSTRACT.

  View details for DOI 10.1016/j.neuron.2016.04.009

  View details for PubMedID 27161522

  View details for PubMedCentralID PMC5097044

• Prenatal Nicotine Exposure Impairs Executive Control Signals in Medial Prefrontal Cortex. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Bryden, D. W., Burton, A. C., Barnett, B. R., Cohen, V. J., Hearn, T. N., Jones, E. A., Kariyil, R. J., Kunin, A. n., Kwak, S. I., Lee, J. n., Lubinski, B. L., Rao, G. K., Zhan, A. n., Roesch, M. R. 2016; 41 (3): 716–25

  Abstract

  Prenatal nicotine exposure (PNE) is linked to numerous psychiatric disorders including attention deficit hyperactivity disorder (ADHD). Current literature suggests that core deficits observed in ADHD reflect abnormal inhibitory control governed by the prefrontal cortex. Yet, it is unclear how neural activity in the medial prefrontal cortex (mPFC) is modulated during tasks that assess response inhibition or if these neural correlates, along with behavior, are affected by PNE. To address this issue, we recorded from single mPFC neurons in control and PNE rats as they performed a stop-signal task. We found that PNE rats were faster for all trial-types, made more premature responses, and were less likely to inhibit behavior on 'STOP' trials during which rats had to inhibit an already initiated response. Activity in mPFC was modulated by response direction and was positively correlated with accuracy and movement time in control but not PNE rats. Although the number of single neurons correlated with response direction was significantly reduced by PNE, neural activity observed on general STOP trials was largely unaffected. However, dramatic behavioral deficits on STOP trials immediately following non-conflicting (GO) trials in the PNE group appear to be mediated by the loss of conflict monitoring signals in mPFC. We conclude that prenatal nicotine exposure makes rats impulsive and disrupts firing of mPFC neurons that carry signals related to response direction and conflict monitoring.

  View details for DOI 10.1038/npp.2015.197

  View details for PubMedID 26189451

  View details for PubMedCentralID PMC4707818