Charlotte Sophia Herber

All Publications

• Spatial coding dysfunction and network instability in the aging medial entorhinal cortex. Nature communications Herber, C. S., Pratt, K. J., Shea, J. M., Villeda, S. A., Giocomo, L. M. 2025; 16 (1): 8770

  Abstract

  Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged in vivo electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments. In aged grid cells, we observed impaired stabilization of context-specific spatial firing, correlated with spatial memory deficits. Additionally, aged grid networks shifted firing patterns often, but with poor alignment to context changes. Aged spatial firing was also unstable in an unchanging environment. In these same mice, we identified 458 genes differentially expressed with age in MEC, 61 of which had expression correlated with spatial coding quality. These genes were interneuron-enriched and related to synaptic plasticity, notably including a perineuronal net component. Together, these findings identify coordinated transcriptomic, cellular, and network changes in MEC implicated in impaired spatial memory in aging.

  View details for DOI 10.1038/s41467-025-63229-0

  View details for PubMedID 41044154

  View details for PubMedCentralID PMC12494969

• Spatial Coding Dysfunction and Network Instability in the Aging Medial Entorhinal Cortex. bioRxiv : the preprint server for biology Herber, C. S., Pratt, K. J., Shea, J. M., Villeda, S. A., Giocomo, L. M. 2024

  Abstract

  Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged in vivo electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments. In aged grid cells, we observed impaired stabilization of context-specific spatial firing, correlated with spatial memory deficits. Additionally, aged grid networks shifted firing patterns often but with poor alignment to context changes. Aged spatial firing was also unstable in an unchanging environment. In these same mice, we identified 458 genes differentially expressed with age in MEC, 61 of which had expression correlated with spatial firing stability. These genes were enriched among interneurons and related to synaptic transmission. Together, these findings identify coordinated transcriptomic, cellular, and network changes in MEC implicated in impaired spatial memory in aging.

  View details for DOI 10.1101/2024.04.12.588890

  View details for PubMedID 38659809

  View details for PubMedCentralID PMC11042240

• Transcriptional regulation of neural stem cell expansion in the adult hippocampus ELIFE Guo, N., McDermott, K. D., Shih, Y., Zanga, H., Ghosh, D., Herber, C., Meara, W. R., Coleman, J., Zagouras, A., Wong, L., Sadreyev, R., Goncalves, J., Sahay, A. 2022; 11

  Abstract

  Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors (TFs) in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of TFs regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the TF Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital two-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell cycle, fatty acid oxidation, and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.

  View details for DOI 10.7554/eLife.72195.sa2

  View details for Web of Science ID 000758046300001

  View details for PubMedID 34982030

  View details for PubMedCentralID PMC8820733

• Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β JOURNAL OF BIOLOGICAL CHEMISTRY Nies, S., Takahashi, H., Herber, C. S., Huttner, A., Chase, A., Strittmatter, S. M. 2021; 297 (4): 101159

  Abstract

  In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Aβ copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and AppNL-F/NL-F knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Aβ, and the Aβ coinjection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Aβ from tau extracts. These data suggest that Aβ and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer-induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. These studies refine our knowledge of factors capable of modulating tau spreading.

  View details for DOI 10.1016/j.jbc.2021.101159

  View details for Web of Science ID 000713015100004

  View details for PubMedID 34480901

  View details for PubMedCentralID PMC8477193

• Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization NATURE MEDICINE Guo, N., Soden, M. E., Herber, C., Kim, M., Besnard, A., Lin, P., Ma, X., Cepko, C. L., Zweifel, L. S., Sahay, A. 2018; 24 (4): 438-+

  Abstract

  Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.

  View details for DOI 10.1038/nm.4491

  View details for Web of Science ID 000429639800015

  View details for PubMedID 29529016

  View details for PubMedCentralID PMC5893385

• Conditional Deletion of <i>Prnp</i> Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease JOURNAL OF NEUROSCIENCE Salazar, S. V., Gallardo, C., Kaufman, A. C., Herber, C. S., Haas, L. T., Robinson, S., Manson, J. C., Lee, M. K., Strittmatter, S. M. 2017; 37 (38): 9207-9221

  Abstract

  Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrPC) prevents development of memory deficits in APPswe/PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset.SIGNIFICANCE STATEMENT The study presented here further elucidates our understanding of the soluble oligomeric amyloid-β-Aβo-binding cellular prion protein (PrPC) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrPC as a potential therapeutic target for AD. In particular, genetic deletion of Prnp rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrPC deletion given that patients already present symptoms at the time of diagnosis.

  View details for DOI 10.1523/JNEUROSCI.0722-17.2017

  View details for Web of Science ID 000411231700009

  View details for PubMedID 28842420

  View details for PubMedCentralID PMC5607466

• Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer's Mouse Phenotypes CELL REPORTS Haas, L. T., Salazar, S. V., Smith, L. M., Zhao, H. R., Cox, T. O., Herber, C. S., Degnan, A. P., Balakrishnan, A., Macor, J. E., Albright, C. F., Strittmatter, S. M. 2017; 20 (1): 76-88

  Abstract

  Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrPC) bound to Aβo. The SAM compound prevents Aβo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5's role in Aβo-dependent AD phenotypes is separate from its role in glutamate signaling and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window.

  View details for DOI 10.1016/j.celrep.2017.06.023

  View details for Web of Science ID 000404899700008

  View details for PubMedID 28683325

  View details for PubMedCentralID PMC5547898

• The Association between Diffusion MRI-Defined Infarct Volume and NIHSS Score in Patients with Minor Acute Stroke JOURNAL OF NEUROIMAGING Yaghi, S., Herber, C., Boehme, A. K., Andrews, H., Willey, J. Z., Rostanski, S. K., Siket, M., Jayaraman, M. V., McTaggart, R. A., Furie, K. L., Marshall, R. S., Lazar, R. M., Boden-Albala, B. 2017; 27 (4): 388-391

  Abstract

  Prior studies have shown a correlation between the National Institutes of Health Stroke Scale (NIHSS) and stroke volume on diffusion weighted imaging (DWI); data are more limited in patients with minor stroke. We sought to determine the association between DWI lesion(s) volume and the (1) total NIHSS score and (2) NIHSS component scores in patients with minor stroke.We included all patients with minor stroke (NIHSS 0-5) enrolled in the Stroke Warning Information and Faster Treatment study. We calculated lesion(s) volume (cm3 ) on the DWI sequence using Medical Image Processing, Analysis, and Visualization (MIPAV, NIH, Version 7.1.1). We used nonparametric tests to study the association between the primary outcome, DWI lesion(s) volume, and the predictors (NIHSS score and its components).We identified 894 patients with a discharge diagnosis of minor stroke; 709 underwent magnetic resonance imaging and 510 were DWI positive. There was a graded relationship between the NIHSS score and median DWI lesion volume in cm3 : (NIHSS 0: 7.1, NIHSS 1: 8.0, NIHSS 2: 17.1, NIHSS 3: 11.6, NIHSS 4: 19.0, and NIHSS 5: 23.6, P < .01). The median lesion volume was significantly higher in patients with neglect (105.6 vs. 12.5, P = .025), language disorder (34.6 vs. 11.9, P < .001), and visual field impairment (185.6 vs. 11.6, P < .001). Other components of the NIHSS were not associated with lesion volume.In patients with minor stroke, the nature of deficit when used with the NIHSS score can improve prediction of infarct volume. This may have clinical and therapeutic implications.

  View details for DOI 10.1111/jon.12423

  View details for Web of Science ID 000405893900006

  View details for PubMedID 28066971

  View details for PubMedCentralID PMC5518742

• Variability in Motor and Language Recovery during the Acute Stroke Period CEREBROVASCULAR DISEASES EXTRA Dunn, L. E., Schweber, A. B., Manson, D. K., Lendaris, A., Herber, C., Marshall, R. S., Lazar, R. M. 2016; 6 (1): 12-21

  Abstract

  Most stroke recovery occurs by 90 days after onset, with proportional recovery models showing an achievement of about 70% of the maximal remaining recovery. Little is known about recovery during the acute stroke period. Moreover, data are described for groups, not for individuals. In this observational cohort study, we describe for the first time the daily changes of acute stroke patients with motor and/or language deficits over the first week after stroke onset.Patients were enrolled within 24-72 h after stroke onset with upper extremity hemiparesis, aphasia, or both, and were tested daily until day 7 or discharge with the upper-extremity Fugl-Meyer Assessment of Motor Recovery after Stroke, the Boston Naming Test, and the comprehension domain from the Western Aphasia Battery. Discharge scores, and absolute and proportional changes were examined using t-tests for pairwise comparisons and linear regression to determine relative contributions of initial impairment, lesion volume, and age to recovery over this period.Thirty-four patients were enrolled: 19 had motor deficits alone, 8 had aphasia alone, and 7 had motor and language deficits. In a group analysis, statistically significant changes in absolute scores were found in the motor (p < 0.001) and comprehension (p < 0.001) domains but not in naming. Day-by-day recovery curves for individual patients displayed wide variation with comparable initial impairment. Proportional recovery calculations revealed that, on average, patients achieved less than 1/3 of their potential recovery by the time of discharge. Multivariate regression showed that the amount of variance accounted for by initial severity, age, and lesion volume in this early time period was not significant for motor or language domains.Over the first week after stroke onset, recovery of upper extremity hemiparesis and aphasia were not predictable on the basis of initial impairment, lesion volume, or age. In addition, patients only achieved about 1/3 of their remaining possible recovery based on the anticipated 70% proportion found at 90 days. These findings suggest that the complex interaction between poststroke structural repair, regeneration, and functional reorganization during the first week after stroke has yet to be elucidated.

  View details for DOI 10.1159/000444149

  View details for Web of Science ID 000389377600002

  View details for PubMedID 27099611

  View details for PubMedCentralID PMC4836126