memory deficits

Structural and functional characterization of autoimmune antibodies against NMDAR

Project Summary. The goal of this project is to understand the origins and molecular mechanisms underlying the anti-cancer autoimmune response against the N-methyl-D-aspartate receptor (NMDAR) and its correlation with anti-N-methyl-D-aspartate receptor autoimmune encephalitis (NMDARAE). While anti-cancer immune responses can promote tumor elimination, they may also lead to the production of self-reactive antibodies that trigger autoimmune diseases. NMDARAE is the most common form of immune-mediated encephalitis, which results in prominent neuropsychiatric symptoms, including seizures, psychosis, and memory deficits. NMDARs belong to a family of ligand-gated ion channels expressed exclusively in the central nervous system. They are involved in various aspects of brain development and function, including learning and memory. They respond to the neurotransmitter glutamate and a co-agonist, glycine or D-serine, to mediate excitatory neurotransmission, which plays a central role in synaptic plasticity. NMDARAE is associated with ovarian teratomas, where aberrant NMDAR expression is believed to trigger an autoimmune response. In NMDARAE, anti-NMDAR antibodies, as well as B cells and antibody-secreting cells, cross the blood-brain barrier via unknown mechanisms, resulting in the presence of anti-NMDAR antibodies at high titers within the brain and cerebrospinal fluid (CSF). These antibodies target NMDARs, modulating their function and contributing to disease pathology. Emerging evidence, supported by our preliminary data, suggests that NMDARs are also expressed in triple-negative breast cancer (TNBC), extending the relevance of anti-NMDAR autoimmunity beyond ovarian teratomas. In our TNBC mouse model, which ectopically expresses NMDARs (TNBC-NMDAR), we observed the onset of anti-NMDAR autoimmunity, where the produced antibodies cause both anti-tumor activity and symptoms such as lowered seizure threshold, mirroring key features of NMDARAE. Here, we will establish this TNBC mouse model as we develop molecular methods to characterize it. Aim 1 will focus on establishing and characterizing the TNBC- NMDAR mouse model. We will develop a detection method utilizing the intact tetrameric NMDAR channel proteins and a method to isolate B cells expressing B cell receptors against NMDAR from biological samples by using fluorescently labeled intact NMDAR proteins, followed by single-cell RNA sequencing. Aim 2 will utilize single-particle cryo-electron microscopy (cryo-EM) to investigate the interactions between NMDAR and the cloned antibodies, providing insights into epitope recognition, NMDAR subtype specificity, and conformational changes induced by antibody binding. Aim 3 will assess the impact of the cloned antibodies on NMDAR channel activity using electrophysiology. We will also assess anti-tumor activity and NMDARAE onset by each antibody clone. Together, the proposed research will gain insights into the link between anti-cancer anti-NMDAR autoimmunity and NMDARAE. It will also elucidate which functional properties of the cloned antibodies promote anti-tumor activity while contributing to NMDARAE, thereby informing potential therapeutic strategies.

2-Deoxyglucose Therapy for Organophosphate Intoxication

Project Summary The main goal of this project is to determine the therapeutic potential of glycolysis inhibition as an adjunct to midazolam therapy in mitigating the long-term neurological effects from acute organophosphate pesticide and nerve agent (OPNA) exposure. Novel countermeasures are desperately needed for effective mitigation of morbidity and long-term effects of OPNAs. A variety of agents targeting glutamate, GABA and oxidative stress have been proposed, but glycolysis inhibitors have not been widely studied in OPNA intoxication. Dysregulated glucose metabolism plays a key role in seizures and neuronal injury following OPNA exposure. 2-Deoxyglucose (2-DG), a selective glycolysis inhibitor, has anticonvulsant and neuroprotection effects and hence can effectively mitigate acute and long-term OPNA neurotoxicity. In this project, we seek to identify the glycolysis inhibition as novel adjunct neuroprotection to midazolam therapy for OPNA exposure, with the goal of identifying 2-DG or related drugs as medical countermeasures. The glycolytic pathway represents a logical target for such intervention because glycolysis controls seizures and neuronal injury by regulating glucose utilization and activity in neurons and astrocytes in the brain. The proposed therapy is based on the hypothesis that acute OPNA neurotoxicity imparts sustained activation of the glycolysis pathway in the brain and therefore, 2- DG and selective glycolysis inhibitors prevents long-term neuronal damage neurological dysfunction. This hypothesis will be tested by using the FDA-approved (2-DG) or clinical-stage glycolytic inhibitors in two distinct OPNA models in rats: (Aim 1) To investigate the protective efficacy of 2-DG and novel glycolysis inhibitors against DFP-induced acute and long-term neuronal damage and neurological dysfunction. (Aim 2) Aim 2 (Year 2). To determine brain penetration, pilot toxicity and pharmacokinetic of 2-DG or other lead drug in naïve and DFP-exposed animals. Test drugs will be evaluated as per the NIH rigor criteria in a dose-related design in male and female rats and behavior/neuropathology will be checked for 3 months post-exposure. 2-DG and test drugs will be given starting 40-min after exposure to ONAs. Three primary outcome measures will be addressed for therapy effectiveness: (i) acute adjunct neuroprotection; (ii) chronic neuroprotectant efficacy; and (iii) prevention of neurological and behavioral deficits. The primary measures of neuroprotection include longitudinal MRI scanning, and extent of neurodegeneration, neuroinflammation, aberrant neurogenesis, and mossy fiber sprouting. Key neurological outcomes include memory deficits, depression, anxiety behavior, and neurological/motor deficits. The outcome of this project will provide “proof-of-efficacy” of a novel glycolytic therapy with FDA-approvable, repurposed drugs with promising potential to limit long-term effects of OPNAs in humans. Thus, the overall impact of the outcome is enormous for civilians, especially in developing a highly effective and safe post-exposure medical countermeasure for chemical nerve agents.

Hippocampal network dynamics during impaired working memory in epileptic mice

Memory impairment is a common cognitive deficit in temporal lobe epilepsy (TLE). The hippocampus is severely altered in TLE exhibiting multiple anatomical changes that lead to a hyperexcitable network capable of generating frequent epileptic discharges and seizures. In this study we investigated whether hippocampal involvement in epileptic activity drives working memory deficits using bilateral LFP recordings from CA1 during task performance. We discovered that epileptic mice experienced focal rhythmic discharges (FRDs) while they performed the spatial working memory task. Spatial correlation analysis revealed that FRDs were often spatially stable on the maze and were most common around reward zones (25 ‰) and delay zones (50 ‰). Memory performance was correlated with stability of FRDs, suggesting that spatially unstable FRDs interfere with working memory codes in real time.

Neural circuits of visuospatial working memory

One elementary brain function that underlies many of our cognitive behaviors is the ability to maintain parametric information briefly in mind, in the time scale of seconds, to span delays between sensory information and actions. This component of working memory is fragile and quickly degrades with delay length. Under the assumption that behavioral delay-dependencies mark core functions of the working memory system, our goal is to find a neural circuit model that represents their neural mechanisms and apply it to research on working memory deficits in neuropsychiatric disorders. We have constrained computational models of spatial working memory with delay-dependent behavioral effects and with neural recordings in the prefrontal cortex during visuospatial working memory. I will show that a simple bump attractor model with weak inhomogeneities and short-term plasticity mechanisms can link neural data with fine-grained behavioral output in a trial-by-trial basis and account for the main delay-dependent limitations of working memory: precision, cardinal repulsion biases and serial dependence. I will finally present data from participants with neuropsychiatric disorders that suggest that serial dependence in working memory is specifically altered, and I will use the model to infer the possible neural mechanisms affected.

JAK/STAT regulation of the transcriptomic response during epileptogenesis

Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and neural circuit remodeling in the hippocampus resulting in increased susceptibility to spontaneous seizures and cognitive dysfunction. Targeting these cascades could prevent or reverse symptom progression and has the potential to provide viable disease-modifying treatments that could reduce the portion of TLE patients (>30%) not responsive to current medical therapies. Changes in GABA(A) receptor subunit expression have been implicated in the pathogenesis of TLE, and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has been shown to be a key regulator of these changes. The JAK/STAT pathway is known to be involved in inflammation and immunity, and to be critical for neuronal functions such as synaptic plasticity and synaptogenesis. Our laboratories have shown that a STAT3 inhibitor, WP1066, could greatly reduce the number of spontaneous recurrent seizures (SRS) in an animal model of pilocarpine-induced status epilepticus (SE). This suggests promise for JAK/STAT inhibitors as disease-modifying therapies, however, the potential adverse effects of systemic or global CNS pathway inhibition limits their use. Development of more targeted therapeutics will require a detailed understanding of JAK/STAT-induced epileptogenic responses in different cell types. To this end, we have developed a new transgenic line where dimer-dependent STAT3 signaling is functionally knocked out (fKO) by tamoxifen-induced Cre expression specifically in forebrain excitatory neurons (eNs) via the Calcium/Calmodulin Dependent Protein Kinase II alpha (CamK2a) promoter. Most recently, we have demonstrated that STAT3 KO in excitatory neurons (eNSTAT3fKO) markedly reduces the progression of epilepsy (SRS frequency) in the intrahippocampal kainate (IHKA) TLE model and protects mice from kainic acid (KA)-induced memory deficits as assessed by Contextual Fear Conditioning. Using data from bulk hippocampal tissue RNA-sequencing, we further discovered a transcriptomic signature for the IHKA model that contains a substantial number of genes, particularly in synaptic plasticity and inflammatory gene networks, that are down-regulated after KA-induced SE in wild-type but not eNSTAT3fKO mice. Finally, we will review data from other models of brain injury that lead to epilepsy, such as TBI, that implicate activation of the JAK/STAT pathway that may contribute to epilepsy development.

From oscillations to laminar responses - characterising the neural circuitry of autobiographical memories

Autobiographical memories are the ghosts of our past. Through them we visit places long departed, see faces once familiar, and hear voices now silent. These, often decades-old, personal experiences can be recalled on a whim or come unbidden into our everyday consciousness. Autobiographical memories are crucial to cognition because they facilitate almost everything we do, endow us with a sense of self and underwrite our capacity for autonomy. They are often compromised by common neurological and psychiatric pathologies with devastating effects. Despite autobiographical memories being central to everyday mental life, there is no agreed model of autobiographical memory retrieval, and we lack an understanding of the neural mechanisms involved. This precludes principled interventions to manage or alleviate memory deficits, and to test the efficacy of treatment regimens. This knowledge gap exists because autobiographical memories are challenging to study – they are immersive, multi-faceted, multi-modal, can stretch over long timescales and are grounded in the real world. One missing piece of the puzzle concerns the millisecond neural dynamics of autobiographical memory retrieval. Surprisingly, there are very few magnetoencephalography (MEG) studies examining such recall, despite the important insights this could offer into the activity and interactions of key brain regions such as the hippocampus and ventromedial prefrontal cortex. In this talk I will describe a series of MEG studies aimed at uncovering the neural circuitry underpinning the recollection of autobiographical memories, and how this changes as memories age. I will end by describing our progress on leveraging an exciting new technology – optically pumped MEG (OP-MEG) which, when combined with virtual reality, offers the opportunity to examine millisecond neural responses from the whole brain, including deep structures, while participants move within a virtual environment, with the attendant head motion and vestibular inputs.

Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy

Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding, and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed that the mechanisms constraining the generation of Na+ spikes in hippocampal 1st order pyramidal cell dendrites are profoundly degraded in experimental epilepsy. This phenomenon was reversed by selectively blocking Nav1.3 sodium channels. In-vivo two-photon imaging revealed that hippocampal spatial representations were less precise in epileptic mice. Blocking Nav1.3 channels significantly improved the precision of spatial coding, and reversed hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.

Emergent scientists discuss Alzheimer's disease

This seminar is part of our “Emergent Scientists” series, an initiative that provides a platform for scientists at the critical PhD/postdoc transition period to share their work with a broad audience and network. Summary: These talks cover Alzheimer’s disease (AD) research in both mice and humans. Christiana will discuss in particular the translational aspects of applying mouse work to humans and the importance of timing in disease pathology and intervention (e.g. timing between AD biomarkers vs. symptom onset, timing of therapy, etc.). Siddharth will discuss a rare variant of Alzheimer’s disease called “Logopenic Progressive Aphasia”, which presents with temporo-parietal atrophy yet relative sparing of hippocampal circuitry. Siddharth will discuss how, despite the unusual anatomical basis underlying this AD variant, degeneration of the angular gyrus in the left inferior parietal lobule contributes to memory deficits similar to those of typical amnesic Alzheimer’s disease. Christiana’s abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that causes severe deterioration of memory, cognition, behavior, and the ability to perform daily activities. The disease is characterized by the accumulation of two proteins in fibrillar form; Amyloid-β forms fibrils that accumulate as extracellular plaques while tau fibrils form intracellular tangles. Here we aim to translate findings from a commonly used AD mouse model to AD patients. Here we initiate and chronically inhibit neuropathology in lateral entorhinal cortex (LEC) layer two neurons in an AD mouse model. This is achieved by over-expressing P301L tau virally and chronically activating hM4Di DREADDs intracranially using the ligand dechloroclozapine. Biomarkers in cerebrospinal fluid (CSF) is measured longitudinally in the model using microdialysis, and we use this same system to intracranially administer drugs aimed at halting AD-related neuropathology. The models are additionally tested in a novel contextual memory task. Preliminary findings indicate that viral injections of P301L tau into LEC layer two reveal direct projections between this region and the outer molecular layer of dentate gyrus and the rest of hippocampus. Additionally, phosphorylated tau co-localize with ‘starter cells’ and appear to spread from the injection site. Preliminary microdialysis results suggest that the concentrations of CSF amyloid-β and tau proteins mirror changes observed along the disease cascade in patients. The disease-modifying drugs appear to halt neuropathological development in this preclincial model. These findings will lead to a novel platform for translational AD research, linking the extensive research done in rodents to clinical applications. Siddharth’s abstract: A distributed brain network supports our ability to remember past events. The parietal cortex is a critical member of this network, yet, its exact contributions to episodic remembering remain unclear. Neurodegenerative syndromes affecting the posterior neocortex offer a unique opportunity to understand the importance and role of parietal regions to episodic memory. In this talk, I introduce and explore the rare neurodegenerative syndrome of Logopenic Progressive Aphasia (LPA), an aphasic variant of Alzheimer’s disease presenting with early, left-lateralized temporo-parietal atrophy, amidst relatively spared hippocampal integrity. I then discuss two key studies from my recent Ph.D. work showcasing pervasive episodic and autobiographical memory dysfunction in LPA, to a level comparable to typical, amnesic Alzheimer’s disease. Using multimodal neuroimaging, I demonstrate how degeneration of the angular gyrus in the left inferior parietal lobule, and its structural connections to the hippocampus, contribute to amnesic profiles in this syndrome. I finally evaluate these findings in the context of memory profiles in other posterior cortical neurodegenerative syndromes as well as recent theoretical models underscoring the importance of the parietal cortex in the integration and representation of episodic contextual information.

Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by amyloid-β (1-42) oligomers in mice: implication of transforming growth factor-β1 and oxidative stress

A long-term treatment with antidepressants reduces the risk to develop AD and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently studied for their neuroprotective properties in AD. An impairment of neurotrophic factors signaling seems to be a common pathophysiological event in depression and AD. In particular a deficit of transforming growth factor-β1 (TGF-β1) and increased oxidative stress have been found both in depression and AD. In the present work the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype in a non-transgenic mouse model of AD (i.c.v. Aβ1-42 injection) by rescue of TGF-β1 signaling. The same drugs were also tested for their ability to modulate the expression of pro-oxidant genes as well as of genes related to the antioxidant machinery.

Interneuron desynchronization and breakdown of long-term place cell stability in temporal lobe epilepsy

Temporal lobe epilepsy is associated with memory deficits but the circuit mechanisms underlying these cognitive disabilities are not understood. We used electrophysiological recordings, open-source wire-free miniaturized microscopy and computational modeling to probe these deficits in a model of temporal lobe epilepsy. We find desynchronization of dentate gyrus interneurons with CA1 interneurons during theta oscillations and a loss of precision and stability of place fields. We also find that emergence of place cell dysfunction is delayed, providing a potential temporal window for treatments. Computation modeling shows that desynchronization rather than interneuron cell loss can drive place cell dysfunction. Future studies will uncover cell types driving these changes and transcriptional changes that may be driving dysfunction.

Aberrant survival of Cajal-Retzius cells leads to memory deficits and susceptibility to epileptic seizures

the butyric acid precursor tributyrin modulates hippocampal synaptic plasticity and prevents spatial memory deficits: role of pparγ and ampk

Combination therapy of donepezil and environmental enrichment on memory deficits in amyloid-beta-induced Alzheimer's disease rats

cx-DHED efficiently reduces amyloid beta production and memory deficits more than DHED in a mouse model of Alzheimer’s disease by additional regulation on alpha-secretase activity

IL-1β triggers synaptic and memory deficits in Herpes Simplex Virus Type-1-infected mice

Modulation of N-acylethanolamines – peroxisome proliferator receptor type gamma axis counteracts memory deficits of prenatal and lactation alcohol exposed mice

Neuronal adenosine A2A receptor overexpression exacerbates memory deficits and synaptic loss in an amyloidogenic mouse model of Alzheimer’s disease

Pharmacological and genetic probing of the role of Nociceptin/orphaninFQ receptors in chronic stress-induced memory deficits

BDNF rescues absence seizures and their comorbid memory deficits

FENS Forum 2024

Continuous theta-burst stimulation improves learning/memory deficits and behavioral disturbances in the trimethyltin-induced Alzheimer's-like disease model - relevance for the treatment of neurodegenerative disorders?

FENS Forum 2024

GRIK1 expression at OLM interneurons in the hippocampus and memory deficits in Down syndrome

FENS Forum 2024

HBK-10, a multimodal compound, selectively blocks 5-HT1A receptor-mediated β-arrestin recruitment and mitigates memory deficits in mice

FENS Forum 2024

Motor and memory deficits in nestin-Cre Psip1 KO mice

FENS Forum 2024