Hippocampal Formation Research Articles

Facial nerve axotomy induces morphological changes in hippocampal pyramidal neurons.

Facial nerve injury in rats have been widely used to study functional and structural changes that occur in the injured motoneurons and other central nervous system structures related with sensorimotor processing. A decrease in long-term potentiation of hippocampal CA3-to-CA1 commissural synapse has recently been reported related to this peripheral injury. Additionally, it has been found increased corticosterone plasmatic levels, impairment in spatial memory consolidation, and hippocampal microglial activation in animals with facial nerve axotomy. In this work, we analyzed the neuronal morphology of hippocampal CA1 and CA3 pyramidal neurons in animals with either reversible or irreversible facial nerve injury. For this purpose, brain tissues of injured animals sacrificed at different postlesion times, were stained with the Golgi-Cox method and compared with control brains. It was found that both reversible and irreversible facial nerve injury-induced significant decreases in dendritic tree complexity, dendritic length, branch points, and spine density of hippocampal neurons. However, such changes' timing varied according to hippocampal area (CA1 vs. CA3), dendritic area (apical vs. basal), and lesion type (reversible vs. irreversible). In general, the observed changes were transient when animals had the possibility of motor recovery (reversible injury), but perdurable if the recovery from the lesion was impeded (irreversible injury). CA1 apical and CA3 basal dendritic tree morphology were more sensible to irreversible injury. It is concluded that facial nerve injury induced significant changes in hippocampal CA1 and CA3 pyramidal neurons morphology, which could be related to LTP impairments and microglial activation in the hippocampal formation, previously described.

Behavioral origin of sound-evoked activity in mouse visual cortex

Sensory cortices can be affected by stimuli of multiple modalities and are thus increasingly thought to be multisensory. For instance, primary visual cortex (V1) is influenced not only by images but also by sounds. Here we show that the activity evoked by sounds in V1, measured with Neuropixels probes, is stereotyped across neurons and even across mice. It is independent of projections from auditory cortex and resembles activity evoked in the hippocampal formation, which receives little direct auditory input. Its low-dimensional nature starkly contrasts the high-dimensional code that V1 uses to represent images. Furthermore, this sound-evoked activity can be precisely predicted by small body movements that are elicited by each sound and are stereotyped across trials and mice. Thus, neural activity that is apparently multisensory may simply arise from low-dimensional signals associated with internal state and behavior.

Hyperphosphorylated Tau in Mesial Temporal Lobe Epilepsy: a Neuropathological and Cognitive Study.

Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age- and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal formation extracted from patients with drug-resistant mesial TLE undergoing surgery and postmortem non-sclerotic hippocampal formation of clinically and neuropathologically controls underwent immunohistochemistry against amyloid β (Aβ), hyperphosphorylated tau (p-tau), and TAR DNA-binding protein-43 (TDP-43) proteins, followed by quantitative analysis. Patients underwent a comprehensive neuropsychological evaluation prior to surgery. TLE hippocampi showed a significantly higher burden of p-tau than controls, whereas Aβ deposits and abnormal inclusions of TDP-43 were absent in both groups. Patients with hippocampal sclerosis (HS) type 2 had higher immunostaining for p-tau than patients with HS type 1. In addition, p-tau burden was associated with impairment in attention tasks and seizures frequency. In this series of adults younger than 60 years-old, the increase of p-tau burden associated with higher frequency of seizures and attention impairment suggests the involvement of tau pathology as a potential contributor to cognitive deficits in mesial TLE.

Resilience of Neural Cellularity to the Influence of Low Educational Level.

Education is believed to contribute positively to brain structure and function, as well as to cognitive reserve. One of the brain regions most impacted by education is the medial temporal lobe (MTL), a region that houses the hippocampus, which has an important role in learning processes and in consolidation of memories, and is also known to undergo neurogenesis in adulthood. We aimed to investigate the influence of education on the absolute cell numbers of the MTL (comprised by the hippocampal formation, amygdala, and parahippocampal gyrus) of men without cognitive impairment. The Isotropic Fractionator technique was used to allow the anisotropic brain tissue to be transformed into an isotropic suspension of nuclei, and therefore assess the absolute cell composition of the MTL. We dissected twenty-six brains from men aged 47 to 64 years, with either low or high education. A significant difference between groups was observed in brain mass, but not in MTL mass. No significant difference was found between groups in the number of total cells, number of neurons, and number of non-neuronal cells. Regression analysis showed that the total number of cells, number of neurons, and number of non-neuronal cells in MTL were not affected by education. The results indicate a resilience of the absolute cellular composition of the MTL of typical men to low schooling, suggesting that the cellularity of brain regions is not affected by formal education.

The precuneus as a central node in declarative memory retrieval.

Both, the hippocampal formation and the neocortex are contributing to declarative memory, but their functional specialization remains unclear. We investigated the differential contribution of both memory systems during free recall of word lists. In total, 21 women and 17 men studied the same list but with the help of different encoding associations. Participants associated the words either sequentially with the previous word on the list, with spatial locations on a well-known path, or with unique autobiographical events. After intensive rehearsal, subjects recalled the words during functional magnetic resonance imaging (fMRI). Common activity to all three types of encoding associations was identified in the posterior parietal cortex, in particular in the precuneus. Additionally, when associating spatial or autobiographical material, retrosplenial cortex activity was elicited during word list recall, while hippocampal activity emerged only for autobiographically associated words. These findings support a general, critical function of the precuneus in episodic memory storage and retrieval. The encoding-retrieval repetitions during learning seem to have accelerated hippocampus-independence and lead to direct neocortical integration in the sequentially associated and spatially associated word list tasks. During recall of words associated with autobiographical memories, the hippocampus might add spatiotemporal information supporting detailed scenic and contextual memories.

Deciphering the Role of microRNA Mediated Regulation of Coronin 1C in Glioblastoma Development and Metastasis.

Glioblastoma multiforme (GBM) is a highly heterogenic and malignant brain tumour with a median survival of 15 months. The initial identification of primary glioblastomas is often challenging. Coronin 1C (CORO1C) is a key player in actin rearrangement and cofilin dynamics, as well as enhancing the processes of neurite overgrowth and migration of brain tumour cells. Different bioinformatic databases were accessed to measure CORO1C expression at the mRNA and protein level in normal and malignant brains. CORO1C expression was observed in brain regions which have retained high synaptic plasticity and myelination properties. CORO1C was also expressed mainly within the hippocampus formation, including the Cornu Ammonis (CA) fields: CA1-CA4. Higher expression was also noticed in paediatric GBM in comparison to their adult counterparts. Pediatric cell populations were observed to have an increased log2 expression of CORO1C. Furthermore, 62 miRNAs were found to target the CORO1C gene. Of these, hsa-miR-34a-5p, hsa-miR-512-3p, hsa-miR-136-5p, hsa-miR-206, hsa-miR-128-3p, and hsa-miR-21-5p have shown to act as tumour suppressors or oncomiRs in different neoplasms, including GBM. The elevated expression of CORO1C in high grade metastatic brain malignancies, including GBM, suggests that this protein could have a clinical utility as a biomarker linked to an unfavorable outcome.

Morphological study of the postnatal hippocampal development in the TRPV1 knockout mice

ABSTRACT Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with polymodal sensory function. TRPV1 links to fever, while, according to previous studies on TRPV1 knock-out (KO) mice, the role of the channel in the generation of febrile seizure is debated. In the hippocampal formation, functional TRPV1 channels are expressed by Cajal-Retzius cells, which have a role in guidance of migrating neurons during development. Despite the developmental aspects of febrile seizure as well as of Cajal-Retzius cells, no information is available about the hippocampal development in TRPV1 KO mouse. Therefore, in the present work postnatal development of the hippocampal formation was studied in TRPV1 KO mice. Several morphological characteristics including neuronal positioning and maturation, synaptogenesis and myelination were examined with light microscopy following immunohistochemical detection of protein markers of various neurons, synapses, and myelination. Regarding the cytoarchitectonics, neuronal migration, morphological, and neurochemical maturation, no substantial difference could be detected between TRPV1 KO and wild-type control mice. Our data indicate that synapse formation and myelination occur similarly in TRPV1 KO and in control animals. We have found slightly, but not significantly larger numbers of persisting Cajal-Retzius cells in the KO mice than in controls. Our result strengthens previous suggestion concerning the role of TRPV1 channel in the postnatal apoptotic cell death of Cajal-Retzius cells. However, the fact that the hippocampus of KO mice lacks major developmental abnormalities supports the use of TRPV1 KO in various animal models of diseases and pathological conditions.

Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients.

Rationale: Bilateral sonication with focused ultrasound (FUS) in conjunction with microbubbles has been shown to separately reduce amyloid plaques and hyperphosphorylated tau protein in the hippocampal formation and the entorhinal cortex in different mouse models of Alzheimer's disease (AD) without any therapeutic agents. However, the two pathologies are expressed concurrently in human disease. Therefore, the objective of this study is to investigate the effects of repeated bilateral sonications in the presence of both pathologies. Methods: Herein, we investigate its functional and morphological outcomes on brains bearing both pathologies simultaneously. Eleven transgenic mice of the 3xTg-AD line (14 months old) expressing human amyloid beta and human tau and eleven age-matched wild-type littermates received four weekly bilateral sonications covering the hippocampus followed by working memory testing. Afterwards, immunohistochemistry and immunoassays (western blot and ELISA) were employed to assess any changes in amyloid beta and human tau. Furthermore, we present preliminary data from our clinical trial using a neuronavigation-guided FUS system for sonications in AD patients (NCT04118764). Results: Interestingly, both wild-type and transgenic animals that received FUS experienced improved working memory and spent significantly more time in the escape platform-quadrant, with wild-type animals spending 43.2% (sham: 37.7%) and transgenic animals spending 35.3% (sham: 31.0%) of the trial in the target quadrant. Furthermore, this behavioral amelioration in the transgenic animals correlated with a 58.3% decrease in the neuronal length affected by tau and a 27.2% reduction in total tau levels. Amyloid plaque population, volume and overall load were also reduced overall. Consistently, preliminary data from a clinical trial involving AD patients showed a 1.8% decrease of amyloid PET signal 3-weeks after treatment in the treated hemisphere compared to baseline. Conclusion: For the first time, it is shown that bilateral FUS-induced BBB opening significantly and simultaneously ameliorates both coexistent pathologies, which translated to improvements in spatial memory of transgenic animals with complex AD, the human mimicking phenotype. The level of cognitive improvement was significantly correlated with the volume of BBB opening. Non-transgenic animals were also shown to exhibit similar memory amelioration for the first time, indicating that BBB opening results into benefits in the neuronal function regardless of the existence of AD pathology. A potential mechanism of action for the reduction of the both pathologies investigated was the cholesterol metabolism, specifically the LRP1b receptor, which exhibited increased expression levels in transgenic mice following FUS-induced BBB opening. Initial clinical evidence supported that the beta amyloid reduction shown in rodents could be translatable to humans with significant amyloid reduction shown in the treated hemisphere.

Supplemental Material for Proteome Analysis Indicates Participation of the Dorsal Hippocampal Formation in Fear-Motivated Memory in a Time-Dependent Manner

Supplemental Material for Proteome Analysis Indicates Participation of the Dorsal Hippocampal Formation in Fear-Motivated Memory in a Time-Dependent Manner

Microstructural mapping of dentate gyrus pathology in Alzheimer’s disease: A 16.4 Tesla MRI study

The dentate gyrus (DG) is an integral portion of the hippocampal formation, and it is composed of three layers. Quantitative magnetic resonance (MR) imaging has the capability to map brain tissue microstructural properties which can be exploited to investigate neurodegeneration in Alzheimer’s disease (AD). However, assessing subtle pathological changes within layers requires high resolution imaging and histological validation. In this study, we utilized a 16.4 Tesla scanner to acquire ex vivo multi-parameter quantitative MRI measures in human specimens across the layers of the DG. Using quantitative diffusion tensor imaging (DTI) and multi-parameter MR measurements acquired from AD (N = 4) and cognitively normal control (N = 6) tissues, we performed correlation analyses with histological measurements. Here, we found that quantitative MRI measures were significantly correlated with neurofilament and phosphorylated Tau density, suggesting sensitivity to layer-specific changes in the DG of AD tissues.

EFFECT OF GLYCOLYSIS SUPRESSION ON ULTRASTRUCTURE OF THE HIPPOCAMPAL GIANT SYNAPSES

Suppression of glycolysis in the rat hippocampal formations was induced by daily intracerebroventricular injection of 2-deoxy-D-glucose for 10 days. Using electron microscopy, a disturbance of morphological interactions of axonal terminals of granular neurons with perisynaptic astrocytic processes was found. At the same time, both the determinant ultrastructural characteristics of giant synapses and two types of functional contacts (asymmetric chemical active zones with dendritic spines and symmetric adhesive junctions with dendrites) were retained. However, they showed morphological signs of a weakening of synaptic processes, which were expressed in a decrease in the number of intraterminal active zones, clustering of synaptic vesicles, and their removal from neurotransmitter release sites. Compared to the norm, an increase in the number of small mitochondria with an electron-dense matrix and the evidence of initiation of glycogen synthesis in the form of glycosomes were found in the giant terminals. The data obtained indicate that the giant synapses of the hippocampal mossy fibers are a plastic, self-correcting system that is able to function by adapting its own bioenergetic metabolism, when brain glycolysis is suppressed.

Hippocampal Volume in Children with Attention Deficit Hyperactivity Disorder and Speech and Language Delay.

Hippocampus is a complex brain structure located deep in the temporal lobes of the brain. The structure has been implicated in several disorders related to cognition. Reports are emerging of its involvement in attention deficit hyperactivity disorder (ADHD). The current study was planned to assess the volume of the hippocampus in children with ADHD and speech and language delay with normal birth history using magnetic resonance imaging (MRI) of the brain. MRI brain of 12 children (age range = 3-6 years) and 22 controls with clinical diagnosis of ADHD as per Diagnostic and Statistical Manual-5 were obtained in oblique coronal sequence (T1 weighted). The entire hippocampus formation was outlined manually using Image-J software available freely from www.freesurfer.com. Results were expressed as volume cubic millimeters ± SD. Volumes of the hippocampi of children with ADHD were 2450.2 ± 667 mm3 (R) and 2505.8 ± 878.5 mm3 (L), respectively. The mean volume (bilateral) of the cases was 2478 ± 772.75 mm3. The right hippocampal volume of the controls was 3255.8 ± 1374.3 mm3 (R) and that of the left side was 3159.3 ± 1451 (L) mm3, respectively. Current study reported a substantial shrinkage (23%) of the left and right hippocampus in children with ADHD compared to controls.

Identification of inflammasome signaling proteins in neurons and microglia in early and intermediate stages of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that destroys memory and cognitive function. Inflammasome activation has been suggested to play a critical role in the neuroinflammatory response in AD progression, but the cell-type expression of inflammasome proteins in the brain has not been fully characterized. In this study, we used samples from the hippocampus formation, the subiculum, and the entorhinal cortex brain from 17 donors with low-level AD pathology and 17 intermediate AD donors to assess the expression of inflammasome proteins. We performed analysis of hippocampal thickness, β-amyloid plaques, and hyperphosphorylated tau to ascertain the cellular pathological changes that occur between low and intermediate AD pathology. Next, we determined changes in the cells that express the inflammasome sensor proteins NOD-like receptor proteins (NLRP) 1 and 3, and caspase-1. In addition, we stained section with IC100, a humanized monoclonal antibody directed against the inflammasome adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and a commercially available anti-ASC antibody. Our results indicate that hippocampal cortical thickness did not significantly change between low and intermediate AD pathology, but there was an increase in pTau and β-amyloid clusters in intermediate AD cases. NLRP3 was identified mainly in microglial populations, whereas NLRP1 was seen in neuronal cytoplasmic regions. There was a significant increase of ASC in neurons labeled by IC100, whereas microglia in the hippocampus and subiculum were labeled with the commercial anti-ASC antibody. Caspase-1 was present in the parenchyma in the CA regions where amyloid and pTau were identified. Together, our results indicate increased inflammasome protein expression in the early pathological stages of AD, that IC100 identifies neurons in early stages of AD and that ASC expression correlates with Aβ and pTau in postmortem AD brains.

CA2 orchestrates hippocampal network dynamics.

The hippocampus is composed of various subregions: CA1, CA2, CA3, and the dentate gyrus (DG). Despite the abundant hippocampal research literature, until recently, CA2 received little attention. The development of new genetic and physiological tools allowed recent studies characterizing the unique properties and functional roles of this hippocampal subregion. Despite its small size, the cellular content of CA2 is heterogeneous at the molecular and physiological levels. CA2 has been heavily implicated in social behaviors, including social memory. More generally, the mechanisms by which the hippocampus is involved in memory include the reactivation of neuronal ensembles following experience. This process is coordinated by synchronous network events known as sharp-wave ripples (SWRs). Recent evidence suggests that CA2 plays an important role in the generation of SWRs. The unique connectivity and physiological properties of CA2 pyramidal cells make this region a computational hub at the core of hippocampal information processing. Here, we review recent findings that support the role of CA2 in coordinating hippocampal network dynamics from a systems neuroscience perspective.

The effect of stress on the formation of p53-positive and dark neurons in the hippocampus in a model of septoplasty in rats

The aim of this study was to determine the role of surgical stress on the formation of p53-positive and dark neurons (DN) in the hippocampus, and to examine the parallelism of their formation in the pyramidal layer of the hippocampus. Simulated septoplasty was performed on 20 Wistar rats. The hippocampus and dentate gyrus (DG) were examined, in which the number of DN and p53-positive neurons was determined at 2, 4 and 6 days after surgery. Compared with the control group (n = 5), the number of DN and p53-positive neurons increased in experimental animals at all periods. A direct relationship was obtained between the increase in the number of DN and p53-positive neurons in the hippocampal formation. Septoplasty simulation in rats results in the pathogenetic cascades onset, which, in its turn, changes the morphofunctional properties of neurons of the pyramidal layer of the hippocampus and contributes to their neuroplasticity.Activation of NMDS receptors of neurons during stress apparently, initiates two ways of neuron life – the beginning of p53 protein expression and the DN formation. Both ways can finally lead to apoptosis. The formation of dark neurons and the expression of the p53 protein in them are most likely to be interconnected and can probably provide neuroprotective mechanisms.

NCK1 Modulates Neuronal Actin Dynamics and Promotes Dendritic Spine, Synapse, and Memory Formation.

Memory formation and maintenance is a dynamic process involving the modulation of the actin cytoskeleton at synapses. Understanding the signaling pathways that contribute to actin modulation is important for our understanding of synapse formation and function, as well as learning and memory. Here, we focused on the importance of the actin regulator, noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1), in hippocampal dependent behaviors and development. We report that male mice lacking NCK1 have impairments in both short-term and working memory, as well as spatial learning. Additionally, we report sex differences in memory impairment showing that female mice deficient in NCK1 fail at reversal learning in a spatial learning task. We find that NCK1 is expressed in postmitotic neurons but is dispensable for neuronal proliferation and migration in the developing hippocampus. Morphologically, NCK1 is not necessary for overall neuronal dendrite development. However, neurons lacking NCK1 have lower dendritic spine and synapse densities in vitro and in vivo EM analysis reveal increased postsynaptic density (PSD) thickness in the hippocampal CA1 region of NCK1-deficient mice. Mechanistically, we find the turnover of actin-filaments in dendritic spines is accelerated in neurons that lack NCK1. Together, these findings suggest that NCK1 contributes to hippocampal-dependent memory by stabilizing actin dynamics and dendritic spine formation.SIGNIFICANCE STATEMENT Understanding the molecular signaling pathways that contribute to memory formation, maintenance, and elimination will lead to a better understanding of the genetic influences on cognition and cognitive disorders and will direct future therapeutics. Here, we report that the noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1) adaptor protein modulates actin-filament turnover in hippocampal dendritic spines. Mice lacking NCK1 show sex-dependent deficits in hippocampal memory formation tasks, have altered postsynaptic densities, and reduced synaptic density. Together, our work implicates NCK1 in the regulation of actin cytoskeleton dynamics and normal synapse development which is essential for memory formation.

Unilateral hippocampal lesions and the navigational performance of homing pigeons as revealed by GPS-tracking

The left and right hippocampal formation (HF) of the avian brain have been reported to control some different aspects of homing in pigeons. In the current study, we employed GPS-tracking technology and unilateral HF lesions to further explore what if any aspects of a pigeon’s homing flight might be under dominant control by either the left or right HF. Pigeons were released from three locations prior to any experimental manipulation and released repeatedly from the same three sites as sham-lesioned control, right HF-lesioned and left HF-lesioned treatment groups. Analyses of homing performance and virtual vanishing bearings revealed no effect of either lesion treatment. A more in-depth analysis of path efficiency during the initial decision-making, en route and near home phases of a homing flight also revealed no effect of either lesion treatment. A last analysis on the learning and memory for positions along a previously flown route, a proxy for investigating the development of route fidelity, also revealed no effect of either unilateral lesion. However, independent of treatment group, some statistically significant effects were observed with respect to changes in performance across training and the different release sites. The current study revealed no detectable difference between the left and right HF-lesioned pigeons with respect to several navigational parameters of a homing flight. Although in need of supporting experimentation, the results are consistent with the hypothesis that both the left and right HF are similarly able to support several aspects of homing pigeon navigation.

A circuit from the ventral subiculum to anterior hypothalamic nucleus GABAergic neurons essential for anxiety-like behavioral avoidance

Behavioral observations suggest a connection between anxiety and predator defense, but the underlying neural mechanisms remain unclear. Here we examine the role of the anterior hypothalamic nucleus (AHN), a node in the predator defense network, in anxiety-like behaviors. By in vivo recordings in male mice, we find that activity of AHN GABAergic (AHNVgat+) neurons shows individually stable increases when animals approach unfamiliar objects in an open field (OF) or when they explore the open-arm of an elevated plus-maze (EPM). Moreover, object-evoked AHN activity overlap with predator cue responses and correlate with the object and open-arm avoidance. Crucially, exploration-triggered optogenetic inhibition of AHNVgat+ neurons reduces object and open-arm avoidance. Furthermore, retrograde viral tracing identifies the ventral subiculum (vSub) of the hippocampal formation as a significant input to AHNVgat+ neurons in driving avoidance behaviors in anxiogenic situations. Thus, convergent activation of AHNVgat+ neurons serves as a shared mechanism between anxiety and predator defense to promote behavioral avoidance.

Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation

Alzheimer's disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (Aβ) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKIIα and the nuclear translocation of the transcription factor CREB. It is known that Aβ oligomers (oAβ) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oAβ on CaMKIIα. We found that oAβ produce reactive oxygen species (ROS), that induce CaMKIIα oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKIIα is active independently of the binding to calcium/calmodulin, and that CaMKIIα phosphorylation is mutually exclusive with CaMKIIα oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKIIα. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKIIα induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKIIα oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oAβ.

Identification of transcriptional signatures of cognitive resilience using single nucleus RNA sequencing

AbstractBackgroundIt is estimated that a third of the elderly population is not diagnosed with Alzheimer’s disease (AD) due to the absence of cognitive impairment despite carrying risk variants of AD or presenting AD pathology post‐mortem. This suggests that at‐risk individuals may carry protective mechanisms that promote resilience to cognitive impairment, however the underlying molecular processes that promote resilience remain unknown.MethodTo determine transcriptional changes associated with resilience, we profiled the hippocampal transcriptome at the single cell level in 7 resilient and 7 susceptible strains from the AD‐BXD mouse reference panel1, a genetically diverse mouse model of AD that better mimics human AD. Here, we used contextual fear memory paradigm to assess short‐term memory function in AD‐BXDs carrying the 5XFAD mutation. Resilience was defined based on age‐related change in cognitive function relative to that of the entire AD‐BXD population, where strains showing no or lower than average decline were considered resilient.ResultUsing single nucleus RNA‐sequencing, we profiled ∼220 K nuclei from the hippocampal formation and identified 32 cell clusters representing the major cell types in the hippocampus including glutamatergic neurons, GABAergic neurons, astrocytes, oligodendrocytes and microglia. With the exception of GABAergic neurons, transcriptional changes associated with the 5XFAD mutation were greater in susceptible AD‐BXDs. Gene expression changes associated with cognitive resilience were primarily observed in excitatory neurons, specifically in the CA1 and dentate gyrus and were enriched for ribosomal genes and nuclear encoded mitochondrial genes. In attempt to infer potential ligands that regulate resilience‐associated transcriptional changes we used a ligand‐target interaction analysis and predicted potential ligands regulating resilience programs in excitatory neurons.ConclusionOur findings demonstrate that the rate of cognitive decline is concomitant with increased transcriptional changes associated with the 5XFAD mutation across cell types in the hippocampus. We show that molecular programs associated with resilience in excitatory neurons are enriched in protein metabolism, cellular respiration and translation, possibly indicating a response to energy demand and maintenance of cellular homeostasis.Neuner SM, Heuer SE, Huentelman MJ, O'Connell KMS, Kaczorowski CC. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2019.