RESUMEN
BACKGROUND: Alzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aß) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aß plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aß oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD. METHODS: Hippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aß1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aß-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aß-treated HEBSCs. RESULTS: Neurotoxicity induced by soluble Aß1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aß-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aß neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aß as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aß-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aß-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention. CONCLUSION: Microglia are key mediators of both protection and neurodegeneration in response to Aß. Polarizing microglia toward a protective state could be used as a preventative strategy against Aß-induced neurotoxicity.
Asunto(s)
Péptidos beta-Amiloides , Microglía , Fragmentos de Péptidos , Ligando Inductor de Apoptosis Relacionado con TNF , Microglía/metabolismo , Microglía/efectos de los fármacos , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Animales , Fragmentos de Péptidos/toxicidad , Fragmentos de Péptidos/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/toxicidad , Ratones , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Corteza Entorrinal/metabolismo , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/patología , Técnicas de Cultivo de ÓrganosRESUMEN
Research suggests that increased financial exploitation vulnerability due to declining decision making may be an early behavioral manifestation of brain changes occurring in preclinical Alzheimer's disease. One of the earliest documented brain changes during the preclinical phase is neurodegeneration in the entorhinal cortex. The objective of the current study was to examine the association between a measure of financial exploitation vulnerability and thickness in the entorhinal cortex in 97 cognitively unimpaired older adults. We also investigated financial exploitation vulnerability associations with frontal regions typically associated with decision making (e.g. dorsolateral and ventromedial prefrontal cortices), and additionally examined the interactive effect of age and cortical thickness on financial exploitation vulnerability. Results showed that greater financial exploitation vulnerability was associated with significantly lower entorhinal cortex thickness. There was a significant interaction between age and entorhinal cortex thickness on financial exploitation vulnerability, whereby lower entorhinal cortex thickness was associated with greater financial exploitation vulnerability in older participants. When the group was divided by age using a median split (70+ and <70 years old), lower entorhinal cortex thickness was associated with greater vulnerability only in the older group. Collectively, these findings suggest that financial exploitation vulnerability may serve as a behavioral manifestation of entorhinal cortex thinning, a phenomenon observed in suboptimal brain aging and preclinical Alzheimer's disease.
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Corteza Entorrinal , Imagen por Resonancia Magnética , Humanos , Corteza Entorrinal/diagnóstico por imagen , Corteza Entorrinal/patología , Corteza Entorrinal/anatomía & histología , Anciano , Masculino , Femenino , Envejecimiento/fisiología , Envejecimiento/patología , Anciano de 80 o más Años , Toma de Decisiones/fisiología , Persona de Mediana Edad , Cognición/fisiologíaRESUMEN
Complex sensory information arrives in the brain from an animal's first-person ('egocentric') perspective. However, animals can efficiently navigate as if referencing map-like ('allocentric') representations. The postrhinal (POR) and retrosplenial (RSC) cortices are thought to mediate between sensory input and internal maps, combining egocentric representations of physical cues with allocentric head direction (HD) information. Here we show that neurons in the POR and RSC of female Long-Evans rats are tuned to distinct but complementary aspects of local space. Egocentric bearing (EB) cells recorded in square and L-shaped environments reveal that RSC cells encode local geometric features, while POR cells encode a more global account of boundary geometry. Additionally, POR HD cells can incorporate egocentric information to fire in two opposite directions with two oppositely placed identical visual landmarks, while only a subset of RSC HD cells possess this property. Entorhinal grid and HD cells exhibit consistently allocentric spatial firing properties. These results reveal significant regional differences in the neural encoding of spatial reference frames.
Asunto(s)
Neuronas , Ratas Long-Evans , Percepción Espacial , Animales , Femenino , Neuronas/fisiología , Ratas , Percepción Espacial/fisiología , Señales (Psicología) , Corteza Entorrinal/fisiología , Corteza Entorrinal/citología , Ambiente , Corteza Cerebral/fisiología , Corteza Cerebral/citologíaRESUMEN
Background: The entorhinal cortex is the very earliest involvement of Alzheimer's disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system. Objective: We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline. Methods: Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic brain imaging features of AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI-). Results: Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI-. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70). Conclusions: Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12-15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Imagen por Resonancia Magnética , Síntomas Prodrómicos , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Masculino , Femenino , Anciano , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Imagen por Resonancia Magnética/métodos , Progresión de la Enfermedad , Pruebas Neuropsicológicas , Tomografía Computarizada de Emisión de Fotón Único/métodos , Persona de Mediana Edad , Navegación Espacial/fisiología , Realidad Virtual , Anciano de 80 o más Años , Corteza Entorrinal/diagnóstico por imagen , Corteza Entorrinal/patologíaRESUMEN
Our brains create new memories by capturing the 'who/what', 'where' and 'when' of everyday experiences. On a neuronal level, mechanisms facilitating a successful transfer into episodic memory are still unclear. We investigated this by measuring single neuron activity in the human medial temporal lobe during encoding of item-location associations. While previous research has found predictive effects in population activity in human MTL structures, we could attribute such effects to two specialized sub-groups of neurons: concept cells in the hippocampus, amygdala and entorhinal cortex (EC), and a second group of parahippocampal location-selective neurons. In both item- and location-selective populations, firing rates were significantly higher during successfully encoded trials. These findings are in line with theories of hippocampal indexing, since selective index neurons may act as pointers to neocortical representations. Overall, activation of distinct populations of neurons could directly support the connection of the 'what' and 'where' of episodic memory.
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Amígdala del Cerebelo , Corteza Entorrinal , Memoria Episódica , Neuronas , Humanos , Neuronas/fisiología , Masculino , Femenino , Adulto , Corteza Entorrinal/fisiología , Corteza Entorrinal/citología , Amígdala del Cerebelo/fisiología , Amígdala del Cerebelo/citología , Hipocampo/fisiología , Hipocampo/citología , Lóbulo Temporal/fisiología , Lóbulo Temporal/citología , Adulto Joven , Encéfalo/fisiología , Memoria/fisiologíaRESUMEN
Neuropsychiatric symptoms (NPS) are risk factors for Alzheimer's disease (AD) but can also manifest secondary to AD pathology. Mild behavioral impairment (MBI) refers to later-life emergent and persistent NPS that may mark early-stage AD. To distinguish MBI from NPS that are transient or which represent psychiatric conditions (non-MBI NPS), we investigated the effect of applying MBI criteria on NPS associations with AD structural imaging biomarkers and incident cognitive decline. Data for participants (n = 1273) with normal cognition (NC) or mild cognitive impairment (MCI) in the National Alzheimer's Coordinating Center Uniform Data Set were analyzed. NPS status (MBI, non-MBI NPS) was derived from the Neuropsychiatric Inventory Questionnaire and psychiatric history. Normalized measures of bilateral hippocampal (HPC) and entorhinal cortex (EC) volume, and AD meta-region of interest (ROI) mean cortical thickness were acquired from T1-weighted magnetic resonance imaging scans. Multivariable linear and Cox regressions examined NPS associations with imaging biomarkers and incident cognitive decline, respectively. MBI was associated with lower volume and cortical thickness in all ROIs in both NC and MCI, except for EC volume in NC. Non-MBI NPS were only associated with lower HPC volume in NC. Although both of the NPS groups showed higher hazards for MCI/dementia than No NPS, MBI participants showed more rapid decline. Although both types of NPS were linked to HPC atrophy, only NPS that emerged and persisted in later-life, consistent with MBI criteria, were related to AD neurodegenerative patterns beyond the HPC. Moreover, MBI predicted faster progression to dementia than non-MBI NPS.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Imagen por Resonancia Magnética , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Masculino , Anciano , Femenino , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Anciano de 80 o más Años , Factores de Riesgo , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Corteza Entorrinal/diagnóstico por imagen , Corteza Entorrinal/patología , Biomarcadores , Progresión de la EnfermedadRESUMEN
Preventative treatment for Alzheimer's Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear. Using regional, cell-type-specific proteomics and electrophysiology in wild-type mice, we uncovered a unique susceptibility of the entorhinal cortex to human amyloid precursor protein (hAPP). Entorhinal hyperexcitability resulted from selective vulnerability of parvalbumin (PV) interneurons, with respect to surrounding excitatory neurons. This effect was partially replicated with an APP chimera containing a humanized amyloid-beta sequence. EC hyperexcitability could be ameliorated by co-expression of human Tau with hAPP at the expense of increased pathological tau species, or by enhancing PV interneuron excitability in vivo. This study suggests early interventions targeting inhibitory neurons may protect vulnerable regions from the effects of APP/amyloid and tau pathology.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Corteza Entorrinal , Interneuronas , Ratones Transgénicos , Parvalbúminas , Proteínas tau , Corteza Entorrinal/metabolismo , Corteza Entorrinal/patología , Proteínas tau/metabolismo , Proteínas tau/genética , Animales , Humanos , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Parvalbúminas/metabolismo , Ratones , Interneuronas/metabolismo , Masculino , Ratones Endogámicos C57BL , Femenino , Modelos Animales de EnfermedadRESUMEN
AIMS: 5 mC methylation and hydroxymethylation (5hmC) are associated with Alzheimer's disease (AD). However, previous studies were limited by the absence of a 5hmC calculation. This study aims to find AD associated predictors and potential therapeutic chemicals using bioinformatics approach integrating 5 mC, 5hmC, and expression changes, and an AD mouse model. METHODS: Gene expression microarray and 5 mC and 5hmC sequencing datasets were downloaded from GEO repository. 142 AD and 52 normal entorhinal cortex specimens were enrolled. Data from oxidative bisulfite sequencing (oxBS)-treated samples, which represent only 5 mC, were used to calculate 5hmC level. Functional analyses, random forest supervised classification and methylation validation were applied. Potential chemicals were predicted by CMap. Morris water maze, Y maze and novel object recognition behavior tests were performed using FAD4T AD mice model. Cortex and hippocampus tissues were isolated for immunohistochemical staining. RESULTS: C1QTNF5, UBD, ZFP106, NEDD1, AKT3, and MBP genes involving 13 promoter CpG sites with 5mc, 5hmC methylation and expression difference were identified. AKT3 and MBP were down-regulated in both patients and mouse model. Three CpG sites in AKT3 and MBP showed significant methylation difference on validation. FAD4T AD mice showed recession in brain functions and lower AKT3 expression in both cortex and hippocampus. Ten chemicals were predicted as potential treatments for AD. CONCLUSIONS: AKT3 and MBP may be associated with AD pathology and could serve as biomarkers. The ten predicted chemicals might offer new therapeutic approaches. Our findings could contribute to identifying novel markers and advancing the understanding of AD mechanisms.
Asunto(s)
Enfermedad de Alzheimer , Metilación de ADN , Proteínas Proto-Oncogénicas c-akt , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Animales , Ratones , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Masculino , Modelos Animales de Enfermedad , Biomarcadores/metabolismo , Corteza Entorrinal/metabolismo , Corteza Entorrinal/patología , Femenino , Anciano , Hipocampo/metabolismo , Expresión Génica , Ratones TransgénicosRESUMEN
The intracerebral spread of tau is a critical mechanism associated with functional decline in Alzheimer's disease (AD) and other tauopathies. Recently, a hypothesis has emerged suggesting that tau propagation is linked to functional neuronal connections, specifically driven by neuronal hyperactivity. However, experimental validation of this hypothesis remains limited. In this study, we investigated how tau propagation from the entorhinal cortex to the hippocampus, the neuronal circuit most susceptible to tau pathology in AD, is affected by the selective stimulation of neuronal activity along this circuit. Using a mouse model of seed-induced propagation combined with optogenetics, we found that the chronic stimulation of this neuronal connection over a 4-week period resulted in a significant increase in insoluble tau accumulation in both the entorhinal cortex and hippocampus. Importantly, the ratio of tau accumulation in the hippocampus relative to that in the entorhinal cortex, serving as an indicator of transcellular spreading, was significantly higher in mice subjected to chronic stimulation. These results support the notion that abnormal neuronal activity promotes tau propagation, thereby implicating it in the progression of tauopathy.
Asunto(s)
Modelos Animales de Enfermedad , Corteza Entorrinal , Hipocampo , Neuronas , Tauopatías , Proteínas tau , Animales , Proteínas tau/metabolismo , Tauopatías/metabolismo , Tauopatías/patología , Ratones , Neuronas/metabolismo , Neuronas/patología , Hipocampo/metabolismo , Hipocampo/patología , Corteza Entorrinal/metabolismo , Corteza Entorrinal/patología , Ratones Transgénicos , Optogenética , Masculino , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones Endogámicos C57BLRESUMEN
Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts - including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 - associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology.
Asunto(s)
Enfermedad de Alzheimer , Corteza Entorrinal , Ratones Transgénicos , Isoformas de Proteínas , Proteínas tau , Corteza Entorrinal/metabolismo , Corteza Entorrinal/patología , Animales , Humanos , Proteínas tau/metabolismo , Proteínas tau/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Femenino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratones , Modelos Animales de Enfermedad , Empalme Alternativo/genética , Regulación de la Expresión GénicaRESUMEN
The hippocampus and medial entorhinal cortex (MEC) form a cognitive map that facilitates spatial navigation. As part of this map, MEC grid cells fire in a repeating hexagonal pattern across an environment. This grid pattern relies on inputs from the medial septum (MS). The MS, and specifically GABAergic neurons, are essential for theta rhythm oscillations in the entorhinal-hippocampal network; however, the role of this population in grid cell function is unclear. To investigate this, we use optogenetics to inhibit MS-GABAergic neurons and observe that MS-GABAergic inhibition disrupts grid cell spatial periodicity. Grid cell spatial periodicity is disrupted during both optogenetic inhibition periods and short inter-stimulus intervals. In contrast, longer inter-stimulus intervals allow for the recovery of grid cell spatial firing. In addition, grid cell phase precession is also disrupted. These findings highlight the critical role of MS-GABAergic neurons in maintaining grid cell spatial and temporal coding in the MEC.
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Corteza Entorrinal , Neuronas GABAérgicas , Células de Red , Optogenética , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Animales , Corteza Entorrinal/fisiología , Corteza Entorrinal/metabolismo , Corteza Entorrinal/citología , Células de Red/fisiología , Ratones , Masculino , Ritmo Teta/fisiología , Núcleos Septales/fisiología , Núcleos Septales/metabolismoRESUMEN
The entorhinal cortex represents allocentric spatial geometry and egocentric speed and heading information required for spatial navigation. However, it remains unclear whether it contributes to the prediction of an animal's future location. We discovered grid cells in the medial entorhinal cortex (MEC) that have grid fields representing future locations during goal-directed behavior. These predictive grid cells represented prospective spatial information by shifting their grid fields against the direction of travel. Predictive grid cells discharged at the trough phases of the hippocampal CA1 theta oscillation and, together with other types of grid cells, organized sequences of the trajectory from the current to future positions across each theta cycle. Our results suggest that the MEC provides a predictive map that supports forward planning in spatial navigation.
Asunto(s)
Región CA1 Hipocampal , Corteza Entorrinal , Células de Red , Navegación Espacial , Ritmo Teta , Corteza Entorrinal/fisiología , Corteza Entorrinal/citología , Animales , Navegación Espacial/fisiología , Células de Red/fisiología , Ratas , Región CA1 Hipocampal/fisiología , Región CA1 Hipocampal/citología , Masculino , Ratas Long-EvansRESUMEN
The consolidation of discrete experiences into a coherent narrative shapes the cognitive map, providing structured mental representations of our experiences. In this process, past memories are reactivated and replayed in sequence, fostering hippocampal-cortical dialogue. However, brain-wide engagement coinciding with sequential reactivation (or replay) of memories remains largely unexplored. In this study, employing simultaneous EEG-fMRI, we capture both the spatial and temporal dynamics of memory replay. We find that during mental simulation, past memories are replayed in fast sequences as detected via EEG. These transient replay events are associated with heightened fMRI activity in the hippocampus and medial prefrontal cortex. Replay occurrence strengthens functional connectivity between the hippocampus and the default mode network, a set of brain regions key to representing the cognitive map. On the other hand, when subjects are at rest following learning, memory reactivation of task-related items is stronger than that of pre-learning rest, and is also associated with heightened hippocampal activation and augmented hippocampal connectivity to the entorhinal cortex. Together, our findings highlight a distributed, brain-wide engagement associated with transient memory reactivation and its sequential replay.
Asunto(s)
Encéfalo , Electroencefalografía , Hipocampo , Imagen por Resonancia Magnética , Humanos , Masculino , Hipocampo/fisiología , Hipocampo/diagnóstico por imagen , Femenino , Adulto , Adulto Joven , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Corteza Prefrontal/fisiología , Corteza Prefrontal/diagnóstico por imagen , Mapeo Encefálico , Aprendizaje/fisiología , Memoria/fisiología , Corteza Entorrinal/fisiología , Corteza Entorrinal/diagnóstico por imagenRESUMEN
When subjects navigate through spatial environments, grid cells exhibit firing fields that are arranged in a triangular grid pattern. Direct recordings of grid cells from the human brain are rare. Hence, functional magnetic resonance imaging (fMRI) studies proposed an indirect measure of entorhinal grid-cell activity, quantified as hexadirectional modulation of fMRI activity as a function of the subject's movement direction. However, it remains unclear how the activity of a population of grid cells may exhibit hexadirectional modulation. Here, we use numerical simulations and analytical calculations to suggest that this hexadirectional modulation is best explained by head-direction tuning aligned to the grid axes, whereas it is not clearly supported by a bias of grid cells toward a particular phase offset. Firing-rate adaptation can result in hexadirectional modulation, but the available cellular data is insufficient to clearly support or refute this option. The magnitude of hexadirectional modulation furthermore depends considerably on the subject's navigation pattern, indicating that future fMRI studies could be designed to test which hypothesis most likely accounts for the fMRI measure of grid cells. Our findings also underline the importance of quantifying the properties of human grid cells to further elucidate how hexadirectional modulations of fMRI activity may emerge.
Asunto(s)
Corteza Entorrinal , Células de Red , Imagen por Resonancia Magnética , Modelos Neurológicos , Humanos , Células de Red/fisiología , Corteza Entorrinal/fisiología , Percepción Espacial/fisiologíaRESUMEN
Deep neural networks have made tremendous gains in emulating human-like intelligence, and have been used increasingly as ways of understanding how the brain may solve the complex computational problems on which this relies. However, these still fall short of, and therefore fail to provide insight into how the brain supports strong forms of generalization of which humans are capable. One such case is out-of-distribution (OOD) generalization - successful performance on test examples that lie outside the distribution of the training set. Here, we identify properties of processing in the brain that may contribute to this ability. We describe a two-part algorithm that draws on speciï¬c features of neural computation to achieve OOD generalization, and provide a proof of concept by evaluating performance on two challenging cognitive tasks. First we draw on the fact that the mammalian brain represents metric spaces using grid cell code (e.g., in the entorhinal cortex): abstract representations of relational structure, organized in recurring motifs that cover the representational space. Second, we propose an attentional mechanism that operates over the grid cell code using determinantal point process (DPP), that we call DPP attention (DPP-A) - a transformation that ensures maximum sparseness in the coverage of that space. We show that a loss function that combines standard task-optimized error with DPP-A can exploit the recurring motifs in the grid cell code, and can be integrated with common architectures to achieve strong OOD generalization performance on analogy and arithmetic tasks. This provides both an interpretation of how the grid cell code in the mammalian brain may contribute to generalization performance, and at the same time a potential means for improving such capabilities in artiï¬cial neural networks.
Asunto(s)
Células de Red , Redes Neurales de la Computación , Humanos , Células de Red/fisiología , Algoritmos , Modelos Neurológicos , Animales , Atención/fisiología , Encéfalo/fisiología , Corteza Entorrinal/fisiologíaRESUMEN
Estrogens are believed to modulate cognitive functions in part through the modulation of synaptic transmission in the cortex and hippocampus. Administration of 17ß-estradiol (E2) can rapidly enhance excitatory synaptic transmission in the hippocampus and facilitate excitatory synaptic transmission in rat lateral entorhinal cortex via activation of the G protein-coupled estrogen receptor-1 (GPER1). To assess the mechanisms through which GPER1 activation facilitates synaptic transmission, we assessed the effects of acute 10 nM E2 administration on pharmacologically isolated evoked excitatory and inhibitory synaptic currents in layer II/III entorhinal neurons. Female Long-Evans rats were ovariectomized between postnatal day (PD) 63 and 74 and implanted with a subdermal E2 capsule to maintain continuous low levels of E2. Electrophysiological recordings were obtained between 7 and 20 days after ovariectomy. Application of E2 for 20 min did not significantly affect AMPA or NMDA receptor-mediated excitatory synaptic currents. However, GABA receptor-mediated inhibitory synaptic currents (IPSCs) were markedly reduced by E2 and returned towards baseline levels during the 20-min washout period. The inhibition of GABA-mediated IPSCs was blocked in the presence of the GPER1 receptor antagonist G15. GPER1 can modulate protein kinase A (PKA), but blocking PKA with intracellular KT5720 did not prevent the E2-induced reduction in IPSCs. GPER1 can also stimulate extracellular signal-regulated kinase (ERK), a negative modulator of GABAA receptors, and blocking activation of ERK with PD90859 prevented the E2-induced reduction of IPSCs. E2 can therefore result in a rapid GPER1 and ERK signaling-mediated reduction in GABA-mediated IPSCs. This provides a novel mechanism through which E2 can rapidly modulate synaptic excitability in entorhinal layer II/III neurons and may also contribute to E2 and ERK-dependent alterations in synaptic transmission in other brain areas.
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Corteza Entorrinal , Estradiol , Quinasas MAP Reguladas por Señal Extracelular , Neuronas , Ratas Long-Evans , Receptores Acoplados a Proteínas G , Animales , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Estradiol/farmacología , Femenino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Receptores de Estrógenos/metabolismo , Ovariectomía , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Técnicas de Placa-Clamp , Estrógenos/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidoresRESUMEN
Hippocampal area CA2 has garnered attention in recent times owing to its significant involvement in social memory and distinctive plasticity characteristics. Research has revealed that the CA2 region demonstrates a remarkable resistance to plasticity, particularly in the Schaffer Collateral (SC)-CA2 pathway. In this study we investigated the role of Nogo-A, a well-known axon growth inhibitor and more recently discovered plasticity regulator, in modulating plasticity within the CA2 region. The findings demonstrate that blocking Nogo-A in male rat hippocampal slices facilitates the establishment of both short-term and long-term plasticity in the SC-CA2 pathway, while having no impact on the Entorhinal Cortical (EC)-CA2 pathway. Additionally, the study reveals that inhibiting Nogo-A enables association between the SC and EC pathways. Mechanistically, we confirm that Nogo-A operates through its well-known co-receptor, p75 neurotrophin receptor (p75NTR), and its downstream signaling factor such as Rho-associated protein kinase (ROCK), as their inhibition also allows plasticity induction in the SC-CA2 pathway. Additionally, the induction of long-term depression (LTD) in both the EC and SC-CA2 pathways led to persistent LTD, which was not affected by Nogo-A inhibition. Our study demonstrates the involvement of Nogo-A mediated signaling mechanisms in limiting synaptic plasticity within the CA2 region.
Asunto(s)
Región CA2 Hipocampal , Plasticidad Neuronal , Proteínas Nogo , Sinapsis , Animales , Proteínas Nogo/metabolismo , Masculino , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Región CA2 Hipocampal/fisiología , Región CA2 Hipocampal/metabolismo , Región CA2 Hipocampal/efectos de los fármacos , Ratas Sprague-Dawley , Ratas , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Corteza Entorrinal/fisiología , Corteza Entorrinal/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Vías Nerviosas/fisiología , Proteínas de la Mielina/metabolismo , Proteínas de la Mielina/genética , Proteínas del Tejido Nervioso , Receptores de Factores de CrecimientoRESUMEN
INTRODUCTION: The understanding of the pathological events in Alzheimer's disease (AD) has advanced dramatically, but the successful translation from rodent models into efficient human therapies is still problematic. METHODS: To examine how tau pathology can develop in the primate brain, we injected 12 macaques with a dual tau mutation (P301L/S320F) into the entorhinal cortex (ERC). An investigation was performed using high-resolution microscopy, magnetic resonance imaging (MRI), positron emission tomography (PET), and fluid biomarkers to determine the temporal progression of the pathology 3 and 6 months after the injection. RESULTS: Using quantitative microscopy targeting markers for neurodegeneration and neuroinflammation, as well as fluid and imaging biomarkers, we detailed the progression of misfolded tau spreading and the consequential inflammatory response induced by glial cells. DISCUSSION: By combining the analysis of several in vivo biomarkers with extensive brain microscopy analysis, we described the initial steps of misfolded tau spreading and neuroinflammation in a monkey model highly translatable to AD patients. HIGHLIGHTS: Dual tau mutation delivery in the entorhinal cortex induces progressive tau pathology in rhesus macaques. Exogenous human 4R-tau coaptates monkey 3R-tau during transneuronal spread, in a prion-like manner. Neuroinflammatory response is coordinated by microglia and astrocytes in response to tau pathology, with microglia targeting early tau pathology, while astrocytes engaged later in the progression, coincident with neuronal death. Monthly collection of CSF and plasma revealed a profile of changes in several AD core biomarkers, reflective of neurodegeneration and neuroinflammation as early as 1 month after injection.
Asunto(s)
Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Macaca mulatta , Tomografía de Emisión de Positrones , Proteínas tau , Animales , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Proteínas tau/metabolismo , Imagen por Resonancia Magnética , Enfermedades Neuroinflamatorias/patología , Corteza Entorrinal/patología , Corteza Entorrinal/metabolismo , Biomarcadores , Mutación , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , MasculinoRESUMEN
The olfactory system plays crucial roles in perceiving and interacting with their surroundings. Previous studies have deciphered basic odor perceptions, but how information processing in the olfactory system is associated with learning and memory is poorly understood. In this review, we summarize recent studies on the anatomy and functional dynamics of the mouse olfactory learning pathway, focusing on how neuronal circuits in the olfactory bulb (OB) and olfactory cortical areas integrate odor information in learning. We also highlight in vivo evidence for the role of the lateral entorhinal cortex (LEC) in olfactory learning. Altogether, these studies demonstrate that brain regions throughout the olfactory system are critically involved in forming and representing learned knowledge. The role of olfactory areas in learning and memory, and their susceptibility to dysfunction in neurodegenerative diseases, necessitate further research.
Asunto(s)
Aprendizaje , Vías Olfatorias , Animales , Aprendizaje/fisiología , Vías Olfatorias/fisiología , Bulbo Olfatorio/fisiología , Percepción Olfatoria/fisiología , Humanos , Olfato/fisiología , Ratones , Corteza Olfatoria/fisiología , Corteza Entorrinal/fisiologíaRESUMEN
The importance of visual cues for navigation and goal-directed behavior is well established, although the neural mechanisms supporting sensory representations in navigational circuits are largely unknown. Navigation is fundamentally dependent on the medial entorhinal cortex (MEC), which receives direct projections from neocortical visual areas, including the retrosplenial cortex (RSC). Here, we perform high-density recordings of MEC neurons in awake, head-fixed mice presented with simple visual stimuli and assess the dynamics of sensory-evoked activity. We find that a large fraction of neurons exhibit robust responses to visual input. Visually responsive cells are located primarily in layer 3 of the dorsal MEC and can be separated into subgroups based on functional and molecular properties. Furthermore, optogenetic suppression of RSC afferents within the MEC strongly reduces visual responses. Overall, our results demonstrate that the MEC can encode simple visual cues in the environment that may contribute to neural representations of location necessary for accurate navigation.