Transcription profiling of human hippocampis (layer II stellate neurons (entorhinal cortex) and layer III cortical neurons (hippocampus CA1, middle temporal gyrus, posterior cingulate, superior frontal gyrus, primary visual cortex)
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Lu Lu
PROVIDER: E-GEOD-51 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Considerable debate persists around the definition of risk. Depending on the area of study, the concept of risk may be defined as the variance of the possible outcomes, the probability of a loss, or a combination of the loss probability and its maximum possible loss. Mounting evidence suggests the anterior cingulate cortex (ACC), including the surrounding medial prefrontal cortex (mPFC), and the anterior insula/inferior frontal gyrus (IFG) are key neural regions that represent perceived risks. Yet it remains unclear which of these formalisms best accounts for the pattern of activation in brain regions representing risk, and it is also difficult to disentangle risk from value, as both contribute to perceived utility. To adjudicate among the possible definitions, we used fMRI with a novel gambling task that orthogonalized the variance, loss probability, and maximum possible loss among the risky options, while maintaining a constant expected value across all monetary gambles to isolate the impact of risk rather than value. Here we show that when expected value is controlled for ACC and IFG activation reflect variance, but neither loss probability nor maximum possible loss. Across subjects, variance-related activation within the ACC correlates indirectly with risk aversion. Our results highlight the variance of the prospective outcomes as a formal representation of risk that is reflected both in brain activity and behavior, thus suggestive of a stronger link among formal economic theories of financial risk, naturalistic risk taking, and neural representations of risk.
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Project description:Although hippocampal CA1 pyramidal neurons (PNs) were thought to comprise a uniform population, recent evidence supports two distinct sublayers along the radial axis, with deep neurons more likely to form place cells than superficial neurons. CA1 PNs also differ along the transverse axis with regard to direct inputs from entorhinal cortex (EC), with medial EC (MEC) providing spatial information to PNs toward CA2 (proximal CA1) and lateral EC (LEC) providing non-spatial information to PNs toward subiculum (distal CA1). We demonstrate that the two inputs differentially activate the radial sublayers and that this difference reverses along the transverse axis, with MEC preferentially targeting deep PNs in proximal CA1 and LEC preferentially exciting superficial PNs in distal CA1. This differential excitation reflects differences in dendritic spine numbers. Our results reveal a heterogeneity in EC-CA1 connectivity that may help explain differential roles of CA1 PNs in spatial and non-spatial learning and memory.
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Project description:Glutamate is the main excitatory neurotransmitter in the central nervous system, responsible for a plethora of cellular processes including memory formation and higher cerebral function and has been implicated in various neurological disease states. Alzheimer's disease (AD) is the leading neurodegenerative disorder worldwide and is characterized by significant cell loss and glutamatergic dysfunction. While there has been a focus on ionotropic glutamatergic receptors few studies have attempted to elucidate the pathological changes of metabotropic glutamate receptors (mGluRs) in AD. mGluRs are G-protein coupled receptors which have a wide-ranging functionality, including the regulation of neuronal injury and survival. In particular, the group I mGluRs (mGluR1 and mGluR5) are associated with ionotropic receptor activation and upregulation with resultant glutamate release in normal neuronal functioning. The mGluR subtype 1 splice variant a (mGluR1α) is the longest variant of the mGluR1 receptor, is localized to dendritic processes and is mainly plasma membrane-bound. Activation of mGluR1a has been shown to result in increased constitutive activity of ionotropic receptors, although its role in neurodegenerative and other neurological diseases is controversial, with some animal studies demonstrating potential neuroprotective properties in excito- and neurotoxic environments. In this study, the expression of mGluR1a within normal and AD human hippocampal tissue was quantified using immunohistochemistry. We found a significantly reduced expression of mGluR1α within the stratum pyramidale and radiatum of the CA1subregion, subiculum, and entorhinal cortex. This downregulation could result in potential dysregulation of the glutamatergic system with consequences on AD progression by promoting excitotoxicity, but alternatively may also be a neuroprotective mechanism to prevent mGluR1α associated excitotoxic effects. In summary, more research is required to understand the role and possible consequences of mGluR1α downregulation in the human AD hippocampus, subiculum and entorhinal cortex and its potential as a therapeutic target.
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Project description:Alzheimer's disease (AD) is a neuropathological disorder characterized by the presence and accumulation of amyloid-beta plaques and neurofibrillary tangles. Glutamate dysregulation and the concept of glutamatergic excitotoxicity have been frequently described in the pathogenesis of a variety of neurodegenerative disorders and are postulated to play a major role in the progression of AD. In particular, alterations in homeostatic mechanisms, such as glutamate uptake, have been implicated in AD. An association with excitatory amino acid transporter 2 (EAAT2), the main glutamate uptake transporter, dysfunction has also been described. Several animal and few human studies examined EAAT2 expression in multiple brain regions in AD but studies of the hippocampus, the most severely affected brain region, are scarce. Therefore, this study aims to assess alterations in the expression of EAAT2 qualitatively and quantitatively through DAB immunohistochemistry (IHC) and immunofluorescence within the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus (STG) regions, between human AD and control cases. Although no significant EAAT2 density changes were observed between control and AD cases, there appeared to be increased transporter expression most likely localized to fine astrocytic branches in the neuropil as seen on both DAB IHC and immunofluorescence. Therefore, individual astrocytes are not outlined by EAAT2 staining and are not easily recognizable in the CA1-3 and dentate gyrus regions of AD cases, but the altered expression patterns observed between AD and control hippocampal cases could indicate alterations in glutamate recycling and potentially disturbed glutamatergic homeostasis. In conclusion, no significant EAAT2 density changes were found between control and AD cases, but the observed spatial differences in transporter expression and their functional significance will have to be further explored.
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Project description:Cognitive deficits and behavioral changes that result from chronic alcohol abuse are a consequence of neuropathological changes which alter signal transmission through the neural network. To focus on the changes that occur at the point of connection between the neural network cells, synaptosomal preparations from post-mortem human brain of six chronic alcoholics and six non-alcoholic controls were compared using 2D-DIGE. Functionally affected and spared regions (superior frontal gyrus, SFG, and occipital cortex, OC, respectively) were analyzed from both groups to further investigate the specific pathological response that alcoholism has on the brain. Forty-nine proteins were differentially regulated between the SFG of alcoholics and the SFG of controls and 94 proteins were regulated in the OC with an overlap of 23 proteins. Additionally, the SFG was compared to the OC within each group (alcoholics or controls) to identify region specific differences. A selection were identified by MALDI-TOF mass spectrometry revealing proteins involved in vesicle transport, metabolism, folding and trafficking, and signal transduction, all of which have the potential to influence synaptic activity. A number of proteins identified in this study have been previously related to alcoholism; however, the focus on synaptic proteins has also uncovered novel alcoholism-affected proteins. Further exploration of these proteins will illuminate the mechanisms altering synaptic plasticity, and thus neuronal signaling and response, in the alcoholic brain.
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Project description:Abnormally phosphorylated tau, an early neuropathologic marker of Alzheimer’s disease (AD), first occurs in the brain’s entorhinal cortex layer II (ECII) and then spreads to the CA1 field of the hippocampus. Animal models of tau propagation aiming to recapitulate this phenomenon mostly show tau transfer from ECII stellate neurons to the dentate gyrus, but tau pathology in the dentate gyrus does not appear until advanced stages of AD. Wolframin-1–expressing (Wfs1+) pyramidal neurons have been shown functionally to modulate hippocampal CA1 neurons in mice. Here, we report that Wfs1+ pyramidal neurons are conserved in the ECII of postmortem human brain tissue and that Wfs1 colocalized with abnormally phosphorylated tau in brains from individuals with early AD. Wfs1+ neuron–specific expression of human P301L mutant tau in mouse ECII resulted in transfer of tau to hippocampal CA1 pyramidal neurons, suggesting spread of tau pathology as observed in the early Braak stages of AD. In mice expressing human mutant tau specifically in the ECII brain region, electrophysiological recordings of CA1 pyramidal neurons showed reduced excitability. Multielectrode array recordings of optogenetically stimulated Wfs1+ ECII axons resulted in reduced CA1 neuronal firing. Chemogenetic activation of CA1 pyramidal neurons showed a reduction in c-fos+ cells in the CA1. Last, a fear conditioning task revealed deficits in trace and contextual memory in mice overexpressing human mutant tau in the ECII. This work demonstrates tau transfer from the ECII to CA1 in mouse brain and provides an early Braak stage preclinical model of AD.
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Project description:In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein reelin (Re + ECLII neurons). In rodents, neurons located at the dorsal extreme of the EC, which border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here, we test two predictions deducible from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since the mitochondrial turnover rate serves as a proxy for energy expenditure, the mitophagy rate arguably also qualifies as such. Because messenger RNA of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) is known to be highly expressed in the EC, we predicted that Bnip3 would be upregulated in Re + ECLII neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, supporting that the energy requirement of Re + ECLII neurons is generally high and that there is a systematic increase in metabolic rate as one moves successively closer to the rhinal fissure. Intriguingly, the systematic variation in energy requirement of the neurons that manifest the observed reelin gradient appears to be consonant with the level of spatial and temporal detail by which they encode information about the external environment.
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Project description:Purpose: To identify gene expression changes in entorhinal cortex layer II (ECII) neurons upon Ptbp1 modulation (silencing and overexpression) Method: bacterial artificial chromosome - Translating Ribosome Affinity Purification (bacTRAP) to isolate actively translated mRNA in ECII neurons, 2 weeks after stereotaxic injection of an AAV1 vector in the EC of ECII-bacTRAP mice; followed by RNAseq. Note: Ptbp1 was significantly overexpressed in the overexpression experiment, but no silencing was achieved with the silencing vector, probably because of tight control of Ptbp1 expression
2020-05-29 | GSE151356 | GEO