Neurogranin Regulates Alcohol Sensitivity through AKT Pathway in the Nucleus Accumbens

Nam, Hyung Wook; Grant, Caleb A.; Jorgensen, Ashton N.; Holtz-Heppelmann, Carrie J.; Trutschl, Marjan; Cvek, Urška

doi:10.1002/pmic.201900266

Cited by 4 publications

(2 citation statements)

References 42 publications

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“…For example, it is induced by cocaine in neural progenitor cells [33] and it is related to anhedonia in cocaine users [34]. Moreover, neurogranin in the NAcc also regulates the sensitivity to other drugs, such as alcohol [35]. Another gene in the ontology, Calb1, coding for the protein calbindin, is also responsive to cocaine self-administration in the NAcc [36].…”

Section: Transcriptomic Studiesmentioning

confidence: 99%

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

et al. 2023

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Substance use disorders are more prevalent in schizophrenia, but the causal links between both conditions remain unclear. Maternal immune activation (MIA) is associated with schizophrenia which may be triggered by stressful experiences during adolescence. Therefore, we used a double-hit rat model, combining MIA and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to Sprague-Dawley dams. Their male offspring underwent five episodes of unpredictable stress every other day from postnatal day 28 to 38. When animals reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, Pavlovian and instrumental conditioning, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration and increased the motivation for the drug; however, PUS reduced cocaine intake, an effect that was reversed in MIA + PUS rats. We found concomitant brain alterations: MIA + PUS altered the structure and function of the dorsal striatum, increasing its volume and interfering with glutamatergic dynamics (PUS decreased the levels of NAA + NAAG but only in LPS animals) and modulated specific genes that could account for the restoration of cocaine intake such as the pentraxin family. On its own, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum, also having a profound effect on the dorsal striatal transcriptome. However, these effects were obliterated when PUS occurred in animals with MIA experience. Our results describe an unprecedented interplay between MIA and stress on neurodevelopment and the susceptibility to cocaine addiction.

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Section: Transcriptomic Studiesmentioning

confidence: 99%

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

et al. 2023

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“…For example, the gene for Neurogranin (Nrgn), present in this ontology (Figure 5 A, C; Table S3), responds to cocaine in several ways: it is induced by cocaine in neural progenitor cells (35) and it is related to anhedonia in cocaine users (36). Moreover, neurogranin in the NAcc also regulates the sensitivity to other drugs such as alcohol (37). Another gene present in the ontology, Calb1 coding for the protein calbindin is also responsive to cocaine self-administration in the NAcc (38).…”

Section: -Transcriptomic Studiesmentioning

confidence: 99%

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Capellán

Orihuel

Marcos

et al. 2021

Preprint

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Substance use disorders are more prevalent in schizophrenia, worsening its course and prognosis. Here, we used a double-hit rat model, combining maternal immune activation (MIA) and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to 5 episodes of unpredictable stress every other day during adolescence (from postnatal day 28 to 38). When rats reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, conditioning processes and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration while PUS reduced cocaine intake, an effect that was reversed by MIA. MIA increased motivation for cocaine and reversed the effects of PUS during extended access. Incubation of seeking was unaffected. Neither hit alone nor their combination impacted Pavlovian or instrumental conditioning or impulsiveness. At the brain level, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum. MIA+PUS altered the structure and function of the dorsal striatum increasing its volume and interfering with glutamatergic dynamics. MIA did not affect the gene expression of the nucleus accumbens but, when combined with PUS, modulated specific genes that could account for the restored cocaine intake. PUS had a profound effect on the dorsal striatal transcriptome however, this was obliterated when PUS occurred in animals with MIA. These results describe a complex interplay between MIA and stress on neurodevelopment and in the susceptibility to develop cocaine addiction.

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Endothelial Neurogranin Regulates Blood–Brain Barrier Permeability via Modulation of the AKT Pathway

Akande,

Carter,

Stokes

et al. 2024

Mol Neurobiol

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Neurogranin (Ng) expression is a biomarker for Alzheimer’s disease. A loss of brain Ng and an increase in CSF Ng positively correlate with cognitive decline. Ng is known to regulate neuronal calcium-calmodulin binding and synaptic plasticity, which are critical for learning/memory. Interestingly, we discovered that Ng is also expressed in mouse and human blood–brain barrier (BBB). However, the role of Ng expression in brain vasculature remains largely undefined. In this study, we investigated the role of Ng expression on neurovascular structure and function using Ng null mice and human cerebral microvascular endothelial (hCMEC/D3) cells. We performed brain clearing and immunolabeling of blood vessels from whole brains and brain slices. Deletion of Ng significantly decreases neurovascular density in mice. Using in vivo permeability assays, we found increased neurovascular permeability in Ng null mice. We also observed significant changes in the expression of tight junction proteins using western blot and immunofluorescent staining. To identify the molecular pathways involved, we carried out label-free proteomics on brain lysates from endothelial-specific Ng knockout mice. Ingenuity Pathway Analysis indicated that the AKT pathway is attenuated in the vasculature of endothelial-specific Ng knockout mice. To validate these in vivo findings, we pharmacologically manipulated AKT signaling in hCMEC/D3 cells and observed that inhibition of AKT activation causes increased permeability. Our results indicate that the loss of Ng expression alters neurovascular structure and permeability, potentially contributing to neurological dysfunction. Therefore, modulating Ng expression in the BBB may offer a novel therapeutic approach for Alzheimer’s disease.

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Neurogranin Regulates Alcohol Sensitivity through AKT Pathway in the Nucleus Accumbens

Cited by 4 publications

References 42 publications

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Endothelial Neurogranin Regulates Blood–Brain Barrier Permeability via Modulation of the AKT Pathway

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