Memory recall involves a transient break in excitatory-inhibitory balance

Koolschijn, Renée S.; Shpektor, Anna; Clarke, William T.; Ip, Betina; Dupret, David; Emir, Uzay E.; Barron, Helen C.

doi:10.7554/elife.70071

Cited by 17 publications

(22 citation statements)

References 104 publications

(160 reference statements)

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“…Identified CFC- driven transcript changes in inferior blade, while fewer, followed a similar overall pattern – i.e., transcripts involved in glutamatergic synapse biogenesis were upregulated, while GABA receptor transcripts were downregulated, after CFC. This strongly supports the hypothesis that excitatory- inhibitory balance changes in specific brain circuits accompanies, and benefits, long-term memory storage (54)(20, 55, 56). The finding that these changes are constrained to DG, among all subregions profiled, is consistent with the prior finding of sustained transcriptomic changes occurring specifically within DG engram neurons 24 h post-CFC (57), and may reflect unique dynamics of the DG network (or the engram neurons within it), which could plausibly outlast changes after learning in other hippocampal structures (11, 58, 59).…”

Section: Discussionsupporting

confidence: 85%

Sleep-dependent engram reactivation during hippocampal memory consolidation is associated with subregion-specific biosynthetic changes

Wang

Park

et al. 2022

Preprint

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Post-learning sleep plays an important role in hippocampal memory processing, including contextual fear memory (CFM) consolidation. Here, we used targeted recombination in activated populations (TRAP) to label context-encoding engram neurons in the hippocampal dentate gyrus (DG) and assessed reactivation of these neurons during post-learning sleep. We find that post-learning sleep deprivation (SD), which impairs CFM consolidation, selectively disrupts reactivation in inferior blade DG engram neurons. This change was linked to more general suppression of neuronal activity markers in the inferior, but not superior, DG blade by SD. To further characterize how learning and subsequent sleep or SD affect these (and other) hippocampal subregions, we used subregion-specific spatial profiling of transcripts and proteins. We found that transcriptomic responses to sleep loss differed greatly between hippocampal regions CA1, CA3, and DG inferior blade, superior blade, and hilus. Critically, learning-driven transcriptomic changes, measured 6 h following contextual fear learning, were limited to the two DG blades, differed dramatically between the blades, and were absent from all other regions. Similarly, protein abundance in these hippocampal subregions were differentially impacted by sleep vs. SD and by prior learning, with the majority of alterations to protein expression restricted to DG. Together, these data suggest that the DG plays an essential role in the consolidation of hippocampal memories, and that the effects of sleep and sleep loss on the hippocampus are highly subregion-specific, even within the DG itself.

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Section: Discussionsupporting

confidence: 85%

Sleep-dependent engram reactivation during hippocampal memory consolidation is associated with subregion-specific biosynthetic changes

Wang

Park

et al. 2022

Preprint

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“…Among hippocampal neurometabolites, learning to locate the visible platform in the water maze, learning to locate the hidden platform water maze, and cued fear memory were linked to lower levels of GABA. These data are consistent with the disruption of fear memories following pre-and post-training administration of drugs that facilitate GABA neurotransmission (Makkar et al, 2010) and the increase ratio in glutamate to GABA in hippocampus and visual neocortex when human study participants recalled visual cues in a virtual environment in which specific sounds predicted the appearance of particular visual patterns and some patterns led to a monetary award (Koolschijn et al, 2021). As cued fear memory is not hippocampus-dependent (Phillips and Ledoux, 1992), these data suggest that these relationships are not necessarily restricted to the hippocampus.…”

Section: Discussionsupporting

confidence: 75%

ApoE isoform-dependent effects of xanthohumol on high fat diet-induced cognitive impairments and hippocampal metabolic pathways

et al. 2022

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Consumption of a high fat diet (HFD) is linked to metabolic syndrome and cognitive impairments. This is exacerbated in age-related cognitive decline (ACD) and in individuals with a genetic risk for Alzheimer’s disease (AD). Apolipoprotein E (apoE) is involved in cholesterol metabolism. In humans, there are three major isoforms, E2, E3, and E4. Compared to E3, E4 increases ACD and AD risk and vulnerability to the deleterious cognitive effects of a HFD. The plant compound Xanthohumol (XN) had beneficial effects on cognition and metabolism in C57BL/6J wild-type (WT) male mice put on a HFD at 9 weeks of age for 13 weeks. As the effects of XN in the context of a HFD in older WT, E3, and E4 female and male mice are not known, in the current study male and female WT, E3, and E4 mice were fed a HFD alone or a HFD containing 0.07% XN for 10 or 19 weeks, starting at 6 months of age, prior to the beginning of behavioral and cognitive testing. XN showed sex- and ApoE isoform-dependent effects on cognitive performance. XN-treated E4 and WT, but not E3, mice had higher glucose transporter protein levels in the hippocampus and cortex than HFD-treated mice. E3 and E4 mice had higher glucose transporter protein levels in the hippocampus and lower glucose transporter protein levels in the cortex than WT mice. In the standard experiment, regardless of XN treatment, E4 mice had nearly double as high ceramide and sphingomyelin levels than E3 mice and male mice had higher level of glycosylated ceramide than female mice. When the differential effects of HFD in E3 and E4 males were assessed, the arginine and proline metabolism pathway was affected. In the extended exposure experiment, in E3 males XN treatment affected the arginine and proline metabolism and the glycine, serine, and threonine metabolism. Myristic acid levels were decreased in XN-treated E3 males but not E3 females. These data support the therapeutic potential for XN to ameliorate HFD-induced cognitive impairments and highlight the importance of considering sex and ApoE isoform in determining who might most benefit from this dietary supplement.

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“…This manifests clinically as a decline in memory, cognition, and general functioning over time. Recent research has demonstrated that memory recall in the visual neocortex is strongly dependent on hippocampal glutamate excitatory levels and may explain why memory is disrupted in numerous neuropsychiatric disorders [ 135 ].…”

Section: The Glutamate Hypothesis Of Schizophreniamentioning

confidence: 99%

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

et al. 2022

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The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain’s principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain/body interface via the microbiome, kynurenine pathway, and hypothalamus–pituitary–adrenal axis. Disruption of excitatory/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.

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Memory recall involves a transient break in excitatory-inhibitory balance

Cited by 17 publications

References 104 publications

Sleep-dependent engram reactivation during hippocampal memory consolidation is associated with subregion-specific biosynthetic changes

Sleep-dependent engram reactivation during hippocampal memory consolidation is associated with subregion-specific biosynthetic changes

ApoE isoform-dependent effects of xanthohumol on high fat diet-induced cognitive impairments and hippocampal metabolic pathways

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

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