Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor

Ghersi, Marisa; Gabach, Laura; Buteler, Florencia; Vilcaes, Aldo Alejandro; Schiöth, Helgi B.; Pérez, Mariela Fernanda; Barioglio, Susana Rubiales de

doi:10.1007/s00213-014-3817-6

Cited by 39 publications

(19 citation statements)

References 61 publications

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“…The latter effect is consistent with other studies showing that acute ghrelin receptor agonism enhances glutamatergic neurotransmission and plasticity in the hippocampus (62, 63). It is unclear why ghrelin-mediated signaling in the amygdala favors the reduction, rather than the enhancement, of fear memory.…”

Section: Discussionsupporting

confidence: 93%

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory

Harmatz

Stone

Lim

et al. 2017

Biological Psychiatry

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Background There are many contradictory findings on the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories. Methods We used enzyme-linked immunosorbent assay (ELISA) to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats. Results In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all inter-individual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes both a profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism. Conclusions These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite.

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Section: Discussionsupporting

confidence: 93%

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory

Harmatz

Stone

Lim

et al. 2017

Biological Psychiatry

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“…RNA-seq analysis identified a number of protein-coding genes that were differentially expressed between control and Satb2 cKO mice (25 up-regulated and 15 down-regulated, Figure 6—source data 1). Amongst them we found genes that have previously been identified as highly relevant for learning and memory or directly implicated in memory formation such as Adra2a , Penk , Htr5b , and Ghsr (Diano et al, 2006; Galeotti et al, 2004; Ghersi et al, 2015; Peppin and Raffa, 2015). Pathway analysis revealed significant enrichment (p=0.018) of the ‘neuroactive ligand-receptor interaction pathway’ amongst the regulated genes.…”

Section: Resultsmentioning

confidence: 99%

Satb2 determines miRNA expression and long-term memory in the adult central nervous system

Jaitner

Reddy

Abentung

et al. 2016

eLife

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SATB2 is a risk locus for schizophrenia and encodes a DNA-binding protein that regulates higher-order chromatin configuration. In the adult brain Satb2 is almost exclusively expressed in pyramidal neurons of two brain regions important for memory formation, the cerebral cortex and the CA1-hippocampal field. Here we show that Satb2 is required for key hippocampal functions since deletion of Satb2 from the adult mouse forebrain prevents the stabilization of synaptic long-term potentiation and markedly impairs long-term fear and object discrimination memory. At the molecular level, we find that synaptic activity and BDNF up-regulate Satb2, which itself binds to the promoters of coding and non-coding genes. Satb2 controls the hippocampal levels of a large cohort of miRNAs, many of which are implicated in synaptic plasticity and memory formation. Together, our findings demonstrate that Satb2 is critically involved in long-term plasticity processes in the adult forebrain that underlie the consolidation and stabilization of context-linked memory.DOI: http://dx.doi.org/10.7554/eLife.17361.001

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“…First, fasting as a physiological state affects the transport of appetite-related hormones, such as ghrelin and orexin, into the brain 39 , 40 . Such hormones play important roles in regulating synaptic plasticity 41 – 44 . Fasting was shown to elevate excitatory synaptic inputs through the orexigenic hormone ghrelin 45 .…”

Section: Discussionmentioning

confidence: 99%

Fasting enhances extinction retention and prevents the return of fear in humans

et al. 2018

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Fear is prone to return following extinction that is the basis of exposure therapy for fear-related disorders. Manipulations that enhance the extinction process can be beneficial for treatment. Animal studies have shown that fasting or caloric restriction can enhance extinction and inhibit the return of fear. The present study examined the effects of fasting on fear acquisition, extinction, and the return of fear in humans. One hundred and twenty-five male participants were randomized into a fasting group and food group and exposed to a Pavlovian fear conditioning paradigm. Changes in plasma cortisol and ghrelin levels were examined using enzyme-linked immunosorbent assays. One-night fasting had no effect on fear acquisition but enhanced fear extinction retention and prevented the return of fear, and this effect persisted for at least 6 months. This procedure was also effective for remote fear memory. Plasma ghrelin levels were elevated after fasting and had a negative relationship with the fear response in spontaneous recovery test. However, overnight fasting did not affect cortisol levels. These findings indicate that fasting enhances extinction retention and prevents the return of fear, without influencing fear memory formation. We propose that this novel procedure may open new avenues for promoting extinction-based therapies for fear-related disorders.

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Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor

Cited by 39 publications

References 61 publications

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory

Satb2 determines miRNA expression and long-term memory in the adult central nervous system

Fasting enhances extinction retention and prevents the return of fear in humans

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