BDNF is essential to promote persistence of long-term memory storage

Bekinschtein, Pedro; Cammarota, Martı́n; Katche, Cynthia; Slipczuk, Leandro; Rossato, Janine I.; Goldin, Andrea Paula; Izquierdo, Iván; Medina, Jorge H.

doi:10.1073/pnas.0711863105

Cited by 595 publications

(443 citation statements)

References 36 publications

(58 reference statements)

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“…The results are compatible with a role of the recently described hippocampal mechanism of memory persistence for one-trial avoidance and contextual fear conditioning in rats (12,13). Methylphenidate stimulates dopamine release in the forebrain by influences on the dopamine vesicular transporter (24)(25)(26)(27), and it was reported long ago to enhance learned behaviors in rats (28,29) and, more recently, in humans (30).…”

Section: Discussionsupporting

confidence: 73%

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Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration

Izquierdo

Bevilaqua

Rossato

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Healthy human volunteers 16 -82 years of age with at least 10 years of schooling were exposed to two different memory tasks. The first task involved incidental memory. The subjects were asked, as casually as possible: ''Did you watch any movie on TV 2 days ago? And 7 days ago? If so, do you remember the title of the movie(s) and the name of the first two actors (actresses)?'' Retention scores (maximum ‫؍‬ 3: title, actor 1, and actor 2) were equally high (overall mean ‫؍‬ 2.6, n ‫؍‬ 61) in all age groups (16 -20, 21-30, 31-40, 41-60, and 61-82 years) for the day 2 scores. Scores for the movie seen 7 days before decreased significantly and progressively in the three older groups in relation to age, which indicates reduced persistence of this type of memory beginning at the age of 41-50 years and becoming more extensive over the years. The other task was a formal memory procedure. Subjects were asked to study a brief text with factual information on the 1954 World Soccer Cup for 10 min. They were then exposed to 10 questions on the text 2 days and, again, 7 days later. Retention scores declined between the two tests, but in this task, the decline of persistence occurred to a similar extent in all age groups, and thus was not dependent on age. Methylphenidate (10 mg p.o.) given 12 hours after acquisition markedly enhanced persistence of the two memory types. This suggests an involvement of dopaminergic processes in persistence in the late posttraining period.aging ͉ human aging ͉ incidental memory ͉ formal memory

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Section: Discussionsupporting

confidence: 73%

“…Their persistence depends on several factors: the degree of emotional arousal at the time of consolidation (3, 7), age (8-11 years), perhaps circadian oscillations (6), and other factors (5). A specific BDNF-dependent mechanism for memory persistence has been described in the hippocampus of rats, which is activated around 12 hours after training (12,13).…”

mentioning

confidence: 99%

Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration

Izquierdo

Bevilaqua

Rossato

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…This effect was partly reversed by cross-fostering and fully reversed by the administration of DNMT inhibitors in adulthood (Roth et al, 2009). Given the established role for BDNF in fear learning and cognitive function in general (Alonso et al, 2005;Bekinschtein et al, 2008a;Bekinschtein et al, 2008b;Lubin et al, 2008), these results indicate that early-life experiences may increase the susceptibility to PTSD at least in part through epigenetic regulation of the BDNF gene, but additional studies are required to test this hypothesis directly. Overall, these findings, as well as those from Michael Meaney's lab, are consistent with the emerging unifying hypothesis that the accumulation of aberrant epigenetic marks over the lifespan may be a driver of PTSD-related cellular, cognitive, and physiologic changes.…”

Section: Role Of Bdnf In Ptsdmentioning

confidence: 88%

“…A recent series of studies found that the brain-derived neurotrophic factor BDNF gene locus, which is associated with learning and memory in general and with fear memory in particular (Alonso et al, 2005;Bekinschtein et al, 2007;Bekinschtein et al, 2008a;Bekinschtein et al, 2008b), is also subject to memory-associated changes in DNA methylation. Specifically, contextual fear conditioning was associated with decreased methylation and increased expression of BDNF exon IV, and this effect was regulated by the NMDA receptor Figure 3).…”

Section: Epigenetic Mechanisms In Hippocampus-dependent Fear Consolidmentioning

confidence: 99%

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

Zovkic

Sweatt

2012

Neuropsychopharmacol

172

111

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One of the most exciting discoveries in the learning and memory field in the past two decades is the observation that active regulation of gene expression is necessary for experience to trigger lasting functional and behavioral change, in a wide variety of species, including humans. Thus, as opposed to the traditional view of 'nature' (genes) being separate from 'nurture' (environment and experience), it is now clear that experience actively drives alterations in central nervous system (CNS) gene expression in an ongoing fashion, and that the resulting transcriptional changes are necessary for experience to trigger altered long-term behavior. In parallel over the past decade, epigenetic mechanisms, including regulation of chromatin structure and DNA methylation, have been shown to be potent regulators of gene transcription in the CNS. In this review, we describe data supporting the hypothesis that epigenetic molecular mechanisms, especially DNA methylation and demethylation, drive long-term behavioral change through active regulation of gene transcription in the CNS. Specifically, we propose that epigenetic molecular mechanisms underlie the formation and stabilization of context-and cue-triggered fear conditioning based in the hippocampus and amygdala, a conclusion reached in a wide variety of studies using laboratory animals. Given the relevance of cued and contextual fear conditioning to post-traumatic stress, by extension we propose that these mechanisms may contribute to post-traumatic stress disorder (PTSD) in humans. Moreover, we speculate that epigenetically based pharmacotherapy may provide a new avenue of drug treatment for PTSD-related cognitive and behavioral function.

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“…Furthermore, the specific mechanisms by which exercise increases BDNF expression in the brain and by which these increases translate into improvements in memory remain unclear. The role of BDNF in learning and memory has been well established [8][9][10][11]: BDNF has a wide range of short-term and long-term effects on neurons, most of which are thought to be mediated by its binding to the tyrosine kinase B (TrkB) Receptor, and the consequent activation of plasticity-related signalling cascades [12]. One such signalling cascade is the ERK (extracellular signal-related kinase) pathway [13], which has been shown to be essential to a number of forms of learning and memory [14,15].…”

Section: Introductionmentioning

confidence: 99%

BDNF-stimulated intracellular signalling mechanisms underlie exercise-induced improvement in spatial memory in the male Wistar rat

Bechara

Lyne

Kelly

2014

Behavioural Brain Research

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• Exercised rats successfully completed challenging spatial task.• Exercised rats showed increase in KCl-stimulated BDNF release from dentate gyrus.• Exercised rats displayed increases in BDNF expression and cell division in dentate gyrus.• Exercised rats displayed activation of BDNF-stimulated signalling cascade.• BDNF injections mimicked effects of exercise on both memory and signalling events. a r t i c l e i n f o b s t r a c tExercise-induced improvements in learning are associated with neurotrophic and neurogenic changes in the dentate gyrus, but the intracellular signalling mechanisms that may mediate these improvements remain unknown. In the current study we investigate the effects of one week of forced exercise on spatial memory and analyse in parallel BDNF-stimulated signalling pathways in cells of the dentate gyrus. Additionally, we test whether a single intracerebroventricular (i.c.v.) injection of BDNF can mimic the observed cognitive and signalling changes. Male Wistar rats were assigned to exercised and sedentary groups and tested in a spatial task post-exercise. Tissue from the dentate gyrus was assessed for expression and release of BDNF, and for changes in expression and activation of TrkB, ERK and synapsin-1. In a separate set of experiments, male Wistar rats received a single i.c.v. injection of BDNF and were then tested in the same spatial learning task. Exercised and BDNF-treated (but not control) rats could successfully complete an object displacement task that tests spatial learning. Exercised rats and BDNF-treated rats displayed increases BDNF expression and ERK1 activation, while exercised rats showed increases in cell division, stimulated BDNF release, TrkB activation, and synapsin-1 expression in the dentate gyrus. We conclude that exercise-induced increases in BDNF in the dentate gyrus are sufficient to cause improvements in spatial memory by activating signalling cascades that enhance synaptic transmission in the hippocampus.

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BDNF is essential to promote persistence of long-term memory storage

Cited by 595 publications

References 36 publications

Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration

Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

BDNF-stimulated intracellular signalling mechanisms underlie exercise-induced improvement in spatial memory in the male Wistar rat

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