Upregulation of CREB-Mediated Transcription Enhances Both Short- and Long-Term Memory

Abstract

Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long-lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression.

Voluntary wheel running ameliorates symptoms of MK-801-induced schizophrenia in mice

“…The results of this study are consistent with those of previous studies, which demonstrated that enhanced BDNF expression in the hippocampus improves short-term and long-term memories (34,35). Of note, BDNF expression in the hippocampus is suppressed by traumatic brain injury, suggesting that BDNF exerts a neuroprotective effect (36).…”

Lifelong environmental enrichment in rats: impact on emotional behavior, spatial memory vividness, and cholinergic neurons over the lifespan

“…Indeed, environmental enrichment increases hippocampal neurogenesis and survival of newly formed neurons (e.g., Bruel-Jungerman et al 2005), CREB activation (e.g., Williams et al 2001), long-term potentiation (Duffy et al 2001), and brain-derived neurotrophic factor levels (Bakos et al 2009). All these factors contribute to consolidation and thus memory persistence (Bekinschtein et al 2007;Bruel-Jungerman et al 2005;Sekeres et al 2010;Suzuki et al 2011). Interestingly, the capability of enriched environment to enhance long-term memory for object recognition was lost when neurogenesis was blocked (Bruel-Jungerman et al 2005).…”

Transgenic songbirds with suppressed or enhanced activity of CREB transcription factor

“…3). Genetic manipulation of CREB function in rodents sometimes causes discrepancies in the evaluation of behavioral studies, because enhancement of CREB phosphorylation in mice does not necessarily result in the enhancement of memory formation, depending on the expression level of proteins or the testing context (40,(57)(58)(59). In our hearing threshold analysis (Fig.…”