Age-related disturbance of memory and CREB phosphorylation in CA1 area of hippocampus of rats (original) (raw)
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CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats
The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline. 1 of 23 RESEARCH ARTICLE 2013). The magnitude of this age-related decrease in neuronal excitability correlates with agerelated cognitive deficits . Aged impaired (AI) animals have larger AHPs than both young animals, and aged unimpaired (AU) animals. Interestingly, the AHP amplitude from AU animals is no different than that of young animals . Moreover, pharmacological compounds that reduce the amplitude of the AHP in vitro, ameliorate age-related cognitive impairments in vivo . Based on these findings, we are searching for molecular pathway(s) that modulate both cognition and intrinsic cellular excitability.
Brain Research, 2010
The effects of genetic background on fear trace conditioning were evaluated in relation to phosphorylated levels of cAMP response element-binding protein (CREB) in the hippocampus using two different inbred strains of mice, C57BL/6 and DBA/2. The male mice received a trace fear conditioning protocol and unpaired control groups were included to assess nonassociative effects on test performance. Both C57BL/6 and DBA/2 mice with paired training displayed higher freezing responses during testing than those with unpaired training, respectively. The C57BL/6 mice with paired training also displayed higher freezing responses to the tone-CS during testing than the DBA/2 mice with paired training. Because much evidence implicates the hippocampus as an important neural substrate for trace fear conditioning, the engagement of the hippocampus was examined after testing by measuring levels of CREB and phosphorylated CREB (pCREB). The results revealed that hippocampal CREB levels in both strains of mice were not significantly altered according to the type of training (unpaired vs. paired). However, the hippocampal pCREB levels were significantly higher in the paired training group than the unpaired control group in C57BL/6 mice, but not in DBA/2 mice. These findings indicate that hippocampal pCREB is closely tied to this form of associative conditioning only in C57BL/6 mice and that different neural substrates may support trace conditioning in C57BL/6 and DBA/2 strains.
Hippocampus, 2005
In the present experiments, we used conditioned fear to study whether changes in expression or functional state of proteins known to be involved in hippocampal learning could suggest correlation with age-related memory deficits. We focused on both alterations constitutively present in the hippocampus of aged rats and alterations related to different learning responses. Our results point at the dysregulation of the phosphorylation state of CREB in the hippocampus of aged rats as a primary biochemical correlate of their impaired memory. Other proteins, known to be important for various steps of memory formation and consolidation and linked to CREB, are to some extent altered in their constitutive expression or in the response to learning in the aged hippocampus. In particular, phosphorylated CREB and Arc, a protein functionally related to CREB in memory consolidation, are both present at constitutively higher levels in the hippocampus of aged rats, but they are not susceptible to the learning-related up-regulation occurring in young adults. Two other CREB-regulated proteins involved in memory consolidation, the neurotrophin BDNF and the transcription factor C/EBPb, are expressed at similar levels in the hippocampus of young-adult and aged rats, but their response to conditioned fear learning appears dysregulated by aging. Calcineurin, a protein phosphatase having CREB among its substrates and whose expression negatively correlates with learning, is more expressed in the hippocampus of aged rats. However, while calcineurin expression decreases in the hippocampus of young adults after learning, no changes are observed in the hippocampus of aged, learning-impaired rats. V
CREB-binding protein levels in the rat hippocampus fail to predict chronological or cognitive aging
Neurobiology of Aging, 2013
Normal cognitive aging is associated with deficits in memory processes dependent on the hippocampus, along with large-scale changes in the hippocampal expression of many genes. Histone acetylation can broadly influence gene expression and has been recently linked to learning and memory. We hypothesized that cAMP response element binding (CREB)-binding protein (CBP), a key histone acetyltransferase, may contribute to memory decline in normal aging. Here, we quantified CBP protein levels in the hippocampus of young, aged unimpaired and aged impaired rats, classified on the basis of spatial memory capacity documented in the Morris water maze. First, CBP-immunofluorescence was quantified across the principal cell layers of the hippocampus using both low and high resolution laser scanning imaging approaches. Second, digital images of CBP immunostaining were analyzed by a multipurpose classifier algorithm (WND-CHARM) with validated sensitivity across many types of input materials. Finally, CBP protein levels in the principal subfields of the hippocampus were quantified by quantitative western blotting. CBP levels were equivalent as a function of age and cognitive status in all analyses. The sensitivity of the techniques used was substantial, sufficient to reveal differences across the principal cell fields of the hippocampus, and to correctly classify images from young and aged animals independent of CBP-immunoreactivity. The results are discussed in the context of recent evidence suggesting that CBP decreases may be most relevant in conditions of aging that, unlike normal cognitive aging, involve significant neuron loss.
CREB required for the stability of new and reactivated fear memories
Nature Neuroscience, 2002
Several studies show a universal requirement for protein synthesis in the consolidation of long-term memory (LTM) 1,2 . Evidence from a variety of species, including Aplysia 3 , Drosophila 4,5 , mice 6,7 and rats 8-10 , indicates that members of the cAMP-responsive element-binding protein (CREB) family of transcription factors are key transcription factors regulating the synthesis of proteins necessary for LTM formation. However, most studies so far have not defined the precise memory processes that require CREB. To identify the role of CREB in dissociable memory processes, we used a newly identified inducible system to temporally and reversibly repress CREB function. We fused a CREB repressor (αCREB isoform with a S133A mutation (αCREB S133A )) 11,12 to a ligand-binding domain (LBD) of a human estrogen receptor with a G521R mutation (LBD G521R ), whose activity is regulated not by estrogen but by the synthetic ligand TAM 13-15 . In the absence of TAM, the LBD G521R -CREB S133A fusion protein is inactive 15 . However, administration of TAM activates this inducible CREB-repressor fusion protein (CREB IR ), allowing it to compete with endogenous CREB and disrupt cAMP-responsive element (CRE)-mediated transcription ( , available on the supplementary information page of Nature Neuroscience online).
Hormones and Behavior, 2005
Young animals respond to threatening stimuli in an age-specific way. Their endocrine and behavioral responses reflect the potential threat of the situation at a given age. The aim of the present study was to determine whether corticotropin-releasing factor (CRF) is involved in the endocrine and behavioral responses to threat and their developmental changes in young rats. Preweaning 14-day-old and postweaning 26-day-old rats were exposed to two age-specific threats, cat odor and an adult male rat. The acute behavioral response was determined during exposure. After exposure, the time courses of the corticosterone response and of CRF expression in the paraventricular nucleus of the hypothalamus (PVN) and in extrahypothalamic areas were assessed. Preweaning rats became immobile when exposed to cat odor or the male rat, whereas postweaning rats became immobile to cat odor only. Male exposure increased serum corticosterone levels in 14-day-old rats, but cat odor failed to increase levels at either age. Exposure induced elevation of CRF mRNA levels in the PVN that paralleled changes in corticosterone levels. CRF may thus play a role in endocrine regulation and its developmental changes during early life. Neither cat odor nor the adult male altered CRF mRNA levels in the bed nucleus of the stria terminalis (BNST) or the amygdala, but both stimuli increased levels in the hippocampus. Hippocampal CRF mRNA expression levels did not parallel cat odor or male-induced immobility, indicating that CRF is not involved in this response in young rats but may be involved in aspects of learning and memory.
Behavioural Brain Research, 2002
Regulation of gene transcription via the cyclic adenosine 3?,5?-monophosphate (cAMP)-mediated second messenger pathway has been implicated in learning and memory. Although the cAMP response element-binding protein (CREB) is an important transcription factor involved in long-term memory, it remains to be determined whether the CREB-dependent events are attributed to spatial learning and memory in a radial arm maze. Here we demonstrate that cAMP-dependent protein kinase A (PKA) and CREB are activated in the course of spatial learning. The radial maze training in rats resulted in a significant increase in PKA and CREB phosphorylation in the hippocampus in the course of spatial learning, which was followed by spatial memory formation. On the other hand, neither the phosphorylation of Ca 2' /calmodulin-dependent protein kinase II (CaMKII) and extracellular signalregulated kinase (ERK) nor the mRNA level of brain-derived neurotrophic factor was significantly affected. These results suggest that activation of the PKA/CREB signaling pathway in the hippocampus plays an important role in spatial memory formation. #
Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala
European Journal of Neuroscience, 2001
Fear memory retrieval has been shown to induce a protein-synthesis dependent re-consolidation of memories within the amygdala. Here, using immunocytochemistry, we investigated the molecular basis of this process in the rat and show that retrieval of a cued fear memory induces the activation, by phosphorylation, of the transcription factor CREB within the basal and lateral nuclei of the amygdala, as well as expression of the CREB-regulated immediate-early gene, c-fos, in the basal amygdala. We also show an increase in CREB phosphorylation within the central nucleus of the amygdala following behavioural testing, with an accompanying increase in Fos-immunoreactive nuclei in animals retrieving the cued association. There were no changes in either phosphorylated CREB or Fos in the hippocampus following exposure to discrete fear stimuli. These results show that activation of CREB, which has been shown to be involved in the formation of long-term fear memories, also accompanies memory retrieval, and also suggest a role for CREB phosphorylation in memory re-consolidation following retrieval.
The PDE4 Inhibitor HT-0712 Improves Hippocampus-Dependent Memory in Aged Mice
Neuropsychopharmacology, 2014
Aging is associated with declines in memory and cognitive function. Here, we evaluate the effects of HT-0712 on memory formation and on cAMP response element-binding protein (CREB)-regulated genes in aged mice. HT-0712 enhanced long-term memory formation in normal young mice at brain concentrations similar to those found to increase CRE-mediated gene expression in hippocampal neurons. Aged mice showed significantly poorer contextual and trace conditioning compared with young-adult mice. In aged mice, a single injection of HT-0712 significantly boosted contextual and trace long-term memory. Additional effects of HT-0712 were seen in a spatial memory task. Our parallel biochemical experiments revealed that inductions of the CREB-regulated genes, cFos, Zif268, and Bdnf, after fear conditioning were diminished in aged mice. HT-0712 facilitated expression of these CREB-regulated genes in aged hippocampus, indicating that the drug engages a CREB-regulated mechanism in vivo. These findings corroborate and extend our previous results on the mechanism of action of HT-0712 and its efficacy to enhance memory formation. Our data also indicate that HT-0712 may be effective to treat age-associated memory impairment in humans.
Learning & Memory, 2009
Regulated expression of a constitutively active form of cAMP response element-binding protein (CREB), VP16-CREB, lowers the threshold for the late phase of long-term potentiation in the Schaffer collateral pathway in a de novo gene expression-independent manner, and increases the excitability and reduces afterhyperpolarization of neurons at the amygdala and the hippocampus. We explore the consequences of these changes on the consolidation of fear conditioning and find that the expression of VP16-CREB can bypass the requirement for de novo gene expression associated with long-term memory formation, suggesting that CREB-dependent gene expression is sufficient for fear memory consolidation.