CREB in cognition


The cell transcription factor CREB (cAMP response element binding protein) [1] helps in the learning and stabilization and recovery of long-term memories based on fear. This is mainly due to its expression in the hippocampus and amygdala. Studies that support the role of CREB in cognition include those that eliminate the gene, reduce expression, or overexpress.

Memory
Research suggests that CREB has a role in molecular stages that stabilize memory in the brain, including that of emotional memory. Proof of the role of CREB in emotional memory is divided into three experimental categories: negative manipulations (where CREB levels have been lowered), positive manipulations (where CREB levels have been increased) and non-interventions (where The endogenous levels of CREB were followed before and after learning).

Knockout Knockout
studies in the Aplysia sea slugs indicated that the decreasing CREB function blocks long-term changes in synaptic function but not in the short term. [2] Changes in synaptic function (ie, synaptic plasticity) are necessary for learning and memory [3]. As evidence, a mouse line with a targeted perturbation of CREB α and δ isoforms showed an intact short – term memory, but disrupted long – term memory in several behavioral tasks, including contextual conditioning, Spatial learning in the Morris labyrinth, two independent learning tasks of the hippocampus. Also, The electrophysiological studies of the hippocampus revealed that the CREB mutation disrupted the stability of synaptic plasticity [1] Genetic studies in Drosophila fruit flies also revealed a role for CREB in memory, suggesting that CREB A role in memory retained in an evolutionary way.
Knockdown
There are several methods of removing (reducing the expression of) CREB:

Antisense Antisense
oligonucleotides (single strands of DNA or RNA that are complementary to a selected sequence) against the CREB mRNA of the hippocampus may reduce CREB levels within 6 hours after infusion and Spatial memory. Tests given immediately after training showed that antisense oligonucleotides against CREB do not disturb short-term memory.

Dominant negative
Another strategy to interfere with the CREB function is the use of a dominant negative transgenic strategy. In this strategy, a fragment of the CREB gene was expressed from a transgene in mice. [6] The resulting transgenic protein was designed to interfere with normal CREB function by competent with wild type (non-mutated) CREB for binding sites in DNA; The transgenic protein lacks the necessary domains for the manufacture of functional complexes. To regulate when the dominant negative CREB fragment interferes with the normal CREB function, the mutant DNA was used to generate a fusion protein that also included a mutated ligand binding domain (LBD) of the estrogen receptor, Linking to tamoxifen rather than to estrogen. When exposed to tamoxifen, the dominant negative fragment changed the conformation of the fusion protein, became active and could therefore interfere with CREB binding sites. An advantage of this inducible transgenic system is that the altered protein is constitutively present and can therefore be rapidly activated following the administration of tamoxifen.

The use of the LBD system to kill the CREB protein function during training (using both contextual freezing phenomena and fear of tonality) has resulted in a long-term but not short-term deficit, Of the memory. The decrease of the CREB function did not affect the recovery of the consolidated memory.

RNA interference
See also: RNAi
A small interfering RNA (siRNA) can induce selective degradation of the mRNA of the protein of interest. Infusion of siRNA segments against CREB generated deficiencies in both the contextual conditioning and the forward tracing. [7]

Activation
A line of lacZ reporter mice (mice that have E. coli gene attached to their CREB gene to produce a protein that is easily visualized), when formed with a context protocol, showed high levels of mediated transcription By CREB in the CA1 and CA3 of the hippocampus compared to unformed mice or mice that did not associate content with shock (in the conditioning of fear) due to latent inhibition. Similarly, lacZ mice that were formed with a tone protocol showed higher levels of CREB-dependent gene transcription in the amygdala than untrained mice or mice in the unaccompanied group. There was no difference in the CREB-dependent gene expression in the hippocampus of animals formed with a tone protocol.

Rescue
When CREB-expressing herpes simplex virus was infused into the CREO knockout, the expression of CREB in the amygdala rescued the deficiency, indicating that tonsillar CREB is essential For the memory in the conditioning of the tone. [9]

Overexpression
The role of overexpression of CREB has not been systematically examined in the conditioning of fear, and studies of other conditioning paradigms have produced mixed results. A 2001 study, which used viral transfection to overexpress CREB in the amygdala by basolateral route, revealed that overexpression increased the response of startle potentially stimulated by fear. This suggests that CREB levels are limiting when acquiring startle potentially frightened [clarification needed] and that these levels are related to the strength of this form of memory.

A more recent article (2009), using a similar viral approach in the hippocampus, revealed that the additional CREB expression could also improve the contextual conditioning of fear, a result consistent with a role of the hippocampus in this form of conditioning. [11] While the viral CREB reversed conditioning deficiencies in CREB knockout animals, additional CREB did not appear to improve the memory of wild-type controls.

Chronic improvement of CREB, using genetic manipulations in mice, did not seem to improve memory in a labyrinth task. Another 2009 study, which overexpressed CREB using the transgenic dox system of tetracycline, revealed that if additional CREB did not improve acquisition, this impeded memory recovery, suggesting That there may be an optimal level of CREB activation for the normal memory function. [12] Other documents [13] [14] [15] suggest that CREB helps control intrinsic excitability, providing an additional mechanism by which CREB can contribute to the acquisition and expression of memory.


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