Converting the Memory Trace to the Engram

Although we do not yet know the full details of how honeybees form associations, we can use results from other species to infer how honeybees convert temporary elevations of cAMP and Ca2+ into long-lasting changes in neural pathways. In some animal cells, an increase in cAMP activates the transcription of specific genes. The regulatory region of these genes contains a short DNA sequence called the cyclic AMP response element (CRE). This

Figure 3.3. The catalytic subunit of PKA, once free of its regulatory subunit, migrates into the cell nucleus, where it phosphorylates proteins that regulate gene expression (phosphorylation is indicated by "P"). One target of PKA is cyclic AMP response element binding protein (CREB). Once activated by PKA, CREB binds to the cyclic AMP response element, CRE, a region of some genes that regulates their transcription. CREB can also be phosphorylated by protein kinases otherthan PKA, including Ca2+-dependent kinases such as PKC, thatwould be activated by converging CS-US activity. The activity of genes that contain a CRE sequence is altered by binding with CREB, leading to a change in the production of mRNAs that code for the production of proteins.

Figure 3.3. The catalytic subunit of PKA, once free of its regulatory subunit, migrates into the cell nucleus, where it phosphorylates proteins that regulate gene expression (phosphorylation is indicated by "P"). One target of PKA is cyclic AMP response element binding protein (CREB). Once activated by PKA, CREB binds to the cyclic AMP response element, CRE, a region of some genes that regulates their transcription. CREB can also be phosphorylated by protein kinases otherthan PKA, including Ca2+-dependent kinases such as PKC, thatwould be activated by converging CS-US activity. The activity of genes that contain a CRE sequence is altered by binding with CREB, leading to a change in the production of mRNAs that code for the production of proteins.

CRE sequence is regulated by a specific protein called CRE-binding protein (CREB). CREB is a member of a large family of structurally related proteins that bind to the CRE sequence (fig. 3.3). When CREB is activated by PKA (which is activated by cAMP), it binds to the CRE sequence and regulates gene transcription (Bacskai et al. 1993). Interestingly, other Ca2+-dependent kinases, such as CaMKIV mentioned above, also activate CREB (Ghosh and Greenberg 1995).

Studies of learning in Drosophila (Yin et al. 1994), the sea slug Aplysia (Bartsch et al. 1995), mice (Bourtchuladze et al. 1994), and rats (Lamprecht et al. 1997) confirm that CREB induces changes in long-term memory that depend on protein synthesis. In the honeybee, inhibition of protein synthesis does not disrupt learning measured 24 hours after training (i.e., learning that does not depend on protein synthesis), but does interfere with long-term changes measured 3 days after training (i.e., learning that does depend on protein synthesis; Wustenberg et al. 1998).

In summary, high levels ofPKA activity in the honeybee mushroom body are caused by an elevated level of cAMP, which results from the convergence of CS odor and US sucrose signals in Kenyon cells. Protein kinase A then activates CREB. CREB, in turn, modulates the activity of particular genes. A Ca2+-dependent mechanism can also increase CREB binding and gene expression. CS- and US-induced activity converge at PKA (because Ca2+

enhances cAMP activation of PKA) and at CREB (because a Ca2+-dependent kinase and PKA each independently activate CREB). These events change the amounts or types of proteins produced in neurons that experience the convergence of the CS and US (see fig. 3.3). Change in gene expression produced by pairings of the CS and US provides a mechanism to translate transient stimulus-induced activation of these genes into lasting change in the nervous system.

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