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Visualizing PKA Dynamics in a Learning Center View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neuron Previews Visualizing PKA Dynamics in a Learning Center Troy Zars1,* 1Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2010.02.009 Gervasi et al. report in this issue of Neuron that the mushroom bodies in Drosophila, a critical center for olfactory memory formation, have spatially restricted PKA activity in response to specific neuromodulators. The dunce cAMP-phosphodiesterase and rutabaga adenylyl cyclase genes are necessary for two key properties of PKA dynamics in these neurons. The study of olfactory learning in 2005; Keene and Waddell, 2007; Heisen- by mutation of the tyramine-beta-hydrox- Drosophila has provided key insights into berg and Gerber, 2008), which typically ylase gene (the enzyme critical for synthe- the molecular and neural mechanisms of pairs an odorant with either an electric sizing octopamine) or activating the octo- memory formation (McGuire et al., 2005). shock or a sugar reward as unconditioned paminergic neurons in larval experiments The recent development of tools to visu- stimuli (USs). A second odorant is pre- influences appetitive but not aversive alize cAMP and PKA signaling now allows sented to flies in the absence of either olfactory memory. In contrast, the dopa- one to see the processes that underlie this US. When forced to choose between the minergic system is important for aversive learning. These new approaches have re- two odorants at a T maze choice point, olfactory memory but not for acquisition vealed an unexpected spatial restriction the majority of normal wild-type flies avoid of appetitive olfactory memory (some and a dual-signal-dependent dynamic of a shock-associated odorant or approach dopamine neurons, however, are impor- PKA activity within the mushroom bodies a sugar-associated odorant. Importantly, tant for linking appetitive olfactory mem- of the fruit fly in response to specific neu- previous experiments with flies that have ory retrieval to the hunger state of the fly) romodulators. Mutations of genes that either abnormal mushroom bodies, che- (Krashes et al., 2009). How these neuro- alter memory formation also alter these mical treatments that ablate most of the modulators influence the PKA signal in PKA properties, thus linking the PKA Kenyon cells, or transgenic manipulation the mushroom bodies was unknown. dynamics with learning. of the mushroom bodies all altered olfac- To visualize PKA activity within a ner- The mushroom bodies in insects are a tory memory. vous system, Gervasi et al. (2010) devel- paired structure that are critical for higher- The cAMP/PKA signaling pathway is oped and validated a fluorescence-based order functions. In Drosophila, they are critical for olfactory memory formation tool for Drosophila. Pharmacological made up of 2500 intrinsic neurons (McGuire et al., 2005). Some of the first stimulation of adenylyl cyclase or inhibi- (also called Kenyon cells) per hemisphere genes to be identified in mutant screens tion of cAMP phosphodiesterases of (there are about 200,000 neurons in the fly for learning-impaired flies include the transgenic flies expressing this reporter brain) (Heisenberg and Gerber, 2008). The dunce-cAMP-phosphodiesterase and in the mushroom bodies show that this dendrites of the Kenyon cells are orga- rutabaga adenylyl cyclase. Mutation of reporter can indeed measure PKA activity nized into a structure called the mushroom these genes, and later of a PKA catalytic in spatially restricted regions of a brain. body calyx, where some projection neu- subunit and a PKA anchoring protein, Since the mushroom bodies are critical rons from the antennal lobe provide olfac- strongly implicated cAMP/PKA signaling in establishing a short-term olfactory tory information. The Kenyon cell axons in olfactory memory formation (McGuire memory, one would expect that the neu- course forward in a structure termed the et al., 2005; Schwaerzel et al., 2007). romodulators that are key in reinforcing peduncle to the anterior brain, where Immunolocalization of Dunce, Rutabaga, appetitive and aversive olfactory memo- some of these neurons bifurcate medially and PKA showed expression in much of ries would affect the physiology of the and vertically, forming the medial and the fly brain, including the mushroom Kenyon cells. Measuring PKA activity vertical lobes. The mushroom body lobes bodies. However, the expression pattern with bath application of octopamine are further characterized into a/b, a0/b0, within the mushroom bodies was not showed that several parts, or compart- and g regions (Figure 1). Moreover, the identical for these genes, suggesting ments, of the mushroom bodies were mushroom body lobes receive input from some specialization of protein function activated (Figure 1). That is, the calyx extrinsic neuromodulator neurons (e.g., within this structure. and the a, b, and g lobes of the mushroom dopamine and octopamine). The distinc- Interestingly, appetitive (sugar reward) bodies showed an increase in PKA tion between different lobe systems and and aversive (electric shock) olfactory activity with octopamine presentation. In the extrinsic input to the lobes is important memory formation depend on two dif- all of the experiments, the a0 and b0 lobe for the study of PKA signaling (Gervasi ferent biogenic amines: octopamine and neurons were not analyzed because of et al., 2010). dopamine (Schwaerzel et al., 2003; technical difficulties in recording at this The mushroom bodies are also impor- Schroll et al., 2006; Claridge-Chang site (this limit of the study will hopefully tant for olfactory learning (McGuire et al., et al., 2009). Reducing octopamine levels be resolved as these lobes are important 442 Neuron 65, February 25, 2010 ª2010 Elsevier Inc. Neuron Previews in a delayed memory pro- pending on which neuromo- cessing stage) (Krashes et al., dulator was used. Significant- 2007). Surprisingly, when do- ly, the rise in PKA activity with pamine was applied to the coincident acetylcholine/neu- brain, only the a lobe of the romodulator application de- mushroom body showed an pended on the rut-AC. Thus, increase in PKA activity. This through an elegant series of is a remarkable finding be- experiments, and consistent cause the Kenyon cell neu- with the recent results from rons that supply the b lobes, measuring cAMP levels which did not have increased (Tomchik and Davis, 2009), PKA activity, are the same there is now in vivo evidence cells that make up the a lobe. for the role of the rut-AC That is, the axons of Kenyon protein in coincidence detec- cells in these lobes split in tion that supports memory the anterior brain, with one formation. The role of the neurite projecting dorsally (in dunce-PDE in sequestering the a lobe) and one neurite the rise in PKA activity to the projecting medially (in the a lobe was also found with b lobe). Thus, localized PKA coapplication of acetylcho- activity in the vertical neurite line and dopamine. of these Kenyon cells indi- Questions and conclu- cates either a spatially re- sions: There are a few ques- stricted dopamine receptor tions that arise from Gervasi (which is not supported by et al. (2010). First, changes immunolocalization studies) in cAMP and PKA levels (Kim et al., 2003) or a spatially Figure 1. Stimulation of the Drosophila Brain with Octopamine, have been measured after restricted effector cascade. Dopamine, or Acetylcholine Induces Different Patterns of PKA application of octopamine or The dunce cAMP-phos- Activity in the Mushroom Bodies dopamine (Tomchik and Da- phodiesterase (PDE) provides (A) Baseline levels of PKA activity were measured without a stimulus in wild- vis, 2009; Gervasi et al., type (WT) mushroom body compartments (a, a0, b, b0, g, and the calyces a critical function in olfactory [ca]) (represented as cool colors). 2010). Octopamine and do- learning by abrogating the (B) PKA activity increased in the calyces and the a, b, and g lobes with octop- pamine were shown to in- cAMP signal. Flies with a amine stimulation (represented as warm colors). crease cAMP levels in the (C and D) Dopamine stimulation increased PKA activity in the a lobes in WT mutant dunce-PDE gene brain and increased further in the calyces and b, g lobes in dunce cAMP-phos- mushroom bodies indepen- show lowered olfactory short- phodiesterase (dnc) mutant brain. dent of rut-AC function. In term memory scores and (E and F) Costimulation of WT brain with acetylcholine (Ach) and dopamine contrast, octopamine and drastically increased PKA activity in the a lobes (red) compared to stimulation elevated cAMP levels in brain with either stimulus alone and depends on the rutabaga adenylyl cyclase (rut) dopamine increases in PKA homogenates. When Gervasi gene. activity depend on the rut- et al. (2010) examined PKA AC. It has been proposed dynamics in dunce-PDE mutant brains, activated by both a G protein signal and that this discrepancy could be a conse- PKA responses to octopamine applica- rise in Ca2+ to convert ATP to cAMP. In quence of different concentrations of tion were not different from wild-type re- a molecular model of memory formation, octopamine and dopamine needed to sponses. In contrast, and remarkably, the US pathway (through dopamine or activate a rut-AC-independent adenylyl when dopamine was applied to dunce- octopamine) and the conditioned stim- cyclase that could be detected differently PDE brains, the PKA signal normally local- ulus (CS) pathway (olfactory induced with the cAMP and PKA detection ized in the a lobe was distributed in increases in Ca2+) would activate the rut- methods. Second, the lack of an effect several additional compartments (the AC and increase cAMP levels. Activation of the dunce-PDE mutation on the octop- calyces, b and g lobes) (Figure 1). Thus, of PKA would follow this increase in amine-induced increase on PKA activity the dunce-PDE provides an important cAMP.
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