* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Conditioning: Simple Neural Circuits in the Honeybee
Biological neuron model wikipedia , lookup
Neural oscillation wikipedia , lookup
Catastrophic interference wikipedia , lookup
Stimulus (physiology) wikipedia , lookup
Neural coding wikipedia , lookup
Neuroesthetics wikipedia , lookup
Neuroeconomics wikipedia , lookup
Artificial neural network wikipedia , lookup
Emotion and memory wikipedia , lookup
Neural engineering wikipedia , lookup
Molecular neuroscience wikipedia , lookup
Memory consolidation wikipedia , lookup
Nonsynaptic plasticity wikipedia , lookup
Synaptic gating wikipedia , lookup
Collective memory wikipedia , lookup
Clinical neurochemistry wikipedia , lookup
Eyeblink conditioning wikipedia , lookup
Nervous system network models wikipedia , lookup
Activity-dependent plasticity wikipedia , lookup
Music-related memory wikipedia , lookup
Metastability in the brain wikipedia , lookup
Channelrhodopsin wikipedia , lookup
Reconstructive memory wikipedia , lookup
Development of the nervous system wikipedia , lookup
Types of artificial neural networks wikipedia , lookup
Olfactory bulb wikipedia , lookup
State-dependent memory wikipedia , lookup
Recurrent neural network wikipedia , lookup
Prenatal memory wikipedia , lookup
Sparse distributed memory wikipedia , lookup
Holonomic brain theory wikipedia , lookup
This article was originally published in the Encyclopedia of Neuroscience published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for noncommercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who you know, and providing a copy to your institution’s administrator. All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial Menzel R (2009) Conditioning: Simple Neural Circuits in the Honeybee. In: Squire LR (ed.) Encyclopedia of Neuroscience, volume 3, pp. 43-47. Oxford: Academic Press. Author's personal copy Conditioning: Simple Neural Circuits in the Honeybee 43 Conditioning: Simple Neural Circuits in the Honeybee R Menzel, Freie Universität Berlin, Berlin, Germany ã 2009 Elsevier Ltd. All rights reserved. The Antennal Lobe and the Mushroom Body Are Sequentially Involved in the Olfactory Memory Trace In honeybee olfactory learning, the pathways for the conditioned stimulus (CS, odor) and the unconditioned stimulus (US, sucrose) are well defined. The US pathway is implemented in a single identified neuron, the VUMmx1 neuron. The olfactory pathway (the CS pathway) consists of the olfactory receptor neurons projecting through the antennal nerve to the antennal lobe (AL); the first-order integration neuropil; the olfactory projection neurons (PNs), which connect the AL with the mushroom body (MB); the lateral horn (also called lateral protocerebrum); and other higher-order brain regions. CS and US pathways converge anatomically at three sites: the AL, the lip region of the MB, and the lateral horn. For two of these regions, the AL and the MB, it has been shown with local injections of the putative transmitter of the first ventral unpaired median neuron of the maxillary segment (VUMmx1) as a substitute for the reward stimulus that olfactory memory induces learning by forward pairing (but not by backward pairing). These findings corroborate earlier observations using local cooling as a retrograde amnestic treatment, which documented a cooling-sensitive memory phase for the AL during the first 1–2 min after a single learning trial and such a phase for the MB for the first 5–6 min. The early and late short-term-memory phases after single-trial olfactory conditioning were related to the AL and MB, respectively, on the basis of such findings. Single Neuron Activity Correlate with Olfactory Learning The reward neuron VUMmx1 responds to sucrose with long-lasting spike activity and to various visual, olfactory, and mechanosensory stimuli with low-frequency spike activity. Depolarizing VUMmx1 immediately after CS presentation (forward-pairing, CSþ) leads to learning, but backward-pairing does not (CS ). Thus VUMmx1 constitutes the neural correlate of the US in associative olfactory learning. After differential conditioning in which an odor CSþ is forward paired with sucrose reward (US) and another odor CS is backward paired with US, presentation of the CSþ alone activates and CS inhibits VUMmx1, indicating that the reward pathway learns about the stimuli, a property that may be the neural substrate of secondorder conditioning. In addition, VUMmx1’s response to the US after presentation of the CSþ is greatly reduced, but the response to CS remains normal, indicating that the response of VUMmx1 to US after conditioning depends on US expectation. This property of VUMmx1 is sufficient to explain the behavioral phenomenon of blocking and may thus reflect its neural substrate. These results demonstrate that the single identified neuron VUMmx1 is a sufficient neural substrate for the reinforcing function of the US sucrose in olfactory conditioning and has properties that allow explaining second-order conditioning and blocking. Many other neurons belonging to different tracts leading from the AL toward the MB, or which are extrinsic to the MB, have been tested for associative plasticity by means of the differential conditioning paradigm. PNs connecting the AL with the MB calyx were less clear in CSþ-specific plasticity when intracellular recordings were applied, but recent extracellular multiunit recordings provided compelling evidence for associative plasticity in the minute range after conditioning. Most interesting, particular PNs specifically enhance or reduce their responses to CSþ in about equal proportions, and a CSþ-specific shift in the power spectrum of local field potentials indicates an increase of precise spike timing for the CSþ but not for the CS . This property may explain findings from optical imaging experiments in which Ca2þ activity of the postsynaptic sites of lateral PN neurons in the AL glomeruli was monitored during differential olfactory conditioning. No specific CSþ and CS effects were seen. It appears that the glomerulus as a whole reliably codes odors in a combinatorial pattern together with other glomeruli, whereas single PNs undergo specific associative plasticity. In the case of a balance between associative rise and fall of activity in PNs originating in the same glomerulus, no learning effect will be seen when the whole glomerulus is imaged. It will have to be elucidated in the future whether the associative rise and fall in the rate responses of particular PNs or the precise timing of spikes in particular subsets of PNs represents the learning-related signature in the AL-MB network. Two other observations support the conclusion that the AL network is indeed involved in an early and short-lasting memory trace. First, Ca2þ imaging of glomerular activity after bath application of the Ca2þ indicator (Ca-green FM ester) gave consistently higher responses to CSþ than to CS . The fluorescence signal in such a situation may come predominantly from the presynaptic terminals of olfactory receptor Encyclopedia of Neuroscience (2009), vol. 3, pp. 43-47 Author's personal copy 44 Conditioning: Simple Neural Circuits in the Honeybee neurons (and possibly also from local interneurons and glia cells), indicating that synaptic processing inside the glomerulus converts CSþ-specific plasticity into both enhancement and reduction of odor responses. Second, the postsynaptic sites of lateral PN neurons within the glomeruli show spontaneous Ca2þ fluctuations. After stimulation with an odor, these spontaneous activity fluctuations are more strongly correlated between the glomeruli that had been activated simultaneously by the odor, and the correlations between the spontaneous activity fluctuations suffice to reconstruct the stimulus. It is concluded that these modifiable fluctuations could provide an ideal substrate for Hebbian reverberations and sensory memory in a neural system. It is important to note that all these associative and nonassociative changes seen in the AL glomeruli and PNs last only for a few minutes, corroborating the conclusion that the AL may be involved in the establishment of an olfactory memory trace only shortly after the learning trial. Two kinds of MB-extrinsic neurons have been studied with respect to associative plasticity, a single identified neuron, the pedunculus-extrinsic neuron 1 (PE1), and neurons in the protocerebral-calycal tract (PCT). The PE1 neuron leaves the alpha lobe of the MB and receives its input across the peduncle of the MB at two bands of putative postsynaptic specializations. PE1 responds to a large range of odors. Differential conditioning leads to a CSþ-specific reduction of odor responses, whereas US-only presentations (sensitization) cause an increase of odor responses. Since the CSþ-specific responses – as recorded intracellularly from isolated bee heads – were lost after a few minutes, it was initially concluded that PE1 may be related to short-term memory. However, recent extracellular recordings from the intact animal lasting many hours have shown that the CSþ-specific response reduction is stable over the lifetime of the recording (several hours). Furthermore, the synapses between the MB-intrinsic neurons (Kenyon cells) and the PE1 were found to undergo long-term potentiation if PE1 was depolarized during the tetanic electric stimulation of the Kenyon cells. It is not yet clear how learning-related response reduction and associative long-term potentiation in PE1 can be reconciled. CSþ-specific effects – as compared with CS or US-only effects – were seen in neurons of the PCT. Many of these neurons are g-aminobutyric acid immunoreactive and project back from the alpha lobe of the MB to its input site, the calyx. They terminate both at the presynaptic sites of the PNs and the postsynaptic sites of the MB intrinsic neurons, the Kenyon cells. It is conceivable that PCT neurons provide an adapted inhibitory feedback from the output site of the MB to its input. Since PCT neurons also cross between the sensory domains of the MB, they could also be involved in contextspecific forms of learning. Neural Circuits Underlying Olfactory Conditioning: Signaling Cascades Mediating CS and US Stimuli The different contributions of AL and MB in associative learning are also evident at the level of the molecular machinery implicated in learning and memory formation. Processing CS and US stimuli – even as early as during training – activates different signaling cascades in vivo. Stimulation of the antenna with sucrose, the US, induces a short transient activation of the cyclic adenosine monophosphate (cAMP)dependent protein kinase A (PKA) in the AL, whereas odor stimulation (CS) or mechanical stimulation of the antennae does not affect PKA activity in the ALs. This US-induced PKA activation in the AL is mediated by octopamine, the putative transmitter of the reward neuron VUMmx1. The dense innervation of the VUMmx1 in the AL, the main localization of the PKA in AL interneurons, and the biochemical measurements support a general modulatory function of US-induced processes mediated via the cAMP/PKA cascades in the AL. The specific reinforcing function of octopamine during learning in the AL was supported by silencing the expression of the octopamine receptor which impairs olfactory acquisition but not odor discrimination. Although the calyces, the olfactory input area of the MB, are also densely innervated by the octopaminergic VUMmx1 neuron, stimulation with sucrose (US) does not lead to PKA activation in the MB calyces in vivo. This, and the fact that octopamine can, in principle, stimulate PKA in cultured Kenyon cells of the MBs, supports the idea that octopamine receptors that receive input from VUMmx1 in the MB are most likely coupled to Ca2þ-regulated pathways. The signaling cascade mediating the US function in olfactory conditioning in the MB has not yet been identified. Molecular Signaling Cascades in the ALs Are Critical for the Induction of Olfactory Memory Traces Direct in vivo measurements demonstrate that the temporal characteristics of the US-induced PKA activation in the AL is critically influenced by its pairing with CS stimuli during olfactory conditioning. A single CS/US forward pairing, which induces a weak olfactory memory, leads to a transient increase in PKA activity that returns to basal levels 60 s after Encyclopedia of Neuroscience (2009), vol. 3, pp. 43-47 Author's personal copy Conditioning: Simple Neural Circuits in the Honeybee 45 the conditioning trial. Three CS/US forward-pairings in succession, which induce a long-term memory (LTM), prolong PKA activation in the AL up to more than 3 min. In contrast, US stimulation alone and, independent of the number, US/CS backward pairings induce a significantly shorter PKA activation. This close correlation between training parameters on the one hand and the temporal relation between US and CS stimulation, the number of conditioning trials, and the dynamic properties of PKA activation in the AL on the other hand leads to the hypothesis that prolonged PKA activation in the AL is involved in LTM formation. The hypothesis was tested by photolytic release of caged cAMP in the AL to artificially prolong PKA activation during olfactory conditioning. A local replay of the prolonged PKA activation in the AL in vivo, combined with a single conditioning trial, is sufficient to induce long-lasting memory. This provides direct functional evidence for a link between conditioning parameters, PKA activation in the AL, and its contribution to LTM formation in intact animals. The use of the uncaging technique allowed further identification of the molecular processes underlying the prolonged PKA activation in the AL and thus the mechanisms contributing to induction of LTM in the AL. Nitric oxide, which is required for LTM formation in the honeybee, mediates the prolongation of the PKA activity by activation of the soluble guanylate cyclase and increase of cyclic guanosine monophosphate (cGMP). Inhibition of the soluble guanylate cyclase impairs both the prolonged PKA activation in the AL and LTM formation. Similar to the uncaging of cAMP, photorelease of caged cGMP in the AL – in combination with singletrial conditioning – induces long-lasting memory. Although the target of cGMP has not yet been identified in vivo, the synergistic activation of honeybee PKAII by cAMP and cGMP points to a direct function of cGMP in the prolonged increase in PKA activity (25%) in the AL. These findings demonstrate that molecular processes localized in the neural circuit of the AL critically contribute to LTM formation. Prolongation of PKA activation in the AL in conjunction with singletrial conditioning, however, does not reach the level of conditioned responses after multiple-trial conditioning, and thus it seems feasible that additional molecular processes or neural circuits may contribute to the prolongation. The molecular and neural targets of the early events in the AL that finally lead to LTM are yet unknown. The signaling cascade that involves the Ca2þphospholipid-dependent protein kinase C (PKC) is implicated in a parallel-acting system contributing to olfactory memory at the AL level. In contrast to US-specific activation of the PKA in the AL, PKC is activated by both the US and the CS. The temporal pattern of PKC activation is independent of the sequence of CS and US stimulation or the number of conditioning trials. Since inhibition of PKC activation during the conditioning phase affects neither acquisition nor memory formation, conditioninginduced PKC activation in the AL seems not to be required for memory induction. The analysis of the learning-induced changes in PKC activity in the AL hours and days after training revealed a function of PKC in memory maintenance. In contrast to a single conditioning trial, repeated conditioning trials that induce LTM cause an increase in PKC activity beginning 1 h after conditioning and lasting up to 3 days. This long-lasting PKC activation can be dissected into two mechanistically independent phases. In the early phase (1–16 h), a constitutively active PKC, the PKM, contributes to the elevated activity. PKM is formed by cleavage of the activated PKC by the Ca2þ-dependent protease calpain. Blocking calpain activity during conditioning prevents PKM formation in the AL and impairs memory in a time window between 1 and 16 h. This treatment does not affect acquisition, the early memory phase up to 30 min, and memory after 1 day. The late phase of the training-induced increase in PKC activity (1–3 days) in the AL is unaffected by calpain blockers but requires protein and RNA synthesis. Thus, PKM formation in the AL is an independent parallel process required for maintaining a midterm memory phase. The function of the late phase (1–3 days) is still unclear but is probably one of several parallel mechanisms occurring in different brain circuits required for the formation of the late phase of LTM. In summary, currently evidence exists for a function of the AL circuitry only in early processes of learning and memory formation, like the nitric oxide-mediated PKA activation involved in LTM induction and the early PKM formation required for maintaining a memory phase in the hours range. Glutamate-Mediated Signaling Cascades in the MBs Contribute to LTM Formation Glutamate is the major excitatory transmitter in mammals and plays a central role in neuronal plasticity in vertebrates. Its function in the insect brain, however, is only poorly understood. Although glutamate receptors have been identified in honeybees and manipulation of glutamate function using pharmacological tools supports a function in learning processes, the results are a matter of controversial discussion. Encyclopedia of Neuroscience (2009), vol. 3, pp. 43-47 Author's personal copy 46 Conditioning: Simple Neural Circuits in the Honeybee Photolytic uncaging of glutamate in the honeybee MB revealed direct evidence for a defined spatial and temporal contribution of glutamate in LTM formation. Uncaging glutamate immediately after a weak training protocol (single-trial training) in the MB improves the formation of a late memory phase (2 days) and thus mimics the effect of a strong training protocol. Uncaging shortly before the weak training has no effect, pointing to a defined function of glutamate with respect to early memory processing rather than learning. This function of glutamate is restricted to the MB circuitry, since glutamate release in the AL does not improve learning or retention. Taken together, glutamate action is restricted to the MBs, where it contributes to induction of a late memory phase in a time window shortly after training. Although it is still unclear whether this late memory phase is mechanistically identical with the LTM induced by a strong training (three-trial conditioning), the findings provide an example for parallel molecular processes underlying learning and memory formation in vivo occurring in different neural circuits. Parallel Molecular Processes Contribute to LTM Memory Formation As in other systems, LTM in honeybees can be divided into an early phase (eLTM, 1–2 days), which requires protein synthesis, and a transcription-dependent late phase (lLTM, 3 days). In all model systems investigated so far, inhibition of PKA activity during the training period results in a loss of both eLTM and lLTM. Although this suggests a single PKA-triggered process, experiments considering the impact of the satiation level in appetitive learning and memory formation in the honeybee provided evidence of a more complex function of the cAMP/PKA cascade in LTM induction. Three-trial conditioning in hungry animals leads to perfect acquisition and induction of midterm memory and both LTM phases. However, feeding bees 4 h before olfactory conditioning impairs acquisition and memory formation. This, and the different basal PKA-activity in honeybee brains at different satiation levels, points to a contribution of the cAMP/PKA cascade. Elevating the low basal PKA-activity levels in animals fed 4 h before conditioning specifically rescues the transcription-dependent lLTM. Acquisition, midterm memory, and eLTM are still impaired. The fact that both eLTM and lLTM require PKA for their induction, but PKA rescue in fed animals improves only lLTM but not eLTM, points to the existence of two parallel cAMP/PKA pathways implicated in memory formation: one process appears to trigger events leading to translation-dependent eLTM; the other is involved in inducing cascades required for transcription-dependent lLTM. Localization of the neural circuits related to these independent cAMP/ PKA pathways will provide important information on the organization of the neural network involved in LTM formation. See also: Communication in the Honeybee; Conditioning: Theories; Learning and Memory in Invertebrates: Honey Bee; Olfaction in Invertebrates: Honeybee; Procedural Learning: Classical Conditioning. Further Reading Abel R, Rybak J, and Menzel R (2001) Structure and response patterns of olfactory interneurons in the honeybee, Apis mellifera. Journal of Comparative Neurology 437: 363–383. Balfanz S, Strunker T, Frings S, and Baumann A (2005) A family of octopamine receptors that specifically induce cyclic AMP production or Ca2þ release in Drosophila melanogaster. Journal of Neurochemistry 93: 440–451. Brandt R, Rohlfing T, Rybak J, et al. (2005) A three-dimensional average-shape atlas of the honeybee brain and its applications. Journal of Comparative Neurology 492: 1–19. Faber T, Joerges J, and Menzel R (1999) Associative learning modifies neural representations of odours in the insect brain. Nature Neuroscience 2: 74–78. Farooqui T, Robinson K, Vaessin H, and Smith BH (2003) Modulation of early olfactory processing by an octopaminergic reinforcement pathway in the honeybee. Journal of Neuroscience 23: 5370–5380. Fiala A, Müller U, and Menzel R (1999) Reversible downregulation of protein kinase A during olfactory learning using antisense technique impairs long-term memory formation in the honeybee, Apis mellifera. Journal of Neuroscience 19: 10125–10134. Galán RF, Weidert M, Menzel R, Herz AV, and Galizia CG (2006) Sensory memory for odors is encoded in spontaneous correlated activity between olfactory glomeruli. Neural Computation 18: 10–25. Ganeshina O and Menzel R (2001) GABA-immunoreactive neurons in the mushroom bodies of the honeybee: An electron microscopic study. Journal of Comparative Neurology 437: 335–349. Grohmann L, Blenau W, Erber J, Ebert PR, Strunker T, and Baumann A (2003) Molecular and functional characterization of an octopamine receptor from honeybee (Apis mellifera) brain. Journal of Neurochemistry 86: 725–735. Grünbaum L and Müller U (1998) Induction of a specific olfactory memory leads to a long-lasting activation of protein kinase C in the antennal lobe of the honeybee. Journal of Neuroscience 18: 4384–4392. Grünewald B (1999) Physiological properties and response modulations of mushroom body feedback neurons during olfactory learning in the honeybee Apis mellifera. Journal of Comparative Physiology A 185: 565–576. Hammer M (1993) An identified neuron mediates the unconditioned stimulus in associative olfactory learning in honeybees. Nature 366: 59–63. Hammer M (1997) The neural basis of associative reward learning in honeybees. Trends in Neurosciences 20: 245–252. Encyclopedia of Neuroscience (2009), vol. 3, pp. 43-47 Author's personal copy Conditioning: Simple Neural Circuits in the Honeybee 47 Hammer M and Menzel R (1998) Multiple sites of associative odour learning as revealed by local brain microinjections of octopamine in honeybees. Learning & Memory 5: 146–156. Hildebrandt H and Müller U (1995) Octopamine mediates rapid stimulation of PKA in the antennal lobe of honeybees. Journal of Neurobiology 27: 44–50. Hildebrandt H and Müller U (1995) PKA activity in the antennal lobe of honeybees is regulated by chemosensory stimulation in vivo. Brain Research 679: 281–288. Leboulle G and Müller U (2004) Synergistic activation of insect cAMP-dependent protein kinase A (type II) by cyclicAMP and cyclicGMP. FEBS Letters 576: 216–220. Locatelli F, Bundrock G, and Müller U (2005) Focal and temporal release of glutamate in the mushroom bodies improves olfactory memory in Apis mellifera. Journal of Neuroscience 25: 11614–11618. Lopatina N, Ryzhova I, and Chesnokova E (2002) The role of nonNMDA-receptors in the process of associative learning in the honeybee Apis mellifera. Journal of Evolutionary Biochemistry and Physiology 38: 211–217. Maleszka R, Helliwell P, and Kucharski R (2000) Pharmacological interference with glutamate re-uptake impairs long-term memory in the honeybee Apis mellifera. Behavioural Brain Research 115: 49–53. Mauelshagen J (1993) Neural correlates of olfactory learning in an identified neuron in the honey bee brain. Journal of Neurophysiology 69: 609–625. Menzel R (1999) Memory dynamics in the honeybee. Journal of Comparative Physiology A 185: 323–340. Menzel R, Erber J, and Masuhr T (1974) Learning and memory in the honeybee. In: Barton-Browne L (ed.) Experimental Analysis of Insect Behaviour, pp. 195–217. Berlin: Springer. Menzel R and Manz G (2005) Neural plasticity of mushroom body-extrinsic neurons in the honeybee brain. Journal of Experimental Biology 208: 4317–4332. Müller U (1996) Inhibition of nitric oxide synthase impairs a distinct form of long-term memory in the honeybee, Apis mellifera. Neuron 16: 541–549. Müller U (1997) Neuronal cAMP-dependent protein kinase type II is concentrated in mushroom bodies of Drosophila melanogaster and the honeybee Apis mellifera. Journal of Neurobiology 33: 33–44. Müller U (2000) Prolonged activation of cAMP-dependent protein kinase during conditioning induces long-term memory in honeybees. Neuron 27: 159–168. Peele P, Ditzen M, Menzel R, and Galizia CG (2006) Appetitive odour learning does not change olfactory coding in a subpopulation of honeybee antennal lobe neurons. Journal of Comparative Physiology A 192(10): 1083–1103. Riedel G, Platt B, and Micheau J (2003) Glutamate receptor function in learning and memory. Behavioural Brain Research 140: 1–47. Rybak J and Menzel R (1998) Integrative properties of the Pe1-neuron, a unique mushroom body output neuron. Learning & Memory 5: 133–145. Si A, Helliwell P, and Maleszka R (2004) Effects of NMDA receptor antagonists on olfactory learning and memory in the honeybee (Apis mellifera). Pharmacology, Biochemistry, and Behavior 77: 191–197. Zannat MT, Locatelli F, Rybak J, Menzel R, and Leboulle G (2006) Identification and localisation of the NR1 sub-unit homologue of the NMDA glutamate receptor in the honeybee brain. Neuroscience Letters 398: 274–279. Encyclopedia of Neuroscience (2009), vol. 3, pp. 43-47