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Animals learn through experience and consolidate the memories into long-time storage. Conditioning parameters to induce protein synthesis-dependent long-term memory (LTM) have been the subject of extensive studies in many animals. Here we found a case in which a conditioning trial inhibits or facilitates LTM formation depending on the intervals from preceding trials. We studied the effects of conditioning parameters on LTM formation in olfactory conditioning of maxillary-palpi extension response with sucrose reward in the cockroach "Periplaneta americana." We found, at first, that translation- and transcription-dependent LTM forms 1 h after training, the fastest so far reported in insects. Second, we observed that multiple-trial training with an intertrial interval (ITI) of 20 or 30 sec, often called massed training, is more effective than spaced training for LTM formation, an observation that differs from the results of most studies in other animals. Third, we found that a conditioning trial inhibits LTM formation when the intervals from preceding trials were in the range of 10-16 min. This inhibitory effect is pairing-specific and is not due to decreased motivation for learning (overtraining effect). To our knowledge, no similar inhibition of LTM formation by a conditioning trial has been reported in any animals. We propose a model to account for the effects of trial number and ITIs on LTM formation. Olfactory conditioning in cockroaches should provide pertinent materials in which to study neuronal and molecular mechanisms underlying the inhibitory and facilitatory processes for LTM formation.

Memory is a dynamic process that allows encoding, storage, and retrieval of information acquired through individual experience. In the honeybee "Apis mellifera," olfactory conditioning of the proboscis extension response (PER) has shown that besides short-term memory (STM) and mid-term memory (MTM), two phases of long-term memory (LTM) are formed upon multiple-trial conditioning: an early phase (e-LTM) which depends on translation from already available mRNA, and a late phase (l-LTM) which requires de novo transcription and translation. Here we combined olfactory PER conditioning and neuropharmacological inhibition and studied the involvement of the NO-cGMP pathway, and of specific molecules, such as cyclic nucleotide-gated channels (CNG), calmodulin (CaM), adenylyl cyclase (AC), and Ca[superscript 2+]/calmodulin-dependent protein kinase (CaMKII), in the formation of olfactory LTM in bees. We show that in addition to NO-cGMP and cAMP-PKA, CNG channels, CaM, AC, and CaMKII also participate in the formation of a l-LTM (72-h post-conditioning) that is specific for the learned odor. Importantly, the same molecules are dispensable for olfactory learning and for the formation of both MTM (in the minute and hour range) and e-LTM (24-h post-conditioning), thus suggesting that the signaling pathways leading to l-LTM or e-LTM involve different molecular actors.

Cyclic AMP pathway plays an essential role in formation of long-term memory (LTM). In some species, the nitric oxide (NO)-cyclic GMP pathway has been found to act in parallel and complementary to the cAMP pathway for LTM formation. Here we describe a new role of the NO-cGMP pathway, namely, stimulation of the cAMP pathway to induce LTM. We have studied the signaling cascade underlying LTM formation by systematically coinjecting various "LTM-inducing" and "LTM-blocking" drugs in crickets. Multiple-trial olfactory conditioning led to LTM that lasted for several days, while memory induced by single-trial conditioning decayed away within several hours. Injection of inhibitors of the enzyme forming NO, cGMP, or cAMP into the hemolymph prior to multiple-trial conditioning blocked LTM, whereas injection of an NO donor, cGMP analog, or cAMP analog prior to single-trial conditioning induced LTM. Induction of LTM by injection of an NO donor or cGMP analog paired with single-trial conditioning was blocked by inhibitors of the cAMP pathway, but induction of LTM by a cAMP analog was unaffected by inhibitors of the NO-cGMP pathway. Inhibitors of cyclic nucleotide-gated channel (CNG channel) or calmodulin-blocked induction of LTM by cGMP analog paired with single-trial conditioning, but they did not affect induction of LTM by cAMP analog. Our findings suggest that the cAMP pathway is a downstream target of the NO-cGMP pathway for the formation of LTM, and that the CNG channel and calcium-calmodulin intervene between the NO-cGMP pathway and the cAMP pathway. (Contains 7 figures and 1 table.)

We studied the capability of the cricket "Gryllus bimaculatus" to select one of a pair of odors and to avoid the other in one context and to do the opposite in another context. One group of crickets was trained to associate one of a pair of odors (conditioned stimulus, CS1) with water reward (appetitive unconditioned stimulus, US+) and another odor (CS2) with saline solution (aversive US, US-) under illumination and to associate CS1 with US- and CS2 with US+ in the dark. Another group of crickets received training of the opposite stimulus arrangement. At 1 d after the training for 3 d, the former group significantly preferred CS1 over CS2 under illumination but preferred CS2 over CS1 in the dark, and the latter group exhibited the opposite odor preference. The results of control experiments showed that the background light condition had no significant effects on memory formation or retrieval unless it was explicitly associated with US during training. Thus, the visual context affected learning performance only when crickets were requested to use it to disambiguate the meaning of CSs and to predict USs. (Contains 4 figures.)

Abstract Background In insect classical conditioning, octopamine (the invertebrate counterpart of noradrenaline) or dopamine has been suggested to mediate reinforcing properties of appetitive or aversive unconditioned stimulus, respectively. However, the roles of octopaminergic and dopaminergic neurons in memory recall have remained unclear. Results We studied the roles of octopaminergic and dopaminergic neurons in appetitive and aversive memory recall in olfactory and visual conditioning in crickets. We found that pharmacological blockade of octopamine and dopamine receptors impaired aversive memory recall and appetitive memory recall, respectively, thereby suggesting that activation of octopaminergic and dopaminergic neurons and the resulting release of octopamine and dopamine are needed for appetitive and aversive memory recall, respectively. On the basis of this finding, we propose a new model in which it is assumed that two types of synaptic connections are formed by conditioning and are activated during memory recall, one type being connections from neurons representing conditioned stimulus to neurons inducing conditioned response and the other being connections from neurons representing conditioned stimulus to octopaminergic or dopaminergic neurons representing appetitive or aversive unconditioned stimulus, respectively. The former is called 'stimulus-response connection' and the latter is called 'stimulus-stimulus connection' by theorists studying classical conditioning in higher vertebrates. Our model predicts that pharmacological blockade of octopamine or dopamine receptors during the first stage of second-order conditioning does not impair second-order conditioning, because it impairs the formation of the stimulus-response connection but not the stimulus-stimulus connection. The results of our study with a cross-modal second-order conditioning were in full accordance with this prediction. Conclusion We suggest that insect classical conditioning involves the formation of two kinds of memory traces, which match to stimulus-stimulus connection and stimulus-response connection. This is the first study to suggest that classical conditioning in insects involves, as does classical conditioning in higher vertebrates, the formation of stimulus-stimulus connection and its activation for memory recall, which are often called cognitive processes.

Abstract Background Synaptic plasticity associated with an important wave of gene transcription and protein synthesis underlies long-term memory processes. Calcium (Ca2+) plays an important role in a variety of neuronal functions and indirect evidence suggests that it may be involved in synaptic plasticity and in the regulation of gene expression correlated to long-term memory formation. The aim of this study was to determine whether Ca2+ is necessary and sufficient for inducing long-term memory formation. A suitable model to address this question is the Pavlovian appetitive conditioning of the proboscis extension reflex in the honeybee Apis mellifera, in which animals learn to associate an odor with a sucrose reward. Results By modulating the intracellular Ca2+ concentration ([Ca2+]i) in the brain, we show that: (i) blocking [Ca2+]i increase during multiple-trial conditioning selectively impairs long-term memory performance; (ii) conversely, increasing [Ca2+]i during single-trial conditioning triggers long-term memory formation; and finally, (iii) as was the case for long-term memory produced by multiple-trial conditioning, enhancement of long-term memory performance induced by a [Ca2+]i increase depends on de novo protein synthesis. Conclusion Altogether our data suggest that during olfactory conditioning Ca2+ is both a necessary and a sufficient signal for the formation of protein-dependent long-term memory. Ca2+ therefore appears to act as a switch between short- and long-term storage of learned information.

Melatonin (MEL) has been reported to enhance cognitive processes, making it a potential treatment for cognitive decline. However, the role of MEL's metabolites, N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine (AFMK) and N1‐acetyl‐5‐methoxykynuramine (AMK), in these effects are unknown. The current study directly investigated the acute effects of systemic MEL, AFMK, and AMK on novel object recognition. We also analyzed MEL, AFMK, and AMK levels in hippocampus and temporal lobe containing the perirhinal cortex following systemic MEL and AMK treatment. AMK administered post‐training had a more potent effect on object memory than MEL and AFMK. AMK was also able to rescue age‐associated declines in memory impairments when object memory was tested up to 4 days following training. Results from administering AMK at varying times around the training trial and the metabolism time course in brain tissue suggest that AMK's memory‐enhancing effects reflect memory consolidation. Furthermore, inhibiting the MEL‐to‐AMK metabolic pathway disrupted object memory at 24 hours post‐training, suggesting that endogenous AMK might play an important role in long‐term memory formation. This is the first study to report that AMK facilitates long‐term object memory performance in mice, and that MEL crosses the blood‐brain barrier and is immediately converted to AMK in brain tissue. Overall, these results support AMK as a potential therapeutic agent to improve or prevent memory decline. [ABSTRACT FROM AUTHOR]