Reversing Stimulus Timing in Visual Conditioning Leads to Memories with Opposite Valence in Drosophila

Animals need to associate different environmental stimuli with each other regardless of whether they temporally overlap or not. Drosophila melanogaster displays olfactory trace conditioning, where an odor is followed by electric shock reinforcement after a temporal gap, leading to conditioned odor avoidance. Reversing the stimulus timing in olfactory conditioning results in the reversal of memory valence such that an odor that follows shock is later on approached (i.e. relief conditioning). Here, we explored the effects of stimulus timing on memory in another sensory modality, using a visual conditioning paradigm. We found that flies form visual memories of opposite valence depending on stimulus timing and can associate a visual stimulus with reinforcement despite being presented with a temporal gap. These results suggest that associative memories with non-overlapping stimuli and the effect of stimulus timing on memory valence are shared across sensory modalities.     

磁共振脑功能成像在小动物嗅觉研究中的应用

综述了磁共振脑功能成像(functional MRI,fMRI)在嗅觉研究中的应用,着重介绍fMRI在小动物嗅觉研究中的优势,以及近10年来fMRI在嗅球(olfactory bulb,OB)信息编码、处理和传输机制研究中所取得的进展．作为人类最古老的感觉方式之一,整个嗅觉系统(除鼻腔中的嗅细胞)都属于边缘系统,这赋予嗅觉系统一般的感觉功能和许多不为人所熟知的对情感、记忆以及生理和心理状态调控的功能．同时,由于缺乏有效手段,其内在性也使得嗅觉系统在大脑中的信息编码、处理、传输和感知等机制的研究极为困难．fMRI由于具有相对高的时间和空间分辨率,并可以无创地、重复地观测大脑任何部位的神经活动而被广泛应用于神经科学的研究．fMRI在嗅觉系统的应用使我们对人的嗅觉高级中枢感知机制方面的研究取得了一定的进展,而嗅球为嗅觉信息编码和处理中心,由于其尺寸和人体MRI空间分辨率的限制,对人OB中编码机制的研究一直无法进行．     

Remembrance of odors past: human olfactory cortex in cross-modal recognition memory

Episodic memory is often imbued with multisensory richness, such that the recall of an event can be endowed with the sights, sounds, and smells of its prior occurrence. While hippocampus and related medial temporal structures are implicated in episodic memory retrieval, the participation of sensory-specific cortex in representing the qualities of an episode is less well established. We combined functional magnetic resonance imaging (fMRI) with a cross-modal paradigm, where objects were presented with odors during memory encoding. We then examined the effect of odor context on neural responses at retrieval when these same objects were presented alone. Primary olfactory (piriform) cortex, as well as anterior hippocampus, was activated during the successful retrieval of old (compared to new) objects. Our findings indicate that sensory features of the original engram are preserved in unimodal olfactory cortex. We suggest that reactivation of memory traces distributed across modality-specific brain areas underpins the sensory qualities of episodic memories.     

Olfactory memory: the long and short of it

It has been proposed that memory for odors does not have a short-term (or working) memory system. The distinction between short- and long- term memory in other sensory modalities has been generally supported by three main lines of evidence: capacity differences between the proposed systems, evidence of differential coding, and differential memory losses in neuropsychological patients. The present paper examines these issues in an effort to establish a similar distinction for the memory of olfactory stimuli. Each of these lines of evidence is examined in relation to the literature on olfactory memory. Based on this examination, it seems that there is at least preliminary support from each of these lines of evidence to advocate a distinction between a long- and short-term memory for olfactory stimuli. Emphasis is placed upon the qualitative similarity of olfactory memory to other memory systems. This similarity is further highlighted through an examination of the literature pertinent to serial position effects in memory for olfactory stimuli.      

A naturalistic analysis of autobiographical memories triggered by olfactory visual and auditory stimuli

The emotional and content qualities of autobiographical memories evoked by three memory cue items (campfire, fresh-cut grass, popcorn) presented in olfactory, visual and auditory form were examined using a new repeated measures paradigm. Results revealed that memories recalled by odors were significantly more emotional and evocative than those recalled by the same cue presented visually or auditorily. However, there were no differences in the content features (vividness, specificity) of memories as a function of cue-form. These findings support previous research in both laboratory and naturalistic settings and is the first comparative sensory memory study to include auditory variants of memory cues. The present data contribute to a growing body of evidence indicating that there is a privileged relationship between olfaction and emotion during recollection. Various subject factors such as age, sex and region of residence were also examined and some were found to affect the quality of memories in interaction with the specific memory cue items, indicating that prior experience is a primary influence in autobiographical memory. Questions for future investigation regarding how odor-evoked memories may be different from other memory experiences are suggested.     

The loss of scents: Do defects in olfactory sensory neuron development underlie human disease?

The olfactory system is a fascinating and beguiling sensory system: olfactory sensory neurons detect odors underlying behaviors essential for mate choice, food selection, and escape from predators, among others. These sensory neurons are unique in that they have dendrites contacting the outside world, yet their first synapse lies in the central nervous system. The information entering the central nervous system is used to create odor memories that play a profound role in recognition of individuals, places, and appropriate foods. Here, the structure of the olfactory epithelium is given as an overview to discuss the origin of the olfactory placode, the plasticity of the olfactory sensory neurons, and finally the origins of the gonadotropin‐releasing hormone neuroendocrine cells. For the purposes of this review, the development of the peripheral sensory system will be analyzed, incorporating recently published studies highlighting the potential novelties in development mechanisms. Specifically, an emerging model where the olfactory epithelium and olfactory bulb develop simultaneously from a continuous neurectoderm patterned at the end of gastrulation, and the multiple origins of the gonadotropin‐releasing hormone neuroendocrine cells associated with the olfactory sensory system development will be presented. Advances in the understanding of the basic mechanisms underlying olfactory sensory system development allows for a more thorough understanding of the potential causes of human disease. Birth Defects Research (Part C) 105:114–125, 2015. © 2015 Wiley Periodicals, Inc.     

嗅球对嗅觉信息的处理

哺乳动物的嗅觉系统拥有惊人的能力,它可以识别和分辨成千上万种分子结构各异的气味分子。这种识别能力是由基因决定的。近年来,分子生物学和神经生理学的研究使得我们对嗅觉识别的分子基础和嗅觉系统神经连接的认识有了质的飞跃。气味分子的识别是由一千多种气味受体完成的,鼻腔中的嗅觉感觉神经元表达这些气味受体基因。每个感觉神经元只表达一种气味受体基因。表达同种气味受体的感觉神经元投射到嗅球表面的一个或几个嗅小球中,从而在嗅球中形成一个精确的二维连接图谱。了解嗅球对气味信息的加工和处理方式是我们研究嗅觉系统信号编码的一个重要环节。文章概述并总结了有关嗅球信号处理的最新研究成果。     

Heterogeneous Sensory Innervation and Extensive Intrabulbar Connections of Olfactory Necklace Glomeruli

The mammalian nose employs several olfactory subsystems to recognize and transduce diverse chemosensory stimuli. These subsystems differ in their anatomical position within the nasal cavity, their targets in the olfactory forebrain, and the transduction mechanisms they employ. Here we report that they can also differ in the strategies they use for stimulus coding. Necklace glomeruli are the sole main olfactory bulb (MOB) targets of an olfactory sensory neuron (OSN) subpopulation distinguished by its expression of the receptor guanylyl cyclase GC-D and the phosphodiesterase PDE2, and by its chemosensitivity to the natriuretic peptides uroguanylin and guanylin and the gas CO₂. In stark contrast to the homogeneous sensory innervation of canonical MOB glomeruli from OSNs expressing the same odorant receptor (OR), we find that each necklace glomerulus of the mouse receives heterogeneous innervation from at least two distinct sensory neuron populations: one expressing GC-D and PDE2, the other expressing olfactory marker protein. In the main olfactory system it is thought that odor identity is encoded by a combinatorial strategy and represented in the MOB by a pattern of glomerular activation. This combinatorial coding scheme requires functionally homogeneous sensory inputs to individual glomeruli by OSNs expressing the same OR and displaying uniform stimulus selectivity; thus, activity in each glomerulus reflects the stimulation of a single OSN type. The heterogeneous sensory innervation of individual necklace glomeruli by multiple, functionally distinct, OSN subtypes precludes a similar combinatorial coding strategy in this olfactory subsystem.     

Diverse mechanisms to remember various odors

Two dorsal paired medial (DPM) neurons express the Amnesiac neuropeptide and project onto mushroom bodies, the Drosophila olfactory memory center. In this issue of Neuron, Keene et al. show that higher-level brain circuits process various olfactory memories differently. DPM neurons are required during acquisition of some odors and during memory consolidation of others. These findings reveal a surprising level of complexity for the formation of olfactory memories in Drosophila.     

A map of pheromone receptor activation in the mammalian brain

In mammals, the detection of pheromones is mediated by the vomeronasal system. We have employed gene targeting to visualize the pattern of projections of axons from vomeronasal sensory neurons in the accessory olfactory bulb. Neurons expressing a specific receptor project to multiple glomeruli that reside within spatially restricted domains. The formation of this sensory map in the accessory olfactory bulb and the survival of vomeronasal organ sensory neurons require the expression of pheromone receptors. In addition, we observe individual glomeruli in the accessory olfactory bulb that receive input from more than one type of sensory neuron. These observations indicate that the organization of the vomeronasal sensory afferents is dramatically different from that of the main olfactory system, and these differences have important implications for the logic of olfactory coding in the vomeronasal organ.     

Chemosensory processing in the fruit fly,Drosophila melanogaster: generalization of a feeding response reveals overlapping odour representations

Insects are capable of detecting, and discriminating between, a very large number of odours. The biological relevance of many of those odours, particularly those related to food, must first be learned. Given that the number of sensory receptors and antennal lobe (AL) glomeruli is limited relative to the number of odours that must be detectable, this ability implies that the olfactory system makes use of a combinatorial coding scheme whereby each sensory cell or AL projection neuron can participate in coding for several different odours. An important step in understanding this coding scheme is to behaviourally quantify the degree to which sets of odours are discriminable. Here we evaluate odour discriminability in the fruit fly,Drosophila melanogaster, by first conditioning individual flies to not respond to any of several odourants using a nonassociative conditioning protocol (habituation). We show that flies habituate unconditioned leg movement responses to both mechanosensory and olfactory stimulation over 25 unreinforceed trials. Habituation is retained for at least 2 h and is subject to dishabituation. Finally, we test the degree to which the conditioned response generalizes to other odourants based on molecular features of the odourants (e.g. carbon chain length and the presence of a target functional group). These tests reveal predictable generalization gradients across these molecular features. These data substantiate the claim that these features are relevant coding dimensions in the fruit fly olfactory system, as has been shown for other insect and vertebrate species.     

Chemosensory apparatus of Drosophila larvae

Many insects, including Drosophila melanogaster, have a rich repertoire of olfactory behavior. Combination of robust behavioral assays, physiological and molecular tools render D. melanogaster as highly suitable system for olfactory studies. The small number of neurons in the olfactory system of fruit flies, especially the number of sensory neurons in the larval stage, makes the exploration of sensory coding at all stages of its nervous system a potentially tractable goal, which is not possible in the foreseeable future in any mammalian preparation. Advances in physiological recordings, olfactory signaling and detailed analysis of behavior, can place larvae in a position to ask previously unanswerable questions.     

Age and rearing environment interact in the retention of early olfactory memories in honeybees

Due to the changing behavioral contexts at which social insects are exposed during the adult lifespan, they are ideal models to analyze the effect of particular sensory stimuli during young adulthood on later behavior. Specifically, our goal is to understand early influences on later foraging behavior. For that, olfactory memories were established by worker honeybees to different pre-foraging ages using either (1) classical conditioning in the proboscis extension response (PER) paradigm or (2) the offering of scented-sugar solution under different rearing conditions. By testing long-term memories (LTM) through a single PER test in workers of foraging ages (17-25 days), we found that retention of the early olfactory memories in honey bees is age-dependent and not time-dependent. Independently of the environmental conditions in which they were reared (laboratory cages or hives), bees were able to retain food-odor association from 5 days after emergence, but rarely before. In most experiments we observed a bi-modal pattern of response: bees exposed to scented-food at 5-8 and 13-16 days showed better retention than those exposed at 9-12 days. These differences disappeared for bees reared in hives. Retrieval of LTMs depending on the timing and the continuous inputs of appropriate sensory stimuli are discussed.     

The Role of Inhibition in an Associative Memory Model of the Olfactory Bulb

The external plexiform layer is where theinteractions between the mitral (excitatory) and granule (inhibitory)cells of the olfactory bulb (OB) take place. Two outstanding features ofthese interactions are that they aredendrodendritic and that there seem to be nonebetween excitatory cells. The latter are usually credited with the role of forming Hebbian cell assemblies.Hence, it would seem that this structure lacks the necessaryingredients for an associative memory system.In this article we show that in spite of these two properties thissystem can serve as an associative memory. Our model incorporates theessential anatomical characteristics of the OB. The memories in oursystem, defined by Hebbian mitral assemblies, are activated viathe interactions with the inhibitory granule cells. The nonlinearityis introduced in our model via a sigmoid function that describesneurotransmitter release in reciprocal dendrodendritic synapses. Thecapacity (maximal number of odors that can be memorized) depends onthe sparseness of coding that is being used. For very low memoryactivities, the capacity grows as a fractional power of the number ofneurons. We validate the theoretical results by numericalsimulations. An interesting result of our model is that its capacityincreases as a function of the ratio of inhibitory to excitatorypopulations. This may provide an explanation for the dominance ofinhibitory cells in the olfactory bulb.     

Neural dynamics of the cognitive map in the hippocampus

The rodent hippocampus has been thought to represent the spatial environment as a cognitive map. In the classical theory, the cognitive map has been explained as a consequence of the fact that different spatial regions are assigned to different cell populations in the framework of rate coding. Recently, the relation between place cell firing and local field oscillation theta in terms of theta phase precession was experimentally discovered and suggested as a temporal coding mechanism leading to memory formation of behavioral sequences accompanied with asymmetric Hebbian plasticity. The cognitive map theory is apparently outside of the sequence memory view. Therefore, theoretical analysis is necessary to consider the biological neural dynamics for the sequence encoding of the memory of behavioral sequences, providing the cognitive map formation. In this article, we summarize the theoretical neural dynamics of the real-time sequence encoding by theta phase precession, called theta phase coding, and review a series of theoretical models with the theta phase coding that we previously reported. With respect to memory encoding functions, instantaneous memory formation of one-time experience was first demonstrated, and then the ability of integration of memories of behavioral sequences into a network of the cognitive map was shown. In terms of memory retrieval functions, theta phase coding enables the hippocampus to represent the spatial location in the current behavioral context even with ambiguous sensory input when multiple sequences were coded. Finally, for utilization, retrieved temporal sequences in the hippocampus can be available for action selection, through the process of reverting theta rhythm-dependent activities to information in the behavioral time scale. This theoretical approach allows us to investigate how the behavioral sequences are encoded, updated, retrieved and used in the hippocampus, as the real-time interaction with the external environment. It may indeed be the bridge to the episodic memory function in human hippocampus.     

Olfactory coding: non-linear amplification separates smells

How does the nervous system encode complex sensory stimuli? A recent study reveals the fly olfactory system compensates for variability in sensory input as odor representations are restructured for enhanced discriminability and coding efficiency.     

Extinction antagonizes olfactory memory at the subcellular level

Memory loss occurs by diverse mechanisms, as different time constants of performance decrement and sensitivities to experimental manipulations suggest. While the phenomena of memory decay, interference, and extinction are well established behaviorally, little is known about them at the circuit or molecular level. In Drosophila, odorant memories lasting up to 3 hr can be localized to mushroom body Kenyon cells, a single neuronal level in the olfactory pathway. The plasticity underlying this memory trace can be induced without Kenyon cell synaptic output. Experimental extinction, i.e., presentation of the conditioned stimulus without the reinforcer, reduces memory performance and does so at the same circuit level as memory formation. Thus, unreinforced presentation of learned odorants antagonizes intracellularly the signaling cascade underlying memory formation.     

Efficient Partitioning of Memory Systems and Its Importance for Memory Consolidation

Long-term memories are likely stored in the synaptic weights of neuronal networks in the brain. The storage capacity of such networks depends on the degree of plasticity of their synapses. Highly plastic synapses allow for strong memories, but these are quickly overwritten. On the other hand, less labile synapses result in long-lasting but weak memories. Here we show that the trade-off between memory strength and memory lifetime can be overcome by partitioning the memory system into multiple regions characterized by different levels of synaptic plasticity and transferring memory information from the more to less plastic region. The improvement in memory lifetime is proportional to the number of memory regions, and the initial memory strength can be orders of magnitude larger than in a non-partitioned memory system. This model provides a fundamental computational reason for memory consolidation processes at the systems level.     

Identification of stimuli and input pathways mediating food-attraction conditioning in the snail, Helix

Snails become conditioned by a single feeding episode to locate foods which they were unable to locate prior to feeding. To identify which of the different stimulus parameters of the food mediate learning, snails were presented with isolated stimulus components during feeding and re-tested the next day for their ability to locate the food. None of the individual components was sufficient to promote conditioning. Odor combined with a bulk stimulus conditioned the animals, as indicated by their subsequently locating the food. Elimination of the olfactory sensory inputs from the anterior and/or posterior tentacles prior to conditioning revealed that the acquisition of the olfactory memory requires olfactory stimulation of the sensory epithelia on the anterior tentacles. Recall of memory during olfactory orientation requires functional epithelia on the posterior tentacles, which suggests that the same odor is processed by different input pathways under different situations. Animals with the olfactory epithelia functional on the same side during conditioning and food searching were able to locate the conditioned food. Animals with different epithelia functional during conditioning and food searching failed, which suggests that olfactory memory is stored within one side of the nervous system and cannot be accessed from the contralateral side. Accepted: 28 November 1997