Olfactory recognition memory in mice depends on task parameters.

We use a simple two-trial odor recognition paradigm to test memory duration, span, and specificity in adult mice. Our paradigm allows mice to encode and/or recall multiple odors in one trial and necessitates no training or food/water deprivation. We show that this paradigm can be used for encoding and/or testing of multiple odors in single trials, leading to shorter behavioral testing. Using this simple paradigm, we show that mice can remember a single odor for up to 10 but no more than 15 min and two odors for up to 5 min. Mice could not remember 3 odors at any delays tested here. We also show that specificity for the encoded odor decreases as delay increases. Our results are important for setting baseline levels of testing for experiments in which memory parameters are expected to be modulated. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Noradrenergic Activity in the Olfactory Bulb Is a Key Element for the Stability of Olfactory Memory.

Memory stability is essential for animal survival when environment and behavioral state change over short or long time spans. The stability of a memory can be expressed by its duration, its perseverance when conditions change as well as its specificity to the learned stimulus. Using optogenetic and pharmacological manipulations in male mice, we show that the presence of noradrenaline in the olfactory bulb during acquisition renders olfactory memories more stable. We show that while inhibition of noradrenaline transmission during an odor-reward acquisition has no acute effects, it alters perseverance, duration, and specificity of the memory. We use a computational approach to propose a proof of concept model showing that a single, simple network effect of noradrenaline on olfactory bulb dynamics can underlie these seemingly different behavioral effects. Our results show that acute changes in network dynamics can have long-term effects that extend beyond the network that was manipulated.SIGNIFICANCE STATEMENT Olfaction guides the behavior of animals. For successful survival, animals have to remember previously learned information and at the same time be able to acquire new memories. We show here that noradrenaline in the olfactory bulb, the first cortical relay of the olfactory information, is important for creating stable and specific olfactory memories. Memory stability, as expressed in perseverance, duration and specificity of the memory, is enhanced when noradrenergic inputs to the olfactory bulb are unaltered. We show that, computationally, our diverse behavioral results can be ascribed to noradrenaline-driven changes in neural dynamics. These results shed light on how very temporary changes in neuromodulation can have a variety of long-lasting effects on neural processing and behavior.

Experience enhances certainty about olfactory stimuli under bulbar cholinergic control.

We present evidence that experience and cholinergic modulation in an early sensory network interact to improve certainty about olfactory stimuli. The data we present are in agreement with existing theoretical ideas about the functional role of acetylcholine but highlight the importance of early sensory networks in addition to cortical networks. We use a simple behavioral paradigm in mice which allows us to measure certainty about a stimulus via the response amplitude to a condition and novel stimuli. We conclude that additional learning increases certainty and that the slope of this relationship can be modulated by activation of muscarinic cholinergic receptors in the olfactory bulb.

Context-dependent odor learning requires the anterior olfactory nucleus.

Learning to associate the context in which a stimulus occurs is an important aspect of animal learning. We propose that the association of an olfactory stimulus with its multisensory context is mediated by projections from ventral hippocampus (vHC) networks to the anterior olfactory nucleus (AON). Using a contextually cued olfactory discrimination task, rats were trained to associate 2 olfactory stimuli with different responses depending on visuospatial context. Temporary lesions of the AON or vHC impaired performance on this task. In contrast, such lesions did not impair performance on a noncontextual olfactory discrimination task. Moreover, vHC lesions also impaired performance on an analogous contextually cued texture discrimination task, whereas AON lesions affected only olfactory contextual associations. We describe a distinct role for the AON in olfactory processing and conclude that early olfactory networks such as the olfactory bulb and AON function as multimodal integration networks rather than processing olfactory signals exclusively. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Central olfactory structures.

Axons from the olfactory bulb (OB) project to multiple central structures of the brain, many of which, in turn, send axons back into the OB and/or to one another. These secondary sensory regions underlie many aspects of odor representation, valence, and learning, as well as serving some nonolfactory functions, though many details remain unclear. We here describe the connectivity and essential structural and functional properties of these postbulbar olfactory regions in the mammalian brain.

A Computational Model of Oxytocin Modulation of Olfactory Recognition Memory.

Social recognition in mammals depends on complex interactions between sensory and other brain areas as well as modulatory inputs by specific neuropeptides such as oxytocin (OXT). Social recognition memory specifically has been shown to depend among others on olfactory processing, and can be probed using methods similar to those used when probing non-social odor memory. We here use a computational model of two interconnected olfactory networks in the mouse, the olfactory bulb (OB) and anterior olfactory nucleus, to propose a mechanism for olfactory short-term recognition memory and its modulation in social situations. Based on previous experiments, we propose one early locus for memory to be the OB. During social encounters in mice, pyramidal cells in the anterior olfactory nucleus, themselves driven by olfactory input, are rendered more excitable by OXT release, resulting in stronger feedback to OB local interneurons. This additional input to the OB creates stronger dynamics and improves signal-to-noise ratio of odor responses in the OB proper. As a consequence, mouse social olfactory memories are more strongly encoded and their duration is modulated.

Cellular and network processes of noradrenergic modulation in the olfactory system.

Norepinephrine (NE), a central neuromodulator, influences sensory processing at the behavioral and physiological levels, potentially by regulating signal-to-noise ratio in sensory neural networks. To understand neuromodulatory function at the perceptual level, one must understand the neural mechanisms underlying these effects. In this review, we illustrate this process using the olfactory system as a model system. We discuss basic computations in the olfactory system and their modulation by NE. We review known cellular effects of NE in the olfactory bulb and cortex and how these effects modulate olfactory computation. We then illustrate how computational modeling can relate cellular and perceptual data using the example of NE modulation of odor detection thresholds.

Noradrenergic effects on olfactory perception and learning.

We here review modulation of olfactory guided behavioral tasks by noradrenaline. In this review we focus on modulation of the main olfactory system in adult rodents. We detail behavioral paradigms commonly used and discuss how sensory perception and learning can be measured using these paradigms. We then describe neuromodulatory effects on several aspects of olfactory processing, including detection and encoding. We describe how memory duration, specificity and duration are affected by noradrenergic modulation.

Opposite regulation of inhibition by adult-born granule cells during implicit versus explicit olfactory learning.

Both passive exposure and active learning through reinforcement enhance fine sensory discrimination abilities. In the olfactory system, this enhancement is thought to occur partially through the integration of adult-born inhibitory interneurons resulting in a refinement of the representation of overlapping odorants. Here, we identify in mice a novel and unexpected dissociation between passive and active learning at the level of adult-born granule cells. Specifically, while both passive and active learning processes augment neurogenesis, adult-born cells differ in their morphology, functional coupling and thus their impact on olfactory bulb output. Morphological analysis, optogenetic stimulation of adult-born neurons and mitral cell recordings revealed that passive learning induces increased inhibitory action by adult-born neurons, probably resulting in more sparse and thus less overlapping odor representations. Conversely, after active learning inhibitory action is found to be diminished due to reduced connectivity. In this case, strengthened odor response might underlie enhanced discriminability.

Stimulation of the Locus Ceruleus Modulates Signal-to-Noise Ratio in the Olfactory Bulb.

Norepinephrine (NE) has been shown to influence sensory, and specifically olfactory processing at the behavioral and physiological levels, potentially by regulating signal-to-noise ratio (S/N). The present study is the first to look at NE modulation of olfactory bulb (OB) in regards to S/N in vivo We show, in male rats, that locus ceruleus stimulation and pharmacological infusions of NE into the OB modulate both spontaneous and odor-evoked neural responses. NE in the OB generated a non-monotonic dose-response relationship, suppressing mitral cell activity at high and low, but not intermediate, NE levels. We propose that NE enhances odor responses not through direct potentiation of the afferent signal per se, but rather by reducing the intrinsic noise of the system. This has important implications for the ways in which an animal interacts with its olfactory environment, particularly as the animal shifts from a relaxed to an alert behavioral state.SIGNIFICANCE STATEMENT Sensory perception can be modulated by behavioral states such as hunger, fear, stress, or a change in environmental context. Behavioral state often affects neural processing via the release of circulating neurochemicals such as hormones or neuromodulators. We here show that the neuromodulator norepinephrine modulates olfactory bulb spontaneous activity and odor responses so as to generate an increased signal-to-noise ratio at the output of the olfactory bulb. Our results help interpret and improve existing ideas for neural network mechanisms underlying behaviorally observed improvements in near-threshold odor detection and discrimination.

Internal Cholinergic Regulation of Learning and Recall in a Model of Olfactory Processing.

In the olfactory system, cholinergic modulation has been associated with contrast modulation and changes in receptive fields in the olfactory bulb, as well the learning of odor associations in olfactory cortex. Computational modeling and behavioral studies suggest that cholinergic modulation could improve sensory processing and learning while preventing pro-active interference when task demands are high. However, how sensory inputs and/or learning regulate incoming modulation has not yet been elucidated. We here use a computational model of the olfactory bulb, piriform cortex (PC) and horizontal limb of the diagonal band of Broca (HDB) to explore how olfactory learning could regulate cholinergic inputs to the system in a closed feedback loop. In our model, the novelty of an odor is reflected in firing rates and sparseness of cortical neurons in response to that odor and these firing rates can directly regulate learning in the system by modifying cholinergic inputs to the system. In the model, cholinergic neurons reduce their firing in response to familiar odors-reducing plasticity in the PC, but increase their firing in response to novel odor-increasing PC plasticity. Recordings from HDB neurons in awake behaving rats reflect predictions from the model by showing that a subset of neurons decrease their firing as an odor becomes familiar.

Neuromodulation of olfactory transformations.

The olfactory bulb and piriform cortex are the best studied structures of the mammalian olfactory system and are heavily innervated by extrinsic neuromodulatory inputs. The state-dependent release of acetylcholine, norepinephrine, serotonin, and other neuromodulators into these olfactory structures alters a constellation of physiological parameters in neurons and synapses that together modify the computations performed on sensory signals. These modifications affect the specificity, detectability, discriminability, and other properties of odor representations and thereby govern perceptual performance. Whereas different neuromodulators have distinct cellular effects, and tend to be associated with nominally different functions, it also is clear that these purported functions overlap substantially, and that ad hoc hypotheses regarding the roles of particular neuromodulators may have reached the limits of their usefulness.

Basal forebrain dynamics during nonassociative and associative olfactory learning.

Cholinergic and GABAergic projections from the horizontal diagonal band (HDB) and medial preoptic area (MCPO) of the basal forebrain to the olfactory system are associated with odor discrimination and odor learning, as well as modulation of neural responses in olfactory structures. Whereas pharmacological and lesion studies give insights into the functional role of these modulatory inputs on a slow timescale, the response dynamics of neurons in the HDB/MCPO during olfactory behaviors have not been investigated. In this study we examined how these neurons respond during two olfactory behaviors: spontaneous investigation of odorants and odor-reward association learning. We observe rich heterogeneity in the response dynamics of individual HDB/MCPO neurons, with a substantial fraction of neurons exhibiting task-related modulation. HDB/MCPO neurons show both rapid and transient responses during bouts of odor investigation and slow, long-lasting modulation of overall response rate based on behavioral demands. Specifically, baseline rates were higher during the acquisition phase of an odor-reward association than during spontaneous investigation or the recall phase of an odor reward association. Our results suggest that modulatory projections from the HDB/MCPO are poised to influence olfactory processing on multiple timescales, from hundreds of milliseconds to minutes, and are therefore capable of rapidly setting olfactory network dynamics during odor processing and learning.

Effects of experimentally necessary changes in husbandry on olfactory memory: Chronic food restriction and social isolation.

Changes to typical procedures in animal husbandry are often necessary to accommodate the needs of behavioral experiments. Two common changes in husbandry for rodents are light chronic food restriction (to motivate animals in reward-association tasks) and social isolation (to accommodate individual feeding schedules or need to reduce interactions because of implants for example). Each of these intervention individually has been shown to modulate behavioral state and with it performance in behavioral tasks. We here systematically test how social isolation and light chronic food restriction modulate olfactory memory in rats. Our results show a strong modulation of olfactory memory after both types of husbandry interventions. These results suggest that common changes in animal husbandry promote distinct and relevant changes in animal behavior.

Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells.

Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function.

Computational modeling suggests distinct, location-specific function of norepinephrine in olfactory bulb and piriform cortex.

Noradrenergic modulation from the locus coerulus is often associated with the regulation of sensory signal-to-noise ratio. In the olfactory system, noradrenergic modulation affects both bulbar and cortical processing, and has been shown to modulate the detection of low concentration stimuli. We here implemented a computational model of the olfactory bulb and piriform cortex, based on known experimental results, to explore how noradrenergic modulation in the olfactory bulb and piriform cortex interact to regulate odor processing. We show that as predicted by behavioral experiments in our lab, norepinephrine can play a critical role in modulating the detection and associative learning of very low odor concentrations. Our simulations show that bulbar norepinephrine serves to pre-process odor representations to facilitate cortical learning, but not recall. We observe the typical non-uniform dose-response functions described for norepinephrine modulation and show that these are imposed mainly by bulbar, but not cortical processing.

Odor Memory and Discrimination Covary as a Function of Delay between Encoding and Recall in Rats.

Nonassociative odor learning paradigms are often used to assess memory, social recognition and neuromodulation of olfactory pathways. We here use a modified object recognition paradigm to investigate how an important task parameter, delay between encoding and recall trials, affects the properties of this memory. We show that both memory for a previously investigated odorant and discrimination of a novel odorant decay with delay time and that rats can remember an odorant for up to 45min after a single trial encoding event. The number of odorants that can be encoded, as well as the specificity of the encoded memory, decrease with increased delay and also depend on stimulus concentration. Memory for an odorant and discrimination of a novel odorant decay at approximately the same rate, whereas the specificity of the formed memory decays faster than the memory itself. These results have important implications for the interpretation of behavioral data obtained with this paradigm.