Gustatory cortex: Taste coding and decision making in one.

A new study reveals that, as mice learn a taste discrimination task, taste responses in gustatory cortex undergo plasticity such that they reflect taste identity and predict the upcoming decision in separate response epochs.

Neural correlates of rapid familiarization to novel taste.

The gustatory cortex (GC) plays a pivotal role in taste perception, with neural ensemble responses reflecting taste quality and influencing behavior. Recent work, however, has shown that GC taste responses change across sessions of novel taste exposure in taste-naïve rats. Here, we use single-trial analyses to explore changes in the cortical taste-code on the scale of individual trials. Contrary to the traditional view of taste perception as innate, our findings suggest rapid, experience-dependent changes in GC responses during initial taste exposure trials. Specifically, we find that early responses to novel taste are less "stereotyped" and encode taste identity less reliably compared to later responses. These changes underscore the dynamic nature of sensory processing and provides novel insights into the real-time dynamics of sensory processing across novel-taste familiarization.

Changes in taste palatability across the estrous cycle are modulated by hypothalamic estradiol signaling.

Food intake varies across the stages of a rat's estrous cycle. It is reasonable to hypothesize that this cyclic fluctuation in consumption reflects an impact of hormones on taste palatability/preference, but evidence for this hypothesis has been mixed, and critical within-subject experiments in which rats sample multiple tastes during each of the four main estrous phases (metestrus, diestrus, proestrus, and estrus) have been scarce. Here, we assayed licking for pleasant (sucrose, NaCl, saccharin) and aversive (quinine-HCl, citric acid) tastes each day for 5-10 days while tracking rats' estrous cycles through vaginal cytology. Initial analyses confirmed the previously-described increased consumption of pleasant stimuli 24-48 hours following the time of high estradiol. A closer look, however, revealed this effect to reflect a general magnification of palatability-higher than normal preferences for pleasant tastes and lower than normal preferences for aversive tastes-during metestrus. We hypothesized that this phenomenon might be related to estradiol processing in the lateral hypothalamus (LH), and tested this hypothesis by inhibiting LH estrogen receptor activity with ICI 182,780 during tasting. Control infusions replicated the metestrus magnification of palatability pattern; ICI infusions blocked this effect as predicted, but failed to render preferences "cycle free," instead delaying the palatability magnification until diestrus. Clearly, estrous phase mediates details of taste palatability in a manner involving hypothalamic actions of estradiol; further work will be needed to explain the lack of a flat response across the cycle with hypothalamic estradiol binding inhibited, a result which perhaps suggests dynamic interplay between brain regions or hormones. Significance Statement: Consummatory behaviors are impacted by many variables, including naturally circulating hormones. While it is clear that consumption is particularly high during the stages following the high-estradiol stage of the rodent's estrous (and human menstrual) cycle, it is as of yet unclear whether this phenomenon reflects cycle stage-specific palatability (i.e., whether pleasant tastes are particularly delicious, and aversive tastes particularly disgusting, at particular phases). Here we show that palatability is indeed modulated by estrous phase, and that this effect is governed, at least in part, by the action of estradiol within the lateral hypothalamus. These findings shed light on the mechanisms underlying the adverse impact on human welfare due to irregularities observed across the otherwise cyclic menstrual process.

Distinct competitive impacts of palatability of taste stimuli on sampling dynamics during a preference test.

Food or taste preference tests are analogous to naturalistic decisions in which the animal selects which stimuli to sample and for how long to sample them. The data acquired in such tests, the relative amounts of the alternative stimuli that are sampled and consumed, indicate the preference for each. While such preferences are typically recorded as a single quantity, an analysis of the ongoing sampling dynamics producing the preference can reveal otherwise hidden aspects of the decision-making process that depend on its underlying neural circuit mechanisms. Here, we perform a dynamic analysis of two factors that give rise to preferences in a two-alternative task, namely the distribution of durations of sampling bouts of each stimulus and the likelihood of returning to the same stimulus or switching to the alternative-that is, the transition probability-following each bout. The results of our analysis support a specific computational model of decision making whereby an exponential distribution of bout durations has a mean that is positively correlated with the palatability of that stimulus but also negatively correlated with the palatability of the alternative. This impact of the alternative stimulus on the distribution of bout durations decays over a timescale of tens of seconds, even though the memory of the alternative stimulus lasts far longer-long enough to impact the transition probabilities upon ending bouts. Together, our findings support a state transition model for bout durations and suggest a separate memory mechanism for stimulus selection. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Coupled Dynamics of Stimulus-Evoked Gustatory Cortical and Basolateral Amygdalar Activity.

Gustatory cortical (GC) single-neuron taste responses reflect taste quality and palatability in successive epochs. Ensemble analyses reveal epoch-to-epoch firing-rate changes in these responses to be sudden, coherent transitions. Such nonlinear dynamics suggest that GC is part of a recurrent network, producing these dynamics in concert with other structures. Basolateral amygdala (BLA), which is reciprocally connected to GC and central to hedonic processing, is a strong candidate partner for GC, in that BLA taste responses evolve on the same general clock as GC and because inhibition of activity in the BLA→GC pathway degrades the sharpness of GC transitions. These facts motivate, but do not test, our overarching hypothesis that BLA and GC act as a single, comodulated network during taste processing. Here, we provide just this test of simultaneous (BLA and GC) extracellular taste responses in female rats, probing the multiregional dynamics of activity to directly test whether BLA and GC responses contain coupled dynamics. We show that BLA and GC response magnitudes covary across trials and within single responses, and that changes in BLA-GC local field potential phase coherence are epoch specific. Such classic coherence analyses, however, obscure the most salient facet of BLA-GC coupling: sudden transitions in and out of the epoch known to be involved in driving gaping behavior happen near simultaneously in the two regions, despite huge trial-to-trial variability in transition latencies. This novel form of inter-regional coupling, which we show is easily replicated in model networks, suggests collective processing in a distributed neural network.SIGNIFICANCE STATEMENT There has been little investigation into real-time communication between brain regions during taste processing, a fact reflecting the dominant belief that taste circuitry is largely feedforward. Here, we perform an in-depth analysis of real-time interactions between GC and BLA in response to passive taste deliveries, using both conventional coherence metrics and a novel methodology that explicitly considers trial-to-trial variability and fast single-trial dynamics in evoked responses. Our results demonstrate that BLA-GC coherence changes as the taste response unfolds, and that BLA and GC specifically couple for the sudden transition into (and out of) the behaviorally relevant neural response epoch, suggesting (although not proving) that: (1) recurrent interactions subserve the function of the dyad as (2) a putative attractor network.

LiCl-induced sickness modulates rat gustatory cortical responses.

Gustatory cortex (GC), a structure deeply involved in the making of consumption decisions, presumably performs this function by integrating information about taste, experiences, and internal states related to the animal's health, such as illness. Here, we investigated this assertion, examining whether illness is represented in GC activity, and how this representation impacts taste responses and behavior. We recorded GC single-neuron activity and local field potentials (LFPs) from healthy rats and rats made ill (via LiCl injection). We show (consistent with the extant literature) that the onset of illness-related behaviors arises contemporaneously with alterations in 7 to 12 Hz LFP power at approximately 12 min following injection. This process was accompanied by reductions in single-neuron taste response magnitudes and discriminability, and with enhancements in palatability-relatedness-a result reflecting the collapse of responses toward a simple "good-bad" code visible in the entire sample, but focused on a specific subset of GC neurons. Overall, our data show that a state (illness) that profoundly reduces consumption changes basic properties of the sensory cortical response to tastes, in a manner that can easily explain illness' impact on consumption.

Cortical taste processing evolves through benign taste exposures.

Experience impacts learning and perception. Familiarity with stimuli that later become the conditioned stimulus (CS) in a learning paradigm, for instance, reduces the strength of that learning-a fact well documented in studies of conditioned taste aversion (CTA; De la Casa & Lubow, 1995; Lubow, 1973; Lubow & Moore, 1959). Recently, we have demonstrated that even experience with "incidental" (i.e., non-CS) stimuli influences CTA learning: Long Evans rats pre-exposed to salty and/or sour tastes later learn unusually strong aversions to novel sucrose (Flores et al., 2016), and exhibit enhanced sucrose-responsiveness after learning in gustatory cortex (GC; Flores et al., 2018). These findings suggest that incidental taste exposure (TE) may change spiking responses that have been shown to underlie the processing of tastes in GC. Here, we test this hypothesis, evaluating whether GC neuron spiking responses change across 3 days of taste exposure. Our results demonstrate that the discriminability of GC ensemble taste responses increases with this familiarization. Analysis of single-neuron responses recorded across multiple sessions reveals that taste exposure not only enriches identity and palatability information in taste-evoked activity but also enhances the discriminability of even novel tastes. These findings demonstrate that "mere" familiarization with incidental episodes of tasting changes the neural spiking responses of taste processing and provides specific insight into how such TE may impact later learning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A model of naturalistic decision making in preference tests.

Decisions as to whether to continue with an ongoing activity or to switch to an alternative are a constant in an animal's natural world, and in particular underlie foraging behavior and performance in food preference tests. Stimuli experienced by the animal both impact the choice and are themselves impacted by the choice, in a dynamic back and forth. Here, we present model neural circuits, based on spiking neurons, in which the choice to switch away from ongoing behavior instantiates this back and forth, arising as a state transition in neural activity. We analyze two classes of circuit, which differ in whether state transitions result from a loss of hedonic input from the stimulus (an "entice to stay" model) or from aversive stimulus-input (a "repel to leave" model). In both classes of model, we find that the mean time spent sampling a stimulus decreases with increasing value of the alternative stimulus, a fact that we linked to the inclusion of depressing synapses in our model. The competitive interaction is much greater in "entice to stay" model networks, which has qualitative features of the marginal value theorem, and thereby provides a framework for optimal foraging behavior. We offer suggestions as to how our models could be discriminatively tested through the analysis of electrophysiological and behavioral data.

Perturbation of amygdala-cortical projections reduces ensemble coherence of palatability coding in gustatory cortex.

Taste palatability is centrally involved in consumption decisions-we ingest foods that taste good and reject those that don't. Gustatory cortex (GC) and basolateral amygdala (BLA) almost certainly work together to mediate palatability-driven behavior, but the precise nature of their interplay during taste decision-making is still unknown. To probe this issue, we discretely perturbed (with optogenetics) activity in rats' BLA→GC axons during taste deliveries. This perturbation strongly altered GC taste responses, but while the perturbation itself was tonic (2.5 s), the alterations were not-changes preferentially aligned with the onset times of previously-described taste response epochs, and reduced evidence of palatability-related activity in the 'late-epoch' of the responses without reducing the amount of taste identity information available in the 'middle epoch.' Finally, BLA→GC perturbations changed behavior-linked taste response dynamics themselves, distinctively diminishing the abruptness of ensemble transitions into the late epoch. These results suggest that BLA 'organizes' behavior-related GC taste dynamics.

Homeostatic synaptic scaling establishes the specificity of an associative memory.

Correlation-based (Hebbian) forms of synaptic plasticity are crucial for the initial encoding of associative memories but likely insufficient to enable the stable storage of multiple specific memories within neural circuits. Theoretical studies have suggested that homeostatic synaptic normalization rules provide an essential countervailing force that can stabilize and expand memory storage capacity. Although such homeostatic mechanisms have been identified and studied for decades, experimental evidence that they play an important role in associative memory is lacking. Here, we show that synaptic scaling, a widely studied form of homeostatic synaptic plasticity that globally renormalizes synaptic strengths, is dispensable for initial associative memory formation but crucial for the establishment of memory specificity. We used conditioned taste aversion (CTA) learning, a form of associative learning that relies on Hebbian mechanisms within gustatory cortex (GC), to show that animals conditioned to avoid saccharin initially generalized this aversion to other novel tastants. Specificity of the aversion to saccharin emerged slowly over a time course of many hours and was associated with synaptic scaling down of excitatory synapses onto conditioning-active neuronal ensembles within gustatory cortex. Blocking synaptic scaling down in the gustatory cortex enhanced the persistence of synaptic strength increases induced by conditioning and prolonged the duration of memory generalization. Taken together, these findings demonstrate that synaptic scaling is crucial for sculpting the specificity of an associative memory and suggest that the relative strengths of Hebbian and homeostatic plasticity can modulate the balance between stable memory formation and memory generalization.

The function of groups of neurons changes from moment to moment.

Modern techniques that enable identification and targeted manipulation of neuron groups are frequently used to bolster theories that attribute specific behavioral functions to specific neuron types. These same techniques can also be used, however, to highlight limitations of such attribution, and to develop the argument that the question "what is the function of these neurons?" is ill-posed in the absence of temporal and network constraints. Here we do this, first reviewing evidence that neural responses are dynamic at multiple time scales, making the point that such changes in firing rates imply changes in what the neuron is doing. Studies involving brief perturbations of neural populations confirm this point, showing that the functions in which these populations participate change across seconds and even milliseconds. Based on these studies, we suggest that it is inappropriate to assign function to sets of neurons without contextualizing that assignment to specific times and network conditions.

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory.

Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms remain poorly understood. RNAseq from BLApn identified changes in multiple candidate learning-related transcripts including the expected immediate early gene Fos and Stk11, a master kinase of the AMP-related kinase pathway with important roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 in BLApn blocked memory prior to training, but not following it and increased neuronal excitability. Conversely, BLApn had reduced excitability following CTA. BLApn knockout of a second learning-related gene, Fos, also increased excitability and impaired learning. Independently increasing BLApn excitability chemogenetically during CTA also impaired memory. STK11 and C-FOS activation were independent of one another. These data suggest key roles for Stk11 and Fos in CTA long-term memory formation, dependent at least partly through convergent action on BLApn intrinsic excitability.

Refinement and Reactivation of a Taste-Responsive Hippocampal Network.

Animals need to remember the locations of nourishing and toxic food sources for survival, a fact that necessitates a mechanism for associating taste experiences with particular places. We have previously identified such responses within hippocampal place cells [1], the activity of which is thought to aid memory-guided behavior by forming a mental map of an animal's environment that can be reshaped through experience [2-7]. It remains unknown, however, whether taste responsiveness is intrinsic to a subset of place cells or emerges as a result of experience that reorganizes spatial maps. Here, we recorded from neurons in the dorsal CA1 region of rats running for palatable tastes delivered via intra-oral cannulae at specific locations on a linear track. We identified a subset of taste-responsive cells that, even prior to taste exposure, had larger place fields than non-taste-responsive cells overlapping with stimulus delivery zones. Taste-responsive cells' place fields then contracted as a result of taste experience, leading to a stronger representation of stimulus delivery zones on the track. Taste-responsive units exhibited increased sharp-wave ripple co-activation during the taste delivery session and subsequent rest periods, which correlated with the degree of place field contraction. Our results reveal that novel taste experience evokes responses within a preconfigured network of taste-responsive hippocampal place cells with large fields, whose spatial representations are refined by sensory experience to signal areas of behavioral salience. This represents a possible mechanism by which animals identify and remember locations where ecologically relevant stimuli are found within their environment.

Single and population coding of taste in the gustatory cortex of awake mice.

Electrophysiological analysis has revealed much about the broad coding and neural ensemble dynamics that characterize gustatory cortical (GC) taste processing in awake rats and about how these dynamics relate to behavior. With regard to mice, however, data concerning cortical taste coding have largely been restricted to imaging, a technique that reveals average levels of neural responsiveness but that (currently) lacks the temporal sensitivity necessary for evaluation of fast response dynamics; furthermore, the few extant studies have thus far failed to provide consensus on basic features of coding. We have recorded the spiking activity of ensembles of GC neurons while presenting representatives of the basic taste modalities (sweet, salty, sour, and bitter) to awake mice. Our first central result is the identification of similarities between rat and mouse taste processing: most mouse GC neurons (~66%) responded distinctly to multiple (3-4) tastes; temporal coding analyses further reveal, for the first time, that single mouse GC neurons sequentially code taste identity and palatability, the latter responses emerging ~0.5 s after the former, with whole GC ensembles transitioning suddenly and coherently from coding taste identity to coding taste palatability. The second finding is that spatial location plays very little role in any aspect of taste responses: neither between- (anterior-posterior) nor within-mouse (dorsal-ventral) mapping revealed anatomic regions with narrow or temporally simple taste responses. These data confirm recent results showing that mouse cortical taste responses are not "gustotopic" but also go beyond these imaging results to show that mice process tastes through time.NEW & NOTEWORTHY Here, we analyzed taste-related spiking activity in awake mouse gustatory cortical (GC) neural ensembles, revealing deep similarities between mouse cortical taste processing and that repeatedly demonstrated in rat: mouse GC ensembles code multiple aspects of taste in a coarse-coded, time-varying manner that is essentially invariant across the spatial extent of GC. These data demonstrate that, contrary to some reports, cortical network processing is distributed, rather than being separated out into spatial subregion.

Impact of precisely-timed inhibition of gustatory cortex on taste behavior depends on single-trial ensemble dynamics.

Sensation and action are necessarily coupled during stimulus perception - while tasting, for instance, perception happens while an animal decides to expel or swallow the substance in the mouth (the former via a behavior known as 'gaping'). Taste responses in the rodent gustatory cortex (GC) span this sensorimotor divide, progressing through firing-rate epochs that culminate in the emergence of action-related firing. Population analyses reveal this emergence to be a sudden, coherent and variably-timed ensemble transition that reliably precedes gaping onset by 0.2-0.3s. Here, we tested whether this transition drives gaping, by delivering 0.5s GC perturbations in tasting trials. Perturbations significantly delayed gaping, but only when they preceded the action-related transition - thus, the same perturbation impacted behavior or not, depending on the transition latency in that particular trial. Our results suggest a distributed attractor network model of taste processing, and a dynamical role for cortex in driving motor behavior.

Recognizing Taste: Coding Patterns Along the Neural Axis in Mammals.

The gustatory system encodes information about chemical identity, nutritional value, and concentration of sensory stimuli before transmitting the signal from taste buds to central neurons that process and transform the signal. Deciphering the coding logic for taste quality requires examining responses at each level along the neural axis-from peripheral sensory organs to gustatory cortex. From the earliest single-fiber recordings, it was clear that some afferent neurons respond uniquely and others to stimuli of multiple qualities. There is frequently a "best stimulus" for a given neuron, leading to the suggestion that taste exhibits "labeled line coding." In the extreme, a strict "labeled line" requires neurons and pathways dedicated to single qualities (e.g., sweet, bitter, etc.). At the other end of the spectrum, "across-fiber," "combinatorial," or "ensemble" coding requires minimal specific information to be imparted by a single neuron. Instead, taste quality information is encoded by simultaneous activity in ensembles of afferent fibers. Further, "temporal coding" models have proposed that certain features of taste quality may be embedded in the cadence of impulse activity. Taste receptor proteins are often expressed in nonoverlapping sets of cells in taste buds apparently supporting "labeled lines." Yet, taste buds include both narrowly and broadly tuned cells. As gustatory signals proceed to the hindbrain and on to higher centers, coding becomes more distributed and temporal patterns of activity become important. Here, we present the conundrum of taste coding in the light of current electrophysiological and imaging techniques at several levels of the gustatory processing pathway.

Interaction of Taste and Place Coding in the Hippocampus.

An animal's survival depends on finding food and the memory of food and contexts are often linked. Given that the hippocampus is required for spatial and contextual memory, it is reasonable to expect related coding of space and food stimuli in hippocampal neurons. However, relatively little is known about how the hippocampus responds to tastes, the most central sensory property of food. In this study, we examined the taste-evoked responses and spatial firing properties of single units in the dorsal CA1 hippocampal region as male rats received a battery of taste stimuli differing in both chemical composition and palatability within a specific spatial context. We identified a subset of hippocampal neurons that responded to tastes, some of which were place cells. These taste and place responses had a distinct interaction: taste-responsive cells tended to have less spatially specific firing fields and place cells only responded to tastes delivered inside their place field. Like neurons in the amygdala and lateral hypothalamus, hippocampal neurons discriminated between tastes predominantly on the basis of palatability, with taste selectivity emerging concurrently with palatability-relatedness; these responses did not reflect movement or arousal. However, hippocampal taste responses emerged several hundred milliseconds later than responses in other parts of the taste system, suggesting that the hippocampus does not influence real-time taste decisions, instead associating the hedonic value of tastes with a particular context. This incorporation of taste responses into existing hippocampal maps could be one way that animals use past experience to locate food sources.SIGNIFICANCE STATEMENT Finding food is essential for animals' survival and taste and context memory are often linked. Although hippocampal responses to space and contexts have been well characterized, little is known about how the hippocampus responds to tastes. Here, we identified a subset of hippocampal neurons that discriminated between tastes based on palatability. Cells with stronger taste responses typically had weaker spatial responses and taste responses were confined to place cells' firing fields. Hippocampal taste responses emerged later than in other parts of the taste system, suggesting that the hippocampus does not influence taste decisions, but rather associates the hedonic value of tastes consumed within a particular context. This could be one way that animals use past experience to locate food sources.

Retronasal Odor Perception Requires Taste Cortex, but Orthonasal Does Not.

Smells can arise from a source external to the body and stimulate the olfactory epithelium upon inhalation through the nares (orthonasal olfaction). Alternatively, smells may arise from inside the mouth during consumption, stimulating the epithelium upon exhalation (retronasal olfaction). Both ortho- and retronasal olfaction produce highly salient percepts, but the two percepts have very different behavioral implications. Here, we use optogenetic manipulation in the context of a flavor preference learning paradigm to investigate differences in the neural circuits that process information in these two submodalities of olfaction. Our findings support a view in which retronasal, but not orthonasal, odors share processing circuitry commonly associated with taste. First, our behavioral results reveal that retronasal odors induce rapid preference learning and have a potentiating effect on orthonasal preference learning. Second, we demonstrate that inactivation of the insular gustatory cortex selectively impairs expression of retronasal preferences. Thus, orally sourced (retronasal) olfactory input is processed by a brain region responsible for taste processing, whereas externally sourced (orthonasal) olfactory input is not.

The role of the gustatory cortex in incidental experience-evoked enhancement of later taste learning.

The strength of learned associations between pairs of stimuli is affected by multiple factors, the most extensively studied of which is prior experience with the stimuli themselves. In contrast, little data is available regarding how experience with "incidental" stimuli (independent of any conditioning situation) impacts later learning. This lack of research is striking given the importance of incidental experience to survival. We have recently begun to fill this void using conditioned taste aversion (CTA), wherein an animal learns to avoid a taste that has been associated with malaise. We previously demonstrated that incidental exposure to salty and sour tastes (taste preexposure-TPE) enhances aversions learned later to sucrose. Here, we investigate the neurobiology underlying this phenomenon. First, we use immediate early gene (c-Fos) expression to identify gustatory cortex (GC) as a site at which TPE specifically increases the neural activation caused by taste-malaise pairing (i.e., TPE did not change c-Fos induced by either stimulus in isolation). Next, we use site-specific infection with the optical silencer Archaerhodopsin-T to show that GC inactivation during TPE inhibits the expected enhancements of both learning and CTA-related c-Fos expression, a full day later. Thus, we conclude that GC is almost certainly a vital part of the circuit that integrates incidental experience into later associative learning.

Memory Retrieval Has a Dynamic Influence on the Maintenance Mechanisms That Are Sensitive to ζ-Inhibitory Peptide (ZIP).

In neuroscientists' attempts to understand the long-term storage of memory, topics of particular importance and interest are the cellular and system mechanisms of maintenance (e.g., those sensitive to ζ-inhibitory peptide, ZIP) and those induced by memory retrieval (i.e., reconsolidation). Much is known about each of these processes in isolation, but less is known concerning how they interact. It is known that ZIP sensitivity and memory retrieval share at least some molecular targets (e.g., recycling α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA, receptors to the plasma membrane); conversely, the fact that sensitivity to ZIP emerges only after consolidation ends suggests that consolidation (and by extension reconsolidation) and maintenance might be mutually exclusive processes, the onset of one canceling the other. Here, we use conditioned taste aversion (CTA) in rats, a cortically dependent learning paradigm, to test this hypothesis. First, we demonstrate that ZIP infusions into gustatory cortex begin interfering with CTA memory 43-45 h after memory acquisition-after consolidation ends. Next, we show that a retrieval trial administered after this time point interrupts the ability of ZIP to induce amnesia and that ZIP's ability to induce amnesia is reengaged only 45 h after retrieval. This pattern of results suggests that memory retrieval and ZIP-sensitive maintenance mechanisms are mutually exclusive and that the progression from one to the other are similar after acquisition and retrieval. They also reveal concrete differences between ZIP-sensitive mechanisms induced by acquisition and retrieval: the latency with which ZIP-sensitive mechanisms are expressed differ for the two processes. SIGNIFICANCE STATEMENT: Memory retrieval and the molecular mechanisms that are sensitive to ζ-inhibitory peptide (ZIP) are the few manipulations that have been shown to effect memory maintenance. Although much is known about their effect on maintenance separately, it is unknown how they interact. Here, we describe a model for the interaction between memory retrieval and ZIP-sensitive mechanisms, showing that retrieval trials briefly (i.e., for 45 h) interrupt these mechanisms. ZIP sensitivity emerges across a similar time window after memory acquisition and retrieval; the maintenance mechanisms that follow acquisition and retrieval differ, however, in the latency with which the impact of ZIP is expressed.