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The gustatory system has evolved to detect molecules dissolved into the saliva. It is responsible for the perception of taste and flavor, for mediating the interaction between perception and internal homoeostatic states, and for driving ingestive decisions. The widely recognized five basic taste categories (sweet, salty, bitter, sour, and umami) provide information about the nutritional or potentially harmful content in what is being consumed. Sweetness is typical of sugars that are carbohydrate dense; saltiness is the percept of ions which are necessary for physiological function and electrolytic homeostasis; bitterness is associated with alkaloids and other potential toxins; sourness is the percept of acidity signaling spoiling foods; and umami is the sensation associated with amino acids in protein-rich foods. In addition to taste, the act of eating also engages sensations of temperature, texture, and odor—the integration of all these sensations leads to the unitary percept of flavor. These same senses, and others such as vision and audition, are also engaged before an ingestive event. Sights, sounds, and smells can alert organisms to the presence of food as well as inform the organism as to the specifics of which taste(s) to expect. As such, the neurophysiology of taste is necessarily intertwined with that of other senses and with that of cognitive and homeostatic systems.

Early experience with food influences taste preference in adulthood. How gustatory experience influences development of taste preferences and refinement of cortical circuits has not been investigated. Here we exposed weanling mice to an array of tastants and determined the effects on the preference for sweet in adulthood. We demonstrate an experience-dependent shift in sucrose preference persisting several weeks following the termination of exposure. A shift in sucrose palatability, altered neural responsiveness to sucrose, and inhibitory synaptic plasticity in the gustatory portion of the insular cortex (GC) were also induced. The modulation of sweet preference occurred within a restricted developmental window, but restoration of the capacity for inhibitory plasticity in adult GC reactivated the sensitivity of sucrose preference to taste experience. Our results establish a fundamental link between gustatory experience, sweet-preference, inhibitory plasticity, and cortical circuit function, and highlight the importance of early life experience in setting taste preferences.

In the rat primary gustatory cortex (GC), a subregion of the larger insular cortex, neurons display time-varying neural responses to gustatory stimuli. GC taste responses are dramatically reduced following inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc). Pharmacological inactivation of VPMpc also has a profound effect on GC spontaneous activity. This indicates that the projection from VPMpc plays a crucial role in GC taste processing as well as in the control of its state. How VPMpc afferents engage GC circuits and drive neuronal ensembles to effectively code tastant identity, as well as modulate the overall state of the GC network, remains unclear. To investigate the synaptic properties and organization of VPMpc afferents in GC, we employed a circuit-breaking optogenetic approach, stimulating VPMpc terminal fields while performing whole-cell patch clamp recordings from GC neurons in rat acute slices. Informed by previous studies of thalamocortical inputs to other sensory cortices, we hypothesized that VPMpc-GC synapses have laminar- and cell-specific properties that gate sensory input, conferring computationally flexibility to how taste information is processed in GC. We found that VPMpc-GC synapses are strongly gated by the activity regime of VPMpc afferents, as well as by feedforward and feedback inhibition onto VPMpc terminals. These results provide novel insight into the circuit underpinning of GC responsiveness to incoming thalamocortical activity.SIGNIFICANCE STATEMENTWe report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared to primary thalamocortical synapses onto other sensory areas. VPMpc afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation, thus they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Feedforward inhibition gates thalamocortical activation and provides local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses support the time-varying response dynamics to taste stimuli observed in GC neuronsin vivo.

The mouse gustatory cortex (GC) is involved in taste-guided decision-making in addition to sensory processing. Rodent GC exhibits metastable neural dynamics during ongoing and stimulus-evoked activity, but how these dynamics evolve in the context of a taste-based decision-making task remains unclear. Here we employ analytical and modeling approaches to i) extract metastable dynamics in ensemble spiking activity recorded from the GC of mice performing a perceptual decision-making task; ii) investigate the computational mechanisms underlying GC metastability in this task; and iii) establish a relationship between GC dynamics and behavioral performance. Our results show that activity in GC during perceptual decision-making is metastable and that this metastability may serve as a substrate for sequentially encoding sensory, abstract cue, and decision information over time. Perturbations of the model’s metastable dynamics indicate that boosting inhibition in different coding epochs differentially impacts network performance, explaining a counterintuitive effect of GC optogenetic silencing on mouse behavior.

In November 2019, the NIH held the “Sensory Nutrition and Disease” workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.

Studies in visual, auditory, and somatosensory cortices have revealed that different cell types as well as neurons located in different laminae display distinct stimulus response profiles. The extent to which these layer and cell type-specific distinctions generalize to gustatory cortex (GC) remains unknown. In this study, we performed extracellular recordings in adult female mice to monitor the activity of putative pyramidal and inhibitory neurons located in deep and superficial layers of GC. Awake, head-restrained mice were trained to lick different tastants (sucrose, salt, citric acid, quinine, and water) from a lick spout. We found that deep layer neurons show higher baseline firing rates (FRs) in GC with deep-layer inhibitory neurons displaying highest FRs at baseline and following the stimulus. GC's activity shows robust modulations before animals' contact with tastants, and this phenomenon is most prevalent in deep-layer inhibitory neurons. Furthermore, we show that licking activity strongly shapes the spiking pattern of GC pyramidal neurons, eliciting phase-locked spiking across trials and tastants. We demonstrate that there is a greater percentage of taste-coding neurons in deep versus superficial layers with chemosensitive neurons across all categories showing similar breadth of tuning, but different decoding performance. Lastly, we provide evidence for functional convergence in GC, with neurons that can show prestimulus activity, licking-related rhythmicity and taste responses. Overall, our results demonstrate that baseline and stimulus-evoked firing profiles of GC neurons and their processing schemes change as a function of cortical layer and cell type in awake mice.SIGNIFICANCE STATEMENTSensory cortical areas show a laminar structure, with each layer composed of distinct cell types embedded in different circuits. While studies in other primary sensory areas have elucidated that pyramidal and inhibitory neurons belonging to distinct layers show distinct response properties, whether and how response properties of gustatory cortex (GC) neurons change as a function of their laminar position and cell type remains uninvestigated. Here, we show that there are several notable differences in baseline, prestimulus, and stimulus-evoked response profiles of pyramidal and inhibitory neurons belonging to deep and superficial layers of GC.

A novel, pleasant taste stimulus becomes aversive if associated with gastric malaise, a form of learning known as conditioned taste aversion (CTA). CTA is common to vertebrates and invertebrates and is an important survival response: eating the wrong food may be deadly. CTA depends on the gustatory portion of the insular cortex (GC) and the basolateral nucleus of the amygdala (BLA) however, its synaptic underpinnings are unknown. Here we report that CTA was associated with decreased expression of immediate early genes in rat GC of both sexes, and with reduced amplitude of BLA-GC synaptic responses, pointing to long term depression (LTD) as a mechanism for learning. Indeed, association of a novel tastant with induction of LTD at the BLA-GC input in vivo was sufficient to change the hedonic value of a taste stimulus. Our results demonstrate a direct role for amygdalocortical LTD in taste aversion learning.

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.

Neurons in the gustatory cortex (GC) process multiple aspects of a tasting experience, encoding not only the physiochemical identity of tastes, but also their anticipation and hedonic value. Information pertaining to these stimulus features is relayed to GC via the gustatory thalamus (VPMpc) and basolateral amygdala (BLA). It is not known whether these inputs drive separate groups of neurons, thus activating separate channels of information, or are integrated by neurons that receive both afferents. Here, we used anterograde labeling andin vivointracellular recordings in anesthetized rats to assess the potential convergence of BLA and VPMpc inputs in GC, and to investigate the dynamics of integration of these inputs. We report substantial anatomic overlap of BLA and VPMpc axonal fields across GC, and identify a population of GC neurons receiving converging BLA and VPMpc inputs. Our data show that BLA modulates the gain of VPMpc-evoked responses in a time-dependent fashion and that this modulation is dependent on the recruitment of synaptic inhibition by both BLA and VPMpc. Our results suggest that BLA shapes cortical processing of thalamic inputs by dynamically gating the excitatory/inhibitory balance of the GC circuit.

The gustatory system contributes to the flavor of foods and beverages and communicates information about nutrients and poisons. This system has evolved to detect and ultimately respond to hydrophilic molecules dissolved in saliva. Taste receptor cells, located in taste buds and distributed throughout the oral cavity, activate nerve afferents that project to the brainstem. From here, information propagates to thalamic, subcortical, and cortical areas, where it is integrated with information from other sensory systems and with homeostatic, visceral, and affective processes. There is considerable divergence, as well as convergence, of information between multiple regions of the central nervous system that interact with the taste pathways, with reciprocal connections occurring between the involved regions. These widespread interactions among multiple systems are crucial for the perception of food. For example, memory, hunger, satiety, and visceral changes can directly affect and can be affected by the experience of tasting. In this chapter, we review the literature on the central processing of taste with a specific focus on the anatomical and physiological responses of single neurons. Emphasis is placed on how information is distributed along multiple systems with the goal of better understanding how the rich and complex sensations associated with flavor emerge from large scale, systems-wide, interactions.

The integration of gustatory and olfactory information is essential to the perception of flavor. Human neuroimaging experiments have pointed to the gustatory cortex (GC) as one of the areas involved in mediating flavor perception. Although GC's involvement in encoding the chemical identity and hedonic value of taste stimuli is well studied, it is unknown how single GC neurons process olfactory stimuli emanating from the mouth. In this study, we relied on multielectrode recordings to investigate how single GC neurons respond to intraorally delivered tastants and tasteless odorants dissolved in water and whether/how these two modalities converge in the same neurons. We found that GC neurons could either be unimodal, responding exclusively to taste (taste-only) or odor (odor-only), or bimodal, responding to both gustatory and olfactory stimuli. Odor responses were confirmed to result from retronasal olfaction: monitoring respiration revealed that exhalation preceded odor-evoked activity and reversible inactivation of olfactory receptors in the nasal epithelium significantly reduced responses to intraoral odorants but not to tastants. Analysis of bimodal neurons revealed that they encode palatability significantly better than the unimodal taste-only group. Bimodal neurons exhibited similar responses to palatable tastants and odorants dissolved in water. This result suggested that odorized water could be palatable. This interpretation was further supported with a brief access task, where rats avoided consuming aversive taste stimuli and consumed the palatable tastants and dissolved odorants. These results demonstrate the convergence of the chemosensory components of flavor onto single GC neurons and provide evidence for the integration of flavor with palatability coding.SIGNIFICANCE STATEMENTFood perception and choice depend upon the concurrent processing of olfactory and gustatory signals from the mouth. The primary gustatory cortex has been proposed to integrate chemosensory stimuli; however, no study has examined the single-unit responses to intraoral odorant presentation. Here we found that neurons in gustatory cortex can respond either exclusively to tastants, exclusively to odorants, or to both (bimodal). Several differences exist between these groups' responses; notably, bimodal neurons code palatability significantly better than unimodal neurons. This group of neurons might represent a substrate for how odorants gain the quality of tastants.

The primary gustatory cortex (GC) receives projections from the basolateral nucleus of the amygdala (BLA). Behavioral and electrophysiological studies demonstrated that this projection is involved in encoding the hedonic value of taste and is a source of anticipatory activity in GC. Anatomically, this projection is largest in the agranular portion of GC; however, its synaptic targets and synaptic properties are currently unknown.In vivoelectrophysiological recordings report conflicting evidence about BLA afferents either selectively activating excitatory neurons or driving a compound response consistent with the activation of inhibitory circuits. Here we demonstrate that BLA afferents directly activate excitatory neurons and two distinct populations of inhibitory neurons in both superficial and deep layers of rat GC. BLA afferents recruit different proportions of excitatory and inhibitory neurons and show distinct patterns of circuit activation in the superficial and deep layers of GC. These results provide the first circuit-level analysis of BLA inputs to a sensory area. Laminar- and target-specific differences of BLA inputs likely explain the complexity of amygdalocortical interactions during sensory processing.SIGNIFICANCE STATEMENTProjections from the basolateral nucleus of the amygdala (BLA) to the cortex convey information about the emotional value and the expectation of a sensory stimulus. Although much work has been done to establish the behavioral role of BLA inputs to sensory cortices, very little is known about the circuit organization of BLA projections. Here we provide the first in-depth analysis of connectivity and synaptic properties of the BLA input to the gustatory cortex. We show that BLA afferents activate excitatory and inhibitory circuits in a layer-specific and pattern-specific manner. Our results provide important new information about how neural circuits establishing the hedonic value of sensory stimuli and driving anticipatory behaviors are organized at the synaptic level.

Visual, auditory, and somatosensory cortices are topographically organized, with neurons responding to similar sensory features clustering in adjacent portions of the cortex. Such topography has not been observed in the piriform cortex, whose responses to odorants are sparsely distributed across the cortex. The spatial organization of taste responses in the gustatory insular cortex (GC) is currently debated, with conflicting evidence from anesthetized rodents pointing to alternative and mutually exclusive models. Here, we rely on calcium imaging to determine how taste and task-related variables are represented in the superficial layers of GC of alert, licking mice. Our data show that the various stimuli evoke sparse responses from a combination of broadly and narrowly tuned neurons. Analysis of the distribution of responses over multiple spatial scales demonstrates that taste representations are distributed across the cortex, with no sign of spatial clustering or topography. Altogether, data presented here support the idea that the representation of taste qualities in GC of alert mice is sparse and distributed, analogous to the representation of odorants in piriform cortex.

Metastable brain dynamics are characterized by abrupt, jump-like modulations so that the neural activity in single trials appears to unfold as a sequence of discrete, quasi-stationary states. Evidence that cortical neural activity unfolds as a sequence of metastable states is accumulating at fast pace. Metastable activity occurs both in response to an external stimulus and during ongoing, self-generated activity. These spontaneous metastable states are increasingly found to subserve internal representations that are not locked to external triggers, including states of deliberations, attention and expectation. Moreover, decoding stimuli or decisions via metastable states can be carried out trial-by-trial. Focusing on metastability will allow us to shift our perspective on neural coding from traditional concepts based on trial-averaging to models based on dynamic ensemble representations. Recent theoretical work has started to characterize the mechanistic origin and potential roles of metastable representations. In this article we review recent findings on metastable activity, how it may arise in biologically realistic models, and its potential role for representing internal states as well as relevant task variables., Comment: 15 pages, 3 figures

Dysfunction of motor cortices is thought to contribute to motor disorders such as Parkinson’s disease (PD). However, little is known on the link between cortical dopaminergic loss, abnormalities in motor cortex neural activity and motor deficits. We address the role of dopamine in modulating motor cortical activity by focusing on the anterior lateral motor cortex (ALM) of mice performing a cued-licking task. We first demonstrate licking deficits and concurrent alterations of spiking activity in ALM of mice with unilateral depletion of dopaminergic neurons (i.e., mice injected with 6-OHDA into the medial forebrain bundle). Hemi-lesioned mice displayed delayed licking initiation, shorter duration of licking bouts, and lateral deviation of tongue protrusions. In parallel with these motor deficits, we observed a reduction in the prevalence of cue responsive neurons and altered preparatory activity. Acute and local blockade of D1 receptors in ALM recapitulated some of the key behavioral and neural deficits observed in hemi-lesioned mice. Altogether, our data show a direct relationship between cortical D1 receptor modulation, cue-evoked and preparatory activity in ALM, and licking initiation.SIGNIFICANCE STATEMENTThe link between dopaminergic signaling, motor cortical activity and motor deficits is not fully understood. This manuscript describes alterations in neural activity of the anterior lateral motor cortex (ALM) that correlate with licking deficits in mice with unilateral dopamine depletion or with intra-ALM infusion of dopamine antagonist. The findings emphasize the importance of cortical dopaminergic modulation in motor initiation. These results will appeal not only to researchers interested in cortical control of licking, but also to a broader audience interested in motor control and dopaminergic modulation in physiological and pathological conditions. Specifically, our data suggest that dopamine deficiency in motor cortex could play a role in the pathogenesis of the motor symptoms of Parkinson’s disease.

The parvicellular portion of the ventroposteromedial nucleus (VPMpc) is the part of the thalamus that processes gustatory information. Anatomical evidence shows that the VPMpc receives ascending gustatory inputs from the parabrachial nucleus (PbN) in the brainstem and sends projections to the gustatory cortex (GC). Although taste processing in PbN and GC has been the subject of intense investigation in behaving rodents, much less is known on how VPMpc neurons encode gustatory information. Here we present results from single-unit recordings in the VPMpc of alert rats receiving multiple tastants. Thalamic neurons respond to taste with time-varying modulations of firing rates, consistent with those observed in GC and PbN. These responses encode taste quality as well as palatability. Comparing responses to tastants either passively delivered, or self-administered after a cue, unveiled the effects of general expectation on taste processing in VPMpc. General expectation led to an improvement of taste coding by modulating response dynamics, and single neuron ability to encode multiple tastants. Our results demonstrate that the time course of taste coding as well as single neurons' ability to encode for multiple qualities are not fixed but rather can be altered by the state of the animal. Together, the data presented here provide the first description that taste coding in VPMpc is dynamic and state-dependent.SIGNIFICANCE STATEMENTOver the past years, a great deal of attention has been devoted to understanding taste coding in the brainstem and cortex of alert rodents. Thanks to this research, we now know that taste coding is dynamic, distributed, and context-dependent. Alas, virtually nothing is known on how the gustatory thalamus (VPMpc) processes gustatory information in behaving rats. This manuscript investigates taste processing in the VPMpc of behaving rats. Our results show that thalamic neurons encode taste and palatability with time-varying patterns of activity and that thalamic coding of taste is modulated by general expectation. Our data will appeal not only to researchers interested in taste, but also to a broader audience of sensory and systems neuroscientists interested in the thalamocortical system.

Reward-related circuits are fundamental for initiating feeding on the basis of food-predicting cues, whereas gustatory circuits are believed to be involved in the evaluation of food during consumption. However, accumulating evidence challenges such a rigid separation. The insular cortex (IC), an area largely studied in rodents for its role in taste processing, is involved in representing anticipatory cues. Although IC responses to anticipatory cues are well established, the role of IC cue-related activity in mediating feeding behaviors is poorly understood. Here, we examined the involvement of the IC in the expression of cue-triggered food approach in mice trained with a Pavlovian conditioning paradigm. We observed a significant change in neuronal firing during presentation of the cue. Pharmacological silencing of the IC inhibited food port approach. Such a behavior could be recapitulated by temporally selective inactivation during the cue. These findings represent the first evidence, to our knowledge, that cue-evoked neuronal activity in the mouse IC modulates behavioral output, and demonstrate a causal link between cue responses and feeding behaviors.

Sensory stimuli can be recognized more rapidly when they are expected. This phenomenon depends on expectation affecting the cortical processing of sensory information. However, virtually nothing is known on the mechanisms responsible for the effects of expectation on sensory networks. Here, we report a novel computational mechanism underlying the expectation-dependent acceleration of coding observed in the gustatory cortex (GC) of alert rats. We use a recurrent spiking network model with a clustered architecture capturing essential features of cortical activity, including the metastable activity observed in GC before and after gustatory stimulation. Relying both on network theory and computer simulations, we propose that expectation exerts its function by modulating the intrinsically generated dynamics preceding taste delivery. Our model, whose predictions are confirmed in the experimental data, demonstrates how the modulation of intrinsic metastable activity can shape sensory coding and mediate cognitive processes such as the expectation of relevant events. Altogether, these results provide a biologically plausible theory of expectation and ascribe a new functional role to intrinsically generated, metastable activity.

In natural conditions, gustatory stimuli are typically expected. Anticipatory and contextual cues provide information that allows animals to predict the availability and the identity of the substance to be ingested. Recording in alert rats trained to self-administer tastants following a go signal revealed that neurons in the primary gustatory cortex (GC) can respond to anticipatory cues. These experiments were optimized to demonstrate that even the most general form of expectation can activate neurons in GC, and did not provide indications on whether cues predicting different tastants could be encoded selectively by GC neurons. Here we recorded single-neuron activity in GC of rats engaged in a task where one auditory cue predicted sucrose, while another predicted quinine. We found that GC neurons respond differentially to the two cues. Cue-selective responses develop in parallel with learning. Comparison between cue and sucrose responses revealed that cues could trigger the activation of anticipatory representations. Additional experiments showed that an expectation of sucrose leads a subset of neurons to produce sucrose-like responses even when the tastant was omitted. Altogether, the data show that primary sensory cortices can encode for cues predicting different outcomes, and that specific expectations result in the activation of anticipatory representations.

Most of the research on cortical processing of taste has focused on either the primary gustatory cortex (GC) or the orbitofrontal cortex (OFC). However, these are not the only areas involved in taste processing. Gustatory information can also reach another frontal region, the medial prefrontal cortex (mPFC), via direct projections from GC. mPFC has been studied extensively in relation to its role in controlling goal-directed action and reward-guided behaviors, yet very little is known about its involvement in taste coding. The experiments presented here address this important point and test whether neurons in mPFC can significantly process the physiochemical and hedonic dimensions of taste. Spiking responses to intraorally delivered tastants were recorded from rats implanted with bundles of electrodes in mPFC and GC. Analysis of single-neuron and ensemble activity revealed similarities and differences between the two areas. Neurons in mPFC can encode the chemosensory identity of gustatory stimuli. However, responses in mPFC are sparser, more narrowly tuned, and have a later onset than in GC. Although taste quality is more robustly represented in GC, taste palatability is coded equally well in the two areas. Additional analysis of responses in neurons processing the hedonic value of taste revealed differences between the two areas in temporal dynamics and sensitivities to palatability. These results add mPFC to the network of areas involved in processing gustatory stimuli and demonstrate significant differences in taste-coding between GC and mPFC.

Sensory cortical circuits are shaped by experience during sensitive periods in development. In the primary visual cortex (V1) altered visual experience results in changes in visual responsiveness of cortical neurons. The experience-dependent refinement of the circuit in V1 is thought to rely on competitive interactions between feedforward circuits driven by the two eyes. However, recent data have provided evidence for an additional role of cortico-cortical circuits in this process. Indeed, experience-dependent changes in intracortical circuits can be induced rapidly and may result in rapid-onset functional changes. Unilateral occlusion of vision rapidly alters visual responsiveness, synaptic strength and connectivity of local circuits in the binocular region of V1 (V1b), where the inputs from the two eyes converge. In the monocular region of rodent V1 (V1m), where feedforward inputs from the ipsilateral eye are virtually absent, visual deprivation induces rapid plasticity in local circuits; however, functional changes seem to occur only after long periods of deprivation. In V1m there is currently no evidence for functional changes occurring within a time window compatible with that of local circuit plasticity. Here, we probed the visual responsiveness of neurons in rat V1m and assessed the effect of one day unilateral eye lid suture on single neuron visual responses. We report a novel form of plasticity within V1m that occurs on a timescale consistent with the earliest known changes in synaptic strength. Our data provide new insights into how sensory experience can rapidly modulate neuronal responses, even in the absence of direct competition between feedforward thalamocortical inputs.

Most of the general principles used to explain sensory cortical function have been inferred from experiments performed on neocortical, primary sensory areas. Attempts to apply a neocortical view to the study of the gustatory cortex (GC) have provided only a limited understanding of this area. Failures to conform GC to classical neocortical principles have been implicitly interpreted as a demonstration of GC's uniqueness. Here we propose to take the opposite perspective, dismissing GC's uniqueness and using principles extracted from its study as a lens for looking at neocortical sensory function. In this review, we describe three significant findings related to gustatory cortical function and advocate their relevance for understanding neocortical sensory areas.

The insular cortex is the primary cortical site devoted to taste processing. A large body of evidence is available for how insular neurons respond to gustatory stimulation in both anesthetized and behaving animals. Most of the reports describe broadly tuned neurons that are involved in processing the chemosensory, physiological and psychological aspects of gustatory experience. However little is known about how these neural responses map onto insular circuits. Particularly mysterious is the functional role of the three subdivisions of the insular cortex: the granular, the dysgranular and the agranular insular cortices. In this article we review data on the organization of the local and long-distance circuits in the three subdivisions. The functional significance of these results is discussed in light of the latest electrophysiological data. A view of the insular cortex as a functionally integrated system devoted to processing gustatory, multimodal, cognitive and affective information is proposed.

SummaryAnimals are not passive spectators of the sensory world in which they live. In natural conditions they often sense objects on the bases of expectations initiated by predictive cues. Expectation profoundly modulates neural activity by altering the background state of cortical networks and modulating sensory processing. The link between these two effects is not known. Here, we studied how cue-triggered expectation of stimulus availability influences processing of sensory stimuli in the gustatory cortex (GC). We found that expected tastants were coded more rapidly than unexpected stimuli. The faster onset of sensory coding related to anticipatory priming of GC by associative auditory cues. Simultaneous recordings and pharmacological manipulations of GC and basolateral amygdala revealed the role of top-down inputs in mediating the effects of anticipatory cues. Altogether, these data provide a model for how cue-triggered expectation changes the state of sensory cortices to achieve rapid processing of natural stimuli.

Brain circuits undergo distributed rearrangements throughout life: development, experience and behavior constantly modify synaptic strength and network connectivity. Despite these changes, neurons and circuits need to preserve their functional stability. Single neurons maintain their spontaneous firing rate within functional working ranges by regulating the efficacy of their synaptic inputs. But how do networks maintain a stable behavior? Is network homeostasis a consequence of cell autonomous mechanisms? In this article we will review recent evidence showing that network homeostasis is more than the sum of single-neuron homeostasis and that high-order network stability can be achieved by coordinated inter-cellular interactions.

We review data demonstrating that single-neuron sensory responses change with the states of the neural networks (indexed in terms of spectral properties of local field potentials) in which those neurons are embedded. We start with broad network changes—different levels of anesthesia and sleep—and then move to studies demonstrating that the sensory response plasticity associated with attention and experience can also be conceptualized as functions of network state changes. This leads naturally to the recent data that can be interpreted to suggest that even brief experience can change sensory responses via changes in network states and that trial-to-trial variability in sensory responses is a nonrandom function of network fluctuations, as well. We suggest that the CNS may have evolved specifically to deal with stimulus variability and that the coupling with network states may be central to sensory processing.

Emotional learning requires the coordinated action of neural populations in limbic and cortical networks. Here, we performed simultaneous extracellular recordings from gustatory cortical (GC) and basolateral amygdalar (BLA) neural ensembles as awake, behaving rats learned to dislike the taste of saccharin [via conditioned taste aversion (CTA)]. Learning-related changes in single-neuron sensory responses were observed in both regions, but the nature of the changes was region specific. In GC, most changes were restricted to relatively late aspects of the response (starting ∼1.0 s after stimulus administration), supporting our hypothesis that in this paradigm palatability-related information resides exclusively in later cortical responses. In contrast, and consistent with data suggesting the amygdala's primary role in judging stimulus palatability, CTA altered all components of BLA taste responses, including the earliest. Finally, learning caused dramatic increases in the functional connectivity (measured in terms of cross-correlation peak heights) between pairs of simultaneously recorded BLA and GC neurons, increases that were evident only during taste processing. Our simultaneous assays of the activity of single neurons in multiple relevant brain regions across learning suggest that the transmission of taste information through amygdala–cortical circuits plays a vital role in CTA memory formation.

The activity of ensembles of simultaneously recorded neurons can be represented as a set of points in the space of firing rates. Even though the dimension of this space is equal to the ensemble size, neural activity can be effectively localized on smaller subspaces. The dimensionality of the neural space is an important determinant of the computational tasks supported by the neural activity. Here, we investigate the dimensionality of neural ensembles from the sensory cortex of alert rats during period of ongoing (inter-trial) and stimulus-evoked activity. We find that dimensionality grows linearly with ensemble size, and grows significantly faster during ongoing activity compared to evoked activity. We explain these results using a spiking network model based on a clustered architecture. The model captures the difference in growth rate between ongoing and evoked activity and predicts a characteristic scaling with ensemble size that could be tested in high-density multi-electrode recordings. Moreover, the model predicts the existence of an upper bound on dimensionality. This upper bound is inversely proportional to the amount of pair-wise correlations and, compared to a homogeneous network without clusters, it is larger by a factor equal to the number of clusters. The empirical estimation of such bounds depends on the number and duration of trials. Together, these results provide a framework to analyze neural dimensionality in alert animals, its behavior under stimulus presentation, and its theoretical dependence on ensemble size, number of clusters, and pair-wise correlations in spiking network models., Comment: 30 pages, 8 figures; v2 in press, 9 figures, major improvements, including comparison to shuffled datasets, analytical derivation of estimation bias; v3, fixed typo in Fig. 8A

Although temporal coding is a frequent topic of neurophysiology research, trial-to-trial variability in temporal codes is typically dismissed as noise and thought to play no role in sensory function. Here, we show that much of this supposed “noise” faithfully reflects stimulus-related processes carried out in coherent neural networks. Cortical neurons responded to sensory stimuli by progressing through sequences of states, identifiable only in examinations of simultaneously recorded ensembles. The specific times at which ensembles transitioned from state to state varied from trial to trial, but the state sequences were reliable and stimulus-specific. Thus, the characterization of ensemble responses in terms of state sequences captured facets of sensory processing that are missing from, and obscured in, other analyses. This work provides evidence that sensory neurons act as parts of a systems-level dynamic process, the nature of which can best be appreciated through observation of distributed ensembles.

Sensory processing is modulated by attention, which is a function of network states. Here we show that changes in such states do more than a simple gating of stimuli: they actually re-arrange cortical coding space to emphasize emotional valences. We delivered taste stimuli to rats before and after a spontaneous state change (“disengagement”) that is associated with a reduction in attention and a concurrent emergence of cortical μ rhythms. The percentage of cortical neurons that responded to tastes, and the average response across neurons, remained stable with disengagement, but the particulars of the responses changed drastically. The distinctiveness of sucrose and quinine—which represent the high and low ends of the palatability spectrum—increased, the distinctiveness of the two aversive tastes (quinine and citric acid) decreased, and the distinctiveness of sucrose and NaCl, which were almost identically palatable to start with, did not change. Overall, then, the changes appeared to be palatability-specific. Two additional findings were consistent with this conclusion: rats’ palatability-related behavioral responses to the tastes changed in similar ways with disengagement and disengagement-related neural changes specifically appeared late in the response, when palatability-specific information emerges in cortical responses. These data suggest that neural state changes can change the content of neural codes.

Over the past few years, it has become clear that oscillatory dynamics of cortical networks are closely involved in sensory coding, attention, memory and sleep. Although most experimental and theoretical studies have focused on the neocortex, we believe that progress in understanding cortical oscillations can be advanced by also considering the olfactory system – which shares many basic properties with the neocortex and shows similar oscillatory patterns. Besides offering the advantage of a greater experimental tractability, the olfactory cortex might prove to be instrumental in uncovering general functional principles of neocortical oscillations, by virtue of the potentially important role of olfaction during neocortical evolution. In this article, we illustrate how such an evolution-based comparative approach can provide novel insights into neocortical slow-wave sleep oscillations and their relationship to respiration.

In this study, we have characterized slow and fast oscillations at several stages of olfactory processing under light and deep ketamine/xylazine anesthesia in the albino rat. While monitoring the animal's respiration, we also obtained field potentials from the olfactory bulb and piriform (olfactory) cortex and simultaneously recorded membrane potentials in piriform cortex pyramidal cells. Our results demonstrate that oscillations are generally found at higher frequencies under lighter and lower frequencies under deeper anesthesia. In previous studies of cerebral cortex, similar results in ketamine/xylazine anesthetized animals have been interpreted to correspond with the higher frequencies found during waking and lower frequencies found in the sleep state. Correlation and coherence analysis between data obtained in the bulb and cortex reveals a clear difference in coupling depending on the anesthetic state of the animal. Specifically, activity recorded in the whole system is highly correlated with respiration during deep anesthesia, whereas only the olfactory bulb, and not the cortex, is correlated with respiration during light anesthesia. These data suggest that global activity in the piriform cortex is actually more directly tied to peripheral slow respiratory input during slow wave than fast wave states and that the coupling between olfactory structures can be dynamically modulated by the level of anesthesia and therefore presumably by different brain states as well.

The 7 to 12 Hz rhythm is a high-voltage oscillatory phenomenon recorded in many rat neocortical regions, largely analogous to the rodent and human somatosensory μ rhythm. Central to any interpretation of the functional significance of this pattern is the analysis of the behavioral context associated with it. Much of the debate on the function of μ, variously believed to represent either an environment-oriented or -isolated state, has relied primarily on its association with quiet immobility. In this report, we describe the relationship between the 7 to 12 Hz rhythm and a more complex behavioral setting, in which we were able to dissociated task orientation from disengagement. We trained head-restrained, water-restricted rats to perform a simple variant of a timed fluid self-administration task, while recording local field potentials from gustatory cortex (GC). Rats progressed through two behavioral states that were clearly distinguishable on the basis of lever-pressing regimes: a task-oriented state and a second state that reflected disengagement from the task. Concurrent GC neural recordings revealed bilaterally coherent oscillations in the 7 to 12 Hz range associated solely with the latter state. Consistent with published recordings of μ rhythm from somatosensory cortex, these rhythmic episodes were endogenously quenched when the rats prepared to lever-press; this inhibition of rhythmic episodes lasted through fluid delivery and consumption, making it clear that GC rhythms are not related to gustatory processing itself. By showing a direct relationship between the 7 to 12 Hz rhythm and disengagement from a task, these data provide strong and novel evidence that this gustatory rhythm in rats is associated with withdrawal from experimental contingencies.

The occurrence of low frequency (in vivointracellular and extracellular field potential recordings obtained under conditions of ketamine-xylazine anesthesia to examine slow-wave behavior in the olfactory system. We demonstrate the occurrence of low-frequency oscillations in field potentials of both the olfactory bulb and cortex and in the membrane potentials of cortical pyramidal cells. By monitoring ongoing breathing, we also show that these oscillations are all correlated with the natural breathing cycle. Using a tracheotomized preparation, we demonstrate that slow oscillatory patterns could occasionally be produced even when air is no longer entering the nose, supporting the view that the olfactory system has an intrinsic propensity to oscillate. However, in the case of tracheotomized rats, the amplitude and regularity of the oscillations as well as their patterns of correlation are disrupted. All temporal relationships were restored when air was pulsed into the nostrils. We conclude that, in the olfactory system of freely breathing rats, there is a strong relationship between the occurrence and timing of slow oscillations and the ongoing periodic sensory input resulting from respiration. This coupling between olfactory cortex slow oscillations and respiration may result from the interaction between respiratory-related rhythmic input and the tendency for olfactory structures to oscillate intrinsically. We believe this finding has important functional as well as evolutionary implications.

Single trial analyses of ensemble activity in alert animals demonstrate that cortical circuits dynamics evolve through temporal sequences of metastable states. Metastability has been studied for its potential role in sensory coding, memory and decision-making. Yet, very little is known about the network mechanisms responsible for its genesis. It is often assumed that the onset of state sequences is triggered by an external stimulus. Here we show that state sequences can be observed also in the absence of overt sensory stimulation. Analysis of multielectrode recordings from the gustatory cortex of alert rats revealed ongoing sequences of states, where single neurons spontaneously attain several firing rates across different states. This single neuron multi-stability represents a challenge to existing spiking network models, where typically each neuron is at most bi-stable. We present a recurrent spiking network model that accounts for both the spontaneous generation of state sequences and the multi-stability in single neuron firing rates. Each state results from the activation of neural clusters with potentiated intra-cluster connections, with the firing rate in each cluster depending on the number of active clusters. Simulations show that the models ensemble activity hops among the different states, reproducing the ongoing dynamics observed in the data. When probed with external stimuli, the model predicts the quenching of single neuron multi-stability into bi-stability and the reduction of trial-by-trial variability. Both predictions were confirmed in the data. Altogether, these results provide a theoretical framework that captures both ongoing and evoked network dynamics in a single mechanistic model., Comment: 34 pages, 11 figures; v2: typos in Methods section corrected; v3: typos corrected

Neuromodulation can be defined as a biophysical process that serves to modify — or modulate — the computation performed by a neuron or network as a function of task demands and behavioral state of the animal. These modulatory effects often involve substances extrinsic to the network under observation, such as acetylcholine (ACh), norepinephrine (NE), histamine, serotonin (5-HT), dopamine (DA), and a variety of neuropeptides. Olfactory and gustatory processes especially need to be adaptive and respond flexibly to changing environments, availability of resources and physiological needs. It is therefore crucial to understand the neuromodulatory processes that regulate the function of these systems.

Taste-related information reaches the gustatory cortex (GC) through two routes: a thalamic and a limbic pathway. While evidence is accumulating on limbic–cortical interactions in taste, very little information is available on the function of the gustatory thalamus in shaping GC activity. Here we rely on behavioral electrophysiological techniques to study taste-evoked activity in GC before and after inactivation of the parvicellular portion of the ventroposteromedial nucleus of thalamus (VPMpc; i.e., the gustatory thalamus). Gustatory stimuli were presented to rats either alone or preceded by an anticipatory cue. The reliance on two different behavioral contexts allowed us to investigate how the VPMpc mediates GC responses to uncued tastants, cued tastants, and anticipatory cues. Inactivation of the thalamus resulted in a dramatic reduction of taste processing in GC. However, responses to anticipatory cues were unaffected by this manipulation. The use of a cue-taste association paradigm also allowed for the identification of two subpopulations of taste-specific neurons: those that responded to gustatory stimulation and to the cue (i.e., cue-and-taste) and those that responded to tastants only (i.e., taste-only). Analyses of these two populations revealed differences in response dynamics and connectivity with the VPMpc.The results provide novel evidence for the role of VPMpc in shaping GC activity and demonstrate a previously unknown association between responsiveness to behavioral events, temporal dynamics, and thalamic connectivity in GC.

Persistent reduction in sensory drive in early development results in multiple plastic changes of different cortical synapses. How these experience-dependent modifications affect the spatio-temporal dynamics of signal propagation in neocortical circuits is poorly understood. Here we demonstrate that brief visual deprivation significantly affects the propagation of electrical signals in the primary visual cortex. The spatio-temporal spread of circuit activation upon direct stimulation of its input layer (Layer 4) is reduced, as is the activation of Layer 2/3 – the main recipient of the output from Layer 4. Our data suggest that the decrease in spatio-temporal activation of L2/3 depends on reduced L4 output, and is not intrinsically generated within L2/3. The data shown here suggest that changes in the synaptic components of the visual cortical circuit result not only in alteration of local integration of excitatory and inhibitory inputs, but also in a significant decrease in overall circuit activation. Furthermore, our data indicate a differential effect of visual deprivation on L4 and L2/3, suggesting that while feedforward activation of L2/3 is reduced, its activation by long range, within layer inputs is unaltered. Thus, brief visual deprivation induces experience-dependent circuit re-organization by modulating not only circuit excitability, but also the spatio-temporal patterns of cortical activation within and between layers.