Cortical Coding of Gustatory and Thermal Signals in Active Licking Mice.

Eating behaviors are influenced by the integration of gustatory, olfactory, and somatosensory signals, which all contribute to the perception of flavor. Although extensive research has explored the neural correlates of taste in the gustatory cortex (GC), less is known about its role in encoding thermal information. This study investigates the encoding of oral thermal and chemosensory signals by GC neurons compared to the oral somatosensory cortex. In this study, we recorded the spiking activity of more than 900 GC neurons and 500 neurons from the oral somatosensory cortex in mice allowed to freely lick small drops of gustatory stimuli or deionized water at varying non-nociceptive temperatures. We then developed and used a Bayesian-based analysis technique to assess neural classification scores based on spike rate and phase timing within the lick cycle. Our results indicate that GC neurons rely predominantly on rate information, although phase information is needed to achieve maximum accuracy, to effectively encode both chemosensory and thermosensory signals. GC neurons can effectively differentiate between thermal stimuli, excelling in distinguishing both large contrasts (14°C vs. 36°C) and, although less effectively, more subtle temperature differences. Finally, a direct comparison of the decoding accuracy of thermosensory signals between the two cortices reveals that while the somatosensory cortex showed higher overall accuracy, the GC still encodes significant thermosensory information. These findings highlight the GC's dual role in processing taste and temperature, emphasizing the importance of considering temperature in future studies of taste processing.

Neural Processing of Taste-Related Signals in the Mediodorsal Thalamus of Mice.

Our consummatory decisions depend on the taste of food and the reward experienced while eating, which are processed through neural computations in interconnected brain areas. Although many gustatory regions of rodents have been explored, the mediodorsal nucleus of the thalamus (MD) remains understudied. The MD, a multimodal brain area connected with gustatory centers, is often studied for its role in processing associative and cognitive information and has been shown to represent intraorally-delivered chemosensory stimuli after strong retronasal odor-taste associations. Key questions remain about whether MD neurons can process taste quality independently of odor-taste associations and how they represent extraoral signals predicting rewarding and aversive gustatory outcomes. Here, we present electrophysiological evidence demonstrating how mouse MD neurons represent and encode 1) the identity and concentrations of basic taste qualities during active licking, and 2) auditory signals anticipating rewarding and aversive taste outcomes. Our data reveal that MD neurons can reliably and dynamically encode taste identity in a broadly tuned manner and taste concentrations with spiking activity positively and negatively correlated with stimulus intensity. Our data also show that MD can represent information related to predictive cues and their associated outcomes, regardless of whether the cue predicts a rewarding or aversive outcome. In summary, our findings suggest that the mediodorsal thalamus is integral to the taste pathway, as it can encode sensory-discriminative dimensions of tastants and participate in processing associative information essential for ingestive behaviors.

Oral thermal processing in the gustatory cortex of awake mice.

Oral temperature is a sensory cue relevant to food preference and nutrition. To understand how orally sourced thermal inputs are represented in the gustatory cortex (GC), we recorded neural responses from the GC of male and female mice presented with deionized water at different innocuous temperatures (14 °C, 25 °C, and 36 °C) and taste stimuli (room temperature). Our results demonstrate that GC neurons encode orally sourced thermal information in the absence of classical taste qualities at the single neuron and population levels, as confirmed through additional experiments comparing GC neuron responses to water and artificial saliva. Analysis of thermal-evoked responses showed broadly tuned neurons that responded to temperature in a mostly monotonic manner. Spatial location may play a minor role regarding thermosensory activity; aside from the most ventral GC, neurons reliably responded to and encoded thermal information across the dorso-ventral and antero-postero cortical axes. Additional analysis revealed that more than half of the GC neurons that encoded chemosensory taste stimuli also accurately discriminated thermal information, providing additional evidence of the GC's involvement in processing thermosensory information important for ingestive behaviors. In terms of convergence, we found that GC neurons encoding information about both taste and temperature were broadly tuned and carried more information than taste-selective-only neurons; both groups encoded similar information about the palatability of stimuli. Altogether, our data reveal new details of the cortical code for the mammalian oral thermosensory system in behaving mice and pave the way for future investigations on GC functions and operational principles with respect to thermogustation.

Intraoral thermal processing in the gustatory cortex of awake mice.

Oral temperature is a sensory cue relevant to food preference and nutrition. To understand how orally-sourced thermal inputs are represented in the gustatory cortex (GC) we recorded neural responses from the GC of male and female mice presented with deionized water at different innocuous temperatures (14 °C, 25 °C, 36 °C) and taste stimuli (room temperature). Our results demonstrate that GC neurons encode orally-sourced thermal information in the absence of classical taste qualities at the single neuron and population levels, as confirmed through additional experiments comparing GC neuron responses to water and artificial saliva. Analysis of thermal-evoked responses showed broadly tuned neurons that responded to temperature in a mostly monotonic manner. Spatial location may play a minor role regarding thermosensory activity; aside from the most ventral GC, neurons reliably responded to and encoded thermal information across the dorso-ventral and antero-postero cortical axes. Additional analysis revealed that more than half of GC neurons that encoded chemosensory taste stimuli also accurately discriminated thermal information, providing additional evidence of the GC's involvement in processing thermosensory information important for ingestive behaviors. In terms of convergence, we found that GC neurons encoding information about both taste and temperature were broadly tuned and carried more information than taste-selective only neurons; both groups encoded similar information about the palatability of stimuli. Altogether, our data reveal new details of the cortical code for the mammalian intraoral thermosensory system in behaving mice and pave the way for future investigations on GC functions and operational principles with respect to thermogustation.

Active Licking Shapes Cortical Taste Coding.

Neurons in the gustatory cortex (GC) represent taste through time-varying changes in their spiking activity. The predominant view is that the neural firing rate represents the sole unit of taste information. It is currently not known whether the phase of spikes relative to lick timing is used by GC neurons for taste encoding. To address this question, we recorded spiking activity from >500 single GC neurons in male and female mice permitted to freely lick to receive four liquid gustatory stimuli and water. We developed a set of data analysis tools to determine the ability of GC neurons to discriminate gustatory information and then to quantify the degree to which this information exists in the spike rate versus the spike timing or phase relative to licks. These tools include machine learning algorithms for classification of spike trains and methods from geometric shape and functional data analysis. Our results show that while GC neurons primarily encode taste information using a rate code, the timing of spikes is also an important factor in taste discrimination. A further finding is that taste discrimination using spike timing is improved when the timing of licks is considered in the analysis. That is, the interlick phase of spiking provides more information than the absolute spike timing itself. Overall, our analysis demonstrates that the ability of GC neurons to distinguish among tastes is best when spike rate and timing is interpreted relative to the timing of licks.SIGNIFICANCE STATEMENT Neurons represent information from the outside world via changes in their number of action potentials (spikes) over time. This study examines how neurons in the mouse gustatory cortex (GC) encode taste information when gustatory stimuli are experienced through the active process of licking. We use electrophysiological recordings and data analysis tools to evaluate the ability of GC neurons to distinguish tastants and then to quantify the degree to which this information exists in the spike rate versus the spike timing relative to licks. We show that the neuron's ability to distinguish between tastes is higher when spike rate and timing are interpreted relative to the timing of licks, indicating that the lick cycle is a key factor for taste processing.

Cortical processing of chemosensory and hedonic features of taste in active licking mice.

In the last two decades, a considerable amount of work has been devoted to investigating the neural processing and dynamics of the primary taste cortex of rats. Surprisingly, much less information is available on cortical taste electrophysiology in awake mice, an animal model that is taking on a more prominent role in taste research. Here we present electrophysiological evidence demonstrating how the gustatory cortex (GC) encodes the basic taste qualities (sweet, salty, sour, and bitter) and water when stimuli are actively sampled through licking, the stereotyped behavior by which mice control the access of fluids in the mouth. Mice were trained to receive each stimulus on a fixed ratio schedule in which they had to lick a dry spout six times to receive a tastant on the seventh lick. Electrophysiological recordings confirmed that GC neurons encode both chemosensory and hedonic aspects of actively sampled tastants. In addition, our data revealed two other main findings: GC neurons rapidly encode information about taste qualities in as little as 120 ms, and nearly half of the recorded neurons exhibit spiking activity entrained to licking at rates up to 8 Hz. Overall, our results highlight how the GC of active licking mice rapidly encodes information about taste qualities as well as ongoing sampling behavior, expanding our knowledge on cortical taste processing.NEW & NOTEWORTHY Relatively little information is available on the neural dynamics of taste processing in the mouse gustatory cortex (GC). In this study we investigate how the GC encodes chemosensory and palatability features of a wide panel of gustatory stimuli when actively sampled through licking. Our results show that GC neurons broadly encode basic taste qualities but also process taste hedonics and licking information in a temporally dynamic manner.

Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus.

As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.