“…However, when the responses of these, and other, cell types were combined, systematic and clear distinctions between mild cooling and extreme cold, and separation of these responses from warming, became apparent (Figure 6D). This observation agrees with the idea that in V pathways, distinctions and transition across a broad range of oral cooling and cold temperatures are mediated by an ensemble, or combinatorial, neural code (Lemon et al, 2016;Leijon et al, 2019;Lemon, 2021); other data on V oral-cooling neurons also agree with ensemble coding (Yarmolinsky et al, 2016). The present results extend this possibility to Vc neurons that maintain axonal projections to the thalamus and potentially drive thalamocortical circuits for thermosensation.…”
Section: Combinatorial Coding Of Oral Coolingsupporting
confidence: 90%
“…We found that cooling sensitive Vc neurons that project to the thalamus include heterogeneous cell types that display diverse tuning and temporal response kinetics to cool and cold stimulation of the oral cavity. The combined activity of these cell types was found to provide neural information that distinguished a broad range of cool and cold temperatures, which agrees with an ensemble, or combinatorial, neural code for cooling (Lemon et al, 2016; Ran et al, 2016; Wang et al, 2018; Leijon et al, 2019; Lemon, 2021). Moreover, silencing TRPM8 resulted in a loss of Vc cells responsive to mild oral cooling but not intense noxious-like cold, implying multiple receptors contribute to neural information about oral cooling represented by V circuits within the brain.…”
Different sets of peripheral and medullary trigeminal neurons respond across a cooling gradient applied to intraoral skin. Here we applied electrophysiology to anesthetized mice to study if different types of cool-driven trigeminothalamic neurons convey oral cooling information to the thalamus. We monitored spiking responses to oral stimulation with cold (≤13°C), cool (21°C to 28°C), neutral (35°C), and warm/hot (≥40°C) water in single trigeminal nucleus caudalis (Vc) neurons physiologically tested for projections to the thalamus. We also recorded oral thermal responses from Vc neurons in mice gene deficient for the cooling and menthol receptor TRPM8 to study afferent mechanisms of central oral thermosensory activity. We found that thalamic-projecting Vc neurons that respond to oral cooling comprise heterogeneous cell types. These cell types showed unique temporal response kinetics across cool and cold temperatures, with tuning to select ranges of a cooling gradient. The combined thermal activity of multiple, differently tuned types of trigeminothalamic cooling neurons offered greater contrast between cold, cool, and warm temperatures in multivariate analysis than the responses of the individual neural types alone, agreeing with a neural population code for cooling information. Compared to control, TRPM8 deficient mice demonstrated a loss of Vc neurons tuned to mild oral cooling, but maintained Vc cells responsive to intense cold. Notably, distinctions between Vc population responses to mild cool and warm temperatures were impaired in TRPM8 deficient mice, suggesting a role for TRPM8 in oral warmth recognition. Diverse receptors and neurons mediate oral cooling signals carried by the trigeminothalamic pathway.
“…However, when the responses of these, and other, cell types were combined, systematic and clear distinctions between mild cooling and extreme cold, and separation of these responses from warming, became apparent (Figure 6D). This observation agrees with the idea that in V pathways, distinctions and transition across a broad range of oral cooling and cold temperatures are mediated by an ensemble, or combinatorial, neural code (Lemon et al, 2016;Leijon et al, 2019;Lemon, 2021); other data on V oral-cooling neurons also agree with ensemble coding (Yarmolinsky et al, 2016). The present results extend this possibility to Vc neurons that maintain axonal projections to the thalamus and potentially drive thalamocortical circuits for thermosensation.…”
Section: Combinatorial Coding Of Oral Coolingsupporting
confidence: 90%
“…We found that cooling sensitive Vc neurons that project to the thalamus include heterogeneous cell types that display diverse tuning and temporal response kinetics to cool and cold stimulation of the oral cavity. The combined activity of these cell types was found to provide neural information that distinguished a broad range of cool and cold temperatures, which agrees with an ensemble, or combinatorial, neural code for cooling (Lemon et al, 2016; Ran et al, 2016; Wang et al, 2018; Leijon et al, 2019; Lemon, 2021). Moreover, silencing TRPM8 resulted in a loss of Vc cells responsive to mild oral cooling but not intense noxious-like cold, implying multiple receptors contribute to neural information about oral cooling represented by V circuits within the brain.…”
Different sets of peripheral and medullary trigeminal neurons respond across a cooling gradient applied to intraoral skin. Here we applied electrophysiology to anesthetized mice to study if different types of cool-driven trigeminothalamic neurons convey oral cooling information to the thalamus. We monitored spiking responses to oral stimulation with cold (≤13°C), cool (21°C to 28°C), neutral (35°C), and warm/hot (≥40°C) water in single trigeminal nucleus caudalis (Vc) neurons physiologically tested for projections to the thalamus. We also recorded oral thermal responses from Vc neurons in mice gene deficient for the cooling and menthol receptor TRPM8 to study afferent mechanisms of central oral thermosensory activity. We found that thalamic-projecting Vc neurons that respond to oral cooling comprise heterogeneous cell types. These cell types showed unique temporal response kinetics across cool and cold temperatures, with tuning to select ranges of a cooling gradient. The combined thermal activity of multiple, differently tuned types of trigeminothalamic cooling neurons offered greater contrast between cold, cool, and warm temperatures in multivariate analysis than the responses of the individual neural types alone, agreeing with a neural population code for cooling information. Compared to control, TRPM8 deficient mice demonstrated a loss of Vc neurons tuned to mild oral cooling, but maintained Vc cells responsive to intense cold. Notably, distinctions between Vc population responses to mild cool and warm temperatures were impaired in TRPM8 deficient mice, suggesting a role for TRPM8 in oral warmth recognition. Diverse receptors and neurons mediate oral cooling signals carried by the trigeminothalamic pathway.
“…These results suggest that PB taste neurons that receive trigeminal projections represent sensory valence common to aversive gustatory (bitter) and oral thermal (noxious heat) sensations (Li and Lemon, 2019;Lemon, 2021). This convergence of cross-modal information onto common cells agrees with a role for the PB nucleus in protective coding.…”
Trigeminal neurons supply somatosensation to craniofacial tissues. In mouse brain, ascending projections from medullary trigeminal neurons arrive at taste neurons in the autonomic parabrachial nucleus, suggesting taste neurons participate in somatosensory processing. However, the genetic cell types that support this convergence were undefined. Using Cre-directed optogenetics and in vivo neurophysiology in anesthetized mice of both sexes, here we studied whether TRPV1-lineage nociceptive and thermosensory fibers are primary neurons that drive trigeminal circuits reaching parabrachial taste cells. We monitored spiking activity in individual parabrachial neurons during photoexcitation of the terminals of TRPV1-lineage fibers that arrived at the dorsal spinal trigeminal nucleus pars caudalis, which relays orofacial somatosensory messages to the parabrachial area. Parabrachial neural responses to oral delivery of taste, chemesthetic, and thermal stimuli were also recorded. We found that optical excitation of TRPV1-lineage fibers frequently stimulated traditionally defined taste neurons in lateral parabrachial nuclei. The tuning of neurons across diverse tastes associated with their sensitivity to excitation of TRPV1-lineage fibers, which only sparingly engaged neurons oriented to preferred tastes like sucrose. Moreover, neurons that responded to photostimulation of TRPV1-lineage afferents showed strong responses to temperature including noxious heat, which predominantly excited parabrachial bitter taste cells. Multivariate analyses revealed the parabrachial confluence of TRPV1-lineage signals with taste captured sensory valence information shared across aversive gustatory, nociceptive, and thermal stimuli. Our results reveal that trigeminal fibers with defined roles in thermosensation and pain communicate with parabrachial taste neurons. This multisensory convergence supports dependencies between gustatory and somatosensory hedonic representations in the brain.
“…First, we applied multiple concentrations and recorded from the 2 nd -order gustatory relay, the PBN, where gustatory responses are typically larger (Van Buskirk and Smith, 1981;Nakamura and Norgren, 1991;Di Lorenzo and Monroe, 1997;Geran and Travers, 2009). Second, we also presented tastants at 30 o C, instead of room temperature, because warming often enhances the magnitude of neural responses and the perceived intensity of sweet stimuli (Lemon, 2017(Lemon, , 2021. Third, because previous studies suggest the possibility that the mGluR4 receptor contributes to glutamate taste (Chaudhari and Roper, 1998;Chaudhari et al, 2000) and that the sodium-glucose transporter, SGLT1, can serve to detect glucose-containing sugars (Yasumatsu et al, 2020), we used antagonists to these receptors to test whether they affected PBN glutamate and sugar responses.…”
Recent findings from our laboratory demonstrated that the rostral nucleus of solitary tract (rNST) retains some responsiveness to glutamate (MSG+amiloride-MSGa) and sugars in mice lacking the canonical T1R receptors for these tastants. Here, we recorded from the parabrachial nucleus (PBN) in mice lacking the T1R1+T1R3 heterodimer (KO1+3), using warm stimuli to optimize sugar responses and employing extended concentrations and pharmacological agents to probe mechanisms. MSGa+IMP responses were not synergized in KO1+3 mice but responses to MSGa were similar to those in B6 (WT) mice. Glutamate responses in the neurons tested were unaffected by topical application of an mGluR4 antagonist. PBN T1R-independent sugar responses, including those to concentrated glucose, were more evident than in rNST. Sugar responses were undiminished by phlorizin, an inhibitor of SGLT, a component of a hypothesized alternative glucose-sensing mechanism. There were no sugar/umami "best" neurons in KO1+3 mice, and instead, sugars activated cells that displayed acid and amiloride-insensitive NaCl responses. In WTs, concentrated sugars activated "sugar/umami" cells but also electrolyte-sensitive neurons. The efficacy of hyperosmotic sugars for driving neurons broadly responsive to electrolytes implied an origin from Type III taste bud cells. To test this, we used the carbonic anhydrase (CA) inhibitor dorzolamide (DRZ), previously shown to inhibit amiloride-insensitive sodium responses arising from Type III cells. Dorzolamide had no effect on sugar-elicited responses in WT sugar/umami PBN neurons but strongly suppressed them in WT and KO electrolyte-generalist neurons. These findings suggest a novel T1R-independent mechanism for hyperosmotic sugars, involving a CA-dependent mechanism in Type-III taste bud cells.
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