9166 • The Journal of Neuroscience, November 25, 2020 • 40(48):9166–9168

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Inhibitory Central Outputs to Control the Gain of

Dheeraj S. Roy Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142 Review of Veldhuizen et al.

The survival of an animal critically mechanisms (VPM, IC, and related gus- muli (Vuilleumier et al., 2004); and (3) depends on its ability to identify nutrient- tatory brain regions) account for the Within the amygdala, the central nucleus rich food and avoid harmful substances. variability remains unclear. Peripheral is sensitive to changes in taste intensity Although olfactory cues and visual infor- mechanisms have received support from perception, and this structure has recip- mation contribute to these processes, the some studies, including one reporting rocal connectivity with all major gusta- taste system is ultimately responsible for that individuals with higher tory regions (NST, VPM, IC; Small recognizing and discriminating between densities reported some as more et al., 2003). To test their hypothesis, the different food qualities. The sensation intense than individuals with fewer taste Veldhuizen et al. (2020) assessed blood of taste begins on the , which buds (Miller and Reedy, 1990). Yet, such oxygenation level-dependent (BOLD) re- contains specialized taste receptor cells mechanisms are thought to be insuffi- sponses to sweet, sour, salty, and bitter thataresensitivetothefivebasictastes cient to explain individual differences in tastants in 28 healthy participants using (Yarmolinsky et al., 2009). In humans, taste intensity perception (Feeney and psychophysiological measurements, regres- taste information travels from the oral Hayes, 2014). Nevertheless, central mech- sion, and dynamic causal modeling. cavity to primary gustatory cortex [insular anisms remain underexplored. This is The first question Veldhuizen et al. cortex (IC)] via the following three synap- an important issue because knowing (2020) addressed was whether amygdala ses: taste receptor cells to the rostral nu- whether central mechanisms play a sig- responses to the different tastants covaried cleus of the (NST); NST to nificant role in interindividual variability with the mean intensity rating across the gustatory thalamic nucleus [ventral in taste perception could help us under- tastants. Using taste psychophysics, they posterior medial nucleus (VPM)]; and stand not only individual differences in found that intensity ratings of sweet, sour, VPM to IC (Oliveira-Maia et al., 2011). food preferences and diet, but also how and salty positively correlated with each In addition to the valence (appetitive gustatory circuit dysfunction may con- other. Functional magnetic resonance imag- or aversive) of a tastant, its intensity is an tribute to obesity. ing showed that these three tastants led important characteristic, because it reflects Veldhuizen et al. (2020) hypothesized to significant activation of IC, operculum, concentration and quantity. Differences in that inhibitory output from the central pre-central and post-central gyrus, left taste intensity perception across indivi- amygdala to gustatory brain regions act as amygdala, cingulate cortex, and putamen, duals have been suggested to underlie a central gain mechanism that influences consistent with previous work (Veldhuizen food preferences, diet, and risk for obesity taste intensity perception. This idea is et al., 2011). In support of their hypothesis, (Prutkin et al., 2000). Despite investiga- supported by three previous findings: (1) BOLD responses in the left central amyg- tions into the source of this variability, patients who had undergone surgical dala were associated with each participant’s whether peripheral mechanisms (at the resection of the anterior medial temporal mean taste intensity rating, which was cal- level of taste receptor cells) and/or central lobe, particularly those involving the culated as an average of the ratings for all amygdala, had increased taste sensitivity three tastants. Associations between mean and stronger ratings of perceived taste taste intensity rating and responses in Received July 17, 2020; revised Oct. 21, 2020; accepted Oct. 20, 2020. (Small et al., 1997, 2001), which hinted at bilateral cuneus were also observed. The author declares no competing financial interests. an inhibitory influence from the amyg- The authors next asked whether the Correspondence should be addressed to Dheeraj S. Roy at droy@ broadinstitute.org. dala; (2) in directed attention tasks, central amygdala was functionally coupled https://doi.org/10.1523/JNEUROSCI.1833-20.2020 amygdala circuits regulate gain by assigning to major gustatory regions, such as NST, Copyright © 2020 the authors greater weights to salient sensory sti- VPM, and IC, and other regions involved Roy · An Amygdalothalamic Circuit for Taste Perception J. Neurosci., November 25, 2020 • 40(48):9166–9168 • 9167 in taste processing. A psychophysiological taste intensity (Spetter et al., 2010; Yeung taste quality, which could also be involved interaction analysis followed by regression et al., 2016), it is reasonable to speculate in taste intensity perception. Additional of the responses of significantly connected that IC may modulate taste intensity studies are required to uncover the con- areas with the mean intensity rating re- perception. A notable observation by the tributions of this circuit in taste process- vealed circuits between the amygdala and authors was that although IC responses ing, both in rodents and in human three regions, mediodorsal (MD) thala- vary with tastant concentration, their ac- participants. mus, VPM/pulvinar thalamus, and mid- tivity does not reflect the perception of In conclusion, the study by Veldhuizen temporal gyrus, that are influenced by taste intensity across tastants. Since IC et al. (2020) fills a critical gap in our taste sensitivity. Of these, gustatory VPM responses do not encode taste intensity understanding of the neural circuits thalamus is a likely target region to perception, and because the first synapse underlying individual differences in taste participate in taste sensitivity, whereas in the ascending gustatory pathway, NST, perception. The projections from the cen- contributions from MD thalamus and also did not show taste intensity-modu- tral amygdala are unlikely to be the only mid-temporal gyrus are unexpected. lated responses, the reported central gain pathways involved in this variability, how- Finally, the authors wanted to know mechanism most likely arises in central ever. Indeed, Veldhuizen et al. (2020) also whether inhibitory output from the amyg- amygdala itself. It would be worthwhile in found that the cuneus was significantly dala establishes effective connectivity with the future to understand how IC and NST associated with taste perception. Given the identified brain regions involved in inputs together give rise to this taste gain that cuneus receives visual information taste sensitivity. To answer this question, mechanism in central amygdala. and its connectivity with amygdala is they examined changes in connectivity The amygdala gain mechanism func- modulated by visual–olfactory integration between these regions in relation to the tions through its connections with two processes (Stickel et al., 2019), it is possible mean intensity rating using Bayesian distinct thalamic nuclei (VPM and MD) that this circuit also supports visual–gusta- model estimation, which revealed inhibi- and the mid-temporal gyrus. VPM rec- tory integration. This should be further tory connections originating from the left eives gustatory input from NST and in examined in future studies. Interestingly, amygdala to bilateral MD and VPM/pulvi- turn projects to IC, and, based on rodent another visual region, the pulvinar, also nar thalamic nuclei. Interestingly, this experiments, is thought to help establish exhibited functional connectivity with the analysis also found bidirectional connec- baseline firing of IC neurons and taste amygdala during taste perception. Although tions between MD and VPM/pulvinar encoding (Samuelsen et al., 2013). There- this structure has received limited attention thalamus, suggesting that a functional net- fore, inhibitory outputs from the amygdala in taste studies, along with the cuneus, it work of the amygdala–MD thalamus– are in a perfect position to regulate the may support visual processes that help taste VPM/pulvinar thalamus plays a critical transfer of gustatory information from perception. Future work using noninvasive role in determining mean taste intensity VPM thalamus to IC. In contrast to VPM, imaging tools that have superior spatial re- ratings. Subsequent analyses showed that the role of MD thalamus in taste process- solution will clarify the exact role of regions connections from amygdala to left VPM/ ing remains unknown, despite the pres- such as the pulvinar in taste perception. pulvinar thalamus and right MD thala- ence of reciprocal connectivity with IC in mus, as well as from right VPM/pulvinar rodents (Shi and Cassell, 1998). Given the References to right MD thalamus, contributed the well documented role of MD thalamus Avery JA, Liu AG, Ingeholm JE, Riddell CD, Gotts most to the predictive model. There- in selectively routing and synchronizing SJ, Martin A (2020) Taste quality representa- fore, consistent with their hypothesis, the behaviorally relevant sensory information tion in the . J Neurosci 40:1042– strength of inhibitory connections from to specific cortical networks depending on 1052. the amygdala to multiple thalamic nuclei is task demands (Saalmann, 2014), it is pos- Crouzet SM, Busch NA, Ohla K (2015) Taste qual- able to predict individual variation in taste sible that central amygdala inputs to MD ity decoding parallels taste sensations. Curr Biol 25:890–896. intensity perception; specifically, greater thalamus regulates taste stimuli processing Feeney EL, Hayes JE (2014) Regional differences in inhibition predicts lower taste intensity by coordinating necessary attentional fun- suprathreshold intensity for bitter and umami perception. ctions. If so, it would mean that distinct stimuli. Chemosens Percept 7:147–157. In summary, Veldhuizen et al. (2020) central amygdala outputs underlie differ- Miller IJ, Reedy FE (1990) Variations in human identified specific central amygdala neural ent processes relevant for taste intensity taste bud density and taste intensity perception. – circuits in humans that act as a gain mech- perception: central amygdala to VPM thal- Physiol Behav 47:1213 1219. Oliveira-Maia AJ, Roberts CD, Simon SA, anism for taste intensity perception. amus for taste intensity coding; and cen- Nicolelis MAL (2011) Gustatory and reward Because peripheral mechanisms cannot tral amygdala to MD thalamus for taste brain circuits in the control of food intake. Adv account for across-tastant intensity per- salience coding. This is an exciting possi- Tech Stand Neurosurg 36:31–59. ception, it is clear that central mechanisms bility,whichmaybeclarifiedbyfuture PrutkinJ,FisherEM,EtterL,FastK,GardnerE, play a major role in this feature of taste studies using optogenetic circuit manipu- Lucchina LA, Snyder DJ, Tie K, Weiffenbach J, processing. An intriguing question is lations in other species (e.g., rodents) dur- Bartoshuk LM (2000) Genetic variation and inferences about perceived taste intensity in whether the gain mechanism arises in ing taste-specific behavioral assays. Like mice and men. Physiol Behav 69:161–173. central amygdala or these responses are MD thalamus, mid-temporal gyrus is Saalmann YB (2014) Intralaminar and medial tha- downstream of an earlier mechanism. not part of the standard taste pathway. lamic influence on cortical synchrony, infor- Taste information reaches the central Although most studies have focused on its mation transmission and cognition. Front Syst amygdala via two routes, directly from IC role in language, , and Neurosci 8:83. and from NST (Schiff et al., 2018). semantic memory, it has previously been Samuelsen CL, Gardner MP, Fontanini A (2013) Because IC represents taste quality using a associated with taste quality processing Thalamic contribution to cortical processing of taste and expectation. J Neurosci 33:1815– distributed population code (Avery et al., (Crouzet et al., 2015). One possibility is 1827. 2020), and both IC and their outputs to that central amygdala inputs to mid-tem- SchiffHC,BouhuisAL,YuK,PenzoMA,LiH,He thalamus are activated as a function of poral gyrus reflects processes related to M, Li B (2018) An insula-central amygdala 9168 • J. Neurosci., November 25, 2020 • 40(48):9166–9168 Roy · An Amygdalothalamic Circuit for Taste Perception

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