Aversive state processing in the posterior insular cortex

Gehrlach, Daniel August; Dolensek, Nejc; Klein, Alexandra S.; Chowdhury, Ritu Roy; Matthys, Arthur; Junghänel, Michaela; Gaitanos, Thomas N.; Podgornik, Alja; Black, Thomas D.; Vaka, Narasimha Reddy; Conzelmann, Karl‐Klaus; Gogolla, Nadine

doi:10.1038/s41593-019-0469-1

Cited by 243 publications

(262 citation statements)

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“…This might reflect a weaker activation of insular cortex neurons, either a smaller number of neurons or a lower expression of ChR2 in the insular cortex could achieve a manipulation more specific to a certain behavior. This possibility was also supported by Gehrlach's finding that a higher frequency (20 Hz) stimulation triggers immobility and many aversive behaviors while a lower frequency (10 Hz) does not (Gehrlach et al, 2019). Stern et al recently found that inhibition of the projection from insular cortex Nos1 neurons to CeA has no effect on normal feeding, but blocks the context conditioned overconsumption, however, the connections from Nos1 neurons to different CeA neurons were not directly mapped (Stern et al, 2019).…”

Section: Discussionmentioning

confidence: 97%

“…For example, it was reported that neurons in the lateral parabrachial nucleus (LPB) that express calcitonin gene-related protein (CGRP) relay danger information and project to the CeA to suppress food intake (Campos et al, 2018;Carter et al, 2013); neurons in insular cortex that encode bitter taste project to CeA to convey negative valence (Schiff et al, 2018;Wang et al, 2018). More recently, Gehrlach et al expressed ChR2 in insular cortex under CamK2a promoter and demonstrated that activation of the insulaàCeA pathway suppresses feeding, increases anxiety and induces other aversive behaviors (Gehrlach et al, 2019).Interestingly, when we used AAVretro-Cre in CeA and Cre-dependent ChR2 in insular cortex, we only observed feeding suppression but not anxiety or other aversive behaviors. This might reflect a weaker activation of insular cortex neurons, either a smaller number of neurons or a lower expression of ChR2 in the insular cortex could achieve a manipulation more specific to a certain behavior.…”

Section: Discussionmentioning

confidence: 99%

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Neural circuit mechanism underlying the feeding controlled by insula-central amygdala pathway

Zhang-Molina

Schmit

Cai

2019

Preprint

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SummaryCentral nucleus of amygdala (CeA) contains distinct populations of neurons that play opposing roles in feeding. The circuit mechanism of how CeA neurons process information sent from their upstream inputs to regulate feeding is still unclear. Here we show that activation of the neural pathway projecting from insular cortex neurons to CeA suppresses food intake. Surprisingly, we find that the inputs from insular cortex form excitatory connections with similar strength to all types of CeA neurons. To reconcile this puzzling result, and previous findings, we developed a conductance-based dynamical systems model for the CeA neuronal network. Computer simulations showed that both the intrinsic electrophysiological properties of individual CeA neurons and the overall synaptic organization of the CeA circuit play a functionally significant role in shaping the CeA neural dynamics. We successfully identified a specific CeA circuit structure that reproduces the desired circuit output consistent with existing experimentally observed feeding behaviors.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Neural circuit mechanism underlying the feeding controlled by insula-central amygdala pathway

Zhang-Molina

Schmit

Cai

2019

Preprint

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“…Rodent studies further demonstrated roles for the IC in multisensory (Gogolla, Takesian, Feng, Fagiolini, & Hensch, 2014; Rodgers, Benison, Klein, & Barth, 2008) and pain processing (Tan et al, 2017), representation of valence (Wang et al, 2018), learning and memory (Bermúdez-Rattoni, Okuda, Roozendaal, & McGaugh, 2005; Lavi, Jacobson, Rosenblum, & Lüthi, 2018), social interactions (Rogers-Carter et al, 2018), gustation (Peng et al, 2015; Wang et al, 2018), drug cravings and malaise (Contreras, Ceric, & Torrealba, 2007), and aversive states such as hunger, thirst, and anxiety (Gehrlach et al, 2019; Livneh et al, 2017, 2020).…”

Section: Introductionmentioning

confidence: 99%

A whole-brain connectivity map of mouse insular cortex

Gehrlach

Gaitanos

Klein

et al. 2020

Preprint

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1The insular cortex (IC) plays key roles in emotional and regulatory brain functions and is 2 affected across psychiatric diseases. However, the brain-wide connections of the mouse IC have 3 not been comprehensively mapped. Here we traced the whole-brain inputs and outputs of the 4 mouse IC across its rostro-caudal extent. We employed cell-type specific monosynaptic rabies 5 virus tracings to characterize afferent connections onto either excitatory or inhibitory IC neurons, 6 and adeno-associated viral tracings to label excitatory efferent axons. While the connectivity 7 between the IC and other cortical regions was highly reciprocal, the IC connectivity with 8 subcortical structures was often unidirectional, revealing prominent top-down and bottom-up 9pathways. The posterior and medial IC exhibited resembling connectivity patterns, while the 10 anterior IC connectivity was distinct, suggesting two major functional compartments. Our results 11 provide insights into the anatomical architecture of the mouse IC and thus a structural basis to 12 guide investigations into its complex functions. 13 50 subdivisions for the two major neuronal subclasses that is excitatory pyramidal neurons and 51 inhibitory interneurons. 52 Results 53 4 Viral tracing approach to reveal the input-output connectivity of the mouse 54 IC 55To map the connectivity of the entire mouse IC, we injected viral tracers into three evenly spaced 56 locations along the rostro-caudal axis with the aim of comprehensively tracing from its entire 57 extent and to assess possible parcellation of the mouse IC into connectivity-based subdomains. 58The most anterior region, aIC ranged from +2.45 mm to +1.20 mm from Bregma; the medial 59 part, mIC, from +1.20 mm to +0.01 mm from Bregma, and the posterior part, pIC, from +0.01 60 mm to -1.22 mm from Bregma (see also Fig. 1c). 61 In order to trace the monosynaptic inputs to the IC we utilized a modified SAD∆G-eGFP(EnvA) 62 rabies virus (RV), which has been shown to label monosynaptic inputs to selected starter cells 63 with high specificity (Wall, Wickersham, Cetin, De La Parra, & Callaway, 2010; Wickersham, 64 Finke, Conzelmann, & Callaway, 2007). This virus lacks the genes coding for the rabies virus 65 glycoprotein (G) and is pseudotyped with the avian viral envelope EnvA. This restricts its 66 infection to neurons expressing the avian TVA receptor and to monosynaptic retrograde infection 67of afferents ( Fig. 1a). We infected the IC of CamKIIα-Cre and GAD2-Cre expressing mouse 68 lines to specifically target TVA and rabies virus glycoprotein expression to excitatory pyramidal 69 or inhibitory interneurons, respectively (see Fig. 1a and Methods). 70 In order to trace and quantify the axonal projections (outputs) of the IC, we injected Cre-71 dependent adeno-associated virus (AAV2/5-DIO-eYFP) into CamKIIα-Cre and GAD2-Cre 72 transgenic mice (see Fig 1b and Methods). We did not observe long-range projections from IC 73 GAD2-Cre tracings (data not shown). Therefore, we here only present outputs from exc...

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“…Furthermore, brain-wide distributed interacting circuit mechanisms could play a role in the formation of single cell plasticity upon associative fear learning, not only in MGB but across multiple fearrelated brain areas (Gehrlach et al, 2019;Herry and Johansen, 2014;Herry et al, 2008;Klavir et al, 2013;Likhtik et al, 2014;Maren et al, 2001;Ozawa et al, 2017;Penzo et al, 2015). The detailed computations within this distributed network (Mobbs et al, 2020) and the role of auditory thalamus are poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Single cell plasticity and population coding stability in auditory thalamus upon associative learning

Taylor

Hasegawa

Benoit

et al. 2020

Preprint

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Cortical and limbic brain areas are regarded as centres for learning. However, how thalamic sensory relays participate in plasticity upon associative learning, yet support stable long-term sensory coding remains unknown. Using a miniature microscope imaging approach, we monitor the activity of populations of auditory thalamus (MGB) neurons in freely moving mice upon fear conditioning. We find that single cells exhibit mixed selectivity and heterogeneous plasticity patterns to auditory and aversive stimuli upon learning, which is conserved in amygdala-projecting MGB neurons. In contrast to individual cells, population level encoding of auditory stimuli remained stable across days. Our data identifies MGB as a site for complex neuronal plasticity in fear learning upstream of the amygdala that is in an ideal position to drive plasticity in cortical and limbic brain areas. These findings suggest that MGB's role goes beyond a sole relay function by balancing experience-dependent, diverse single cell plasticity with consistent ensemble level representations of the sensory environment to support stable auditory perception with minimal affective bias.

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Aversive state processing in the posterior insular cortex

Cited by 243 publications

References 58 publications

Neural circuit mechanism underlying the feeding controlled by insula-central amygdala pathway

Neural circuit mechanism underlying the feeding controlled by insula-central amygdala pathway

A whole-brain connectivity map of mouse insular cortex

Single cell plasticity and population coding stability in auditory thalamus upon associative learning

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