Claustral Neurons Projecting to Frontal Cortex Mediate Contextual Association of Reward

Terem, Anna; Gonzales, Ben J.; Peretz-Rivlin, Noa; Ashwal-Fluss, Reut; Bleistein, Noa; Reus-Garcia, Maria del Mar; Mukherjee, Diptendu; Groysman, Maya; Citri, Ami

doi:10.1016/j.cub.2020.06.064

Cited by 37 publications

(66 citation statements)

References 71 publications

(131 reference statements)

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“…The LHA-VTA-ACB loop has also been implicated in feeding and reward signalling [ 43 ]; however, LHA stimulation was not a common characteristic of the weight-lowering drugs tested. Almost all drugs stimulated the CLA, which receives dopamine inputs and transduces reward-associated signals to the ORB [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Whole-brain activation signatures of weight-lowering drugs

Hansen

Perens

Roostalu

et al. 2021

Molecular Metabolism

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Objective The development of effective anti-obesity therapeutics relies heavily on the ability to target specific brain homeostatic and hedonic mechanisms controlling body weight. To obtain further insight into neurocircuits recruited by anti-obesity drug treatment, the present study aimed to determine whole-brain activation signatures of six different weight-lowering drug classes. Methods Chow-fed C57BL/6J mice (n = 8 per group) received acute treatment with lorcaserin (7 mg/kg; i.p.), rimonabant (10 mg/kg; i.p.), bromocriptine (10 mg/kg; i.p.), sibutramine (10 mg/kg; p.o.), semaglutide (0.04 mg/kg; s.c.) or setmelanotide (4 mg/kg; s.c.). Brains were sampled two hours post-dosing and whole-brain neuronal activation patterns were analysed at single-cell resolution using c-Fos immunohistochemistry and automated quantitative three-dimensional (3D) imaging. Results The whole-brain analysis comprised 308 atlas-defined mouse brain areas. To enable fast and efficient data mining, a web-based 3D imaging data viewer was developed. All weight-lowering drugs demonstrated brain-wide responses with notable similarities in c-Fos expression signatures. Overlapping c-Fos responses were detected in discrete homeostatic and non-homeostatic feeding centres located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures as well as the dopaminergic system. Conclusions Whole-brain c-Fos expression signatures of various weight-lowering drug classes point to a discrete set of brain regions and neurocircuits which could represent key neuroanatomical targets for future anti-obesity therapeutics.

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Section: Discussionmentioning

confidence: 99%

Whole-brain activation signatures of weight-lowering drugs

Hansen

Perens

Roostalu

et al. 2021

Molecular Metabolism

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“…To address the potential role of dorsal striatal assemblies expressing Egr2 in the development of behavioral sensitization to cocaine, we utilized transgenic Egr2-Cre knock-in mice, expressing Cre recombinase under the regulation of the Egr2 promoter (Voiculescu et al, 2000). In these mice, we inhibited the activity of Egr2-expressing neuronal ensembles, by AAV-mediated expression of a CRE-dependent inward-rectifying K + -channel (DIO-Kir2.1) (Atlan et al, 2018; Rothwell et al, 2014; Terem et al, 2020), aiming to transduce a large proportion of the DS. Control mice were transduced with DIO-GFP (DS-Egr2 GFP ) (Figure 1I; infections exhibited a bias for the medial aspect of the striatum; for documentation of sites of infection see Figure 1–figure supplement 5).…”

Section: Resultsmentioning

confidence: 99%

“…Conditioned place preference was assessed in a custom-fitted arena [Plexiglass box (30×30×30 cm)] designed in-house, and placed in individual light- and sound-attenuated chambers [as in (Terem et al, 2020)]. On the preference test days, the arena was divided into two compartments of equal dimensions.…”

Section: Methodsmentioning

confidence: 99%

“…The selective expression of hM4Di enables inhibition of Egr2 + neurons upon administration of CNO (10mg/kg; i.p.) (Atlan et al, 2018;Terem et al, 2020). We then trained mice on a CPP paradigm in which we injected CNO (10 mg/kg) 30 min prior to cocaine training sessions ( Figure 3C).…”

Section: Vls Egr2 Transcriptional Activity Is Necessary For the Develmentioning

confidence: 99%

“…Locomotor activity measured as distance travelled in the open field arena for a period of 15 mins, following either saline/cocaine injections, on each day was quantified by Ethovision (Noldus) software.Conditioned Place Preference -Conditioned place preference was assessed in a custom-fitted arena [Plexiglass box (30×30×30 cm)] designed in-house, and placed in individual light-and sound-attenuated chambers [as in(Terem et al, 2020)]. On the preference test days, the arena was divided into two compartments of equal dimensions.…”

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confidence: 99%

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Egr2 induction in Drd1⁺ ensembles of the ventrolateral striatum supports the development of cocaine reward

Mukherjee

Ashwal-Fluss

et al. 2020

Preprint

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Drug addiction develops due to brain-wide plasticity within neuronal ensembles, mediated by dynamic gene expression. Though the most common approach to identify such ensembles relies on immediate early gene expression, little is known of how the activity of these genes is linked to modified behavior observed following repeated drug exposure. To address this gap, we present a broad-to-specific approach, beginning with a comprehensive investigation of brain-wide cocaine-driven gene expression, through the description of dynamic spatial patterns of gene induction in subregions of the striatum, and finally address functionality of region-specific gene induction in the development of cocaine preference. Our findings reveal differential cell-type specific dynamic transcriptional recruitment patterns within two subdomains of the dorsal striatum following repeated cocaine exposure. Furthermore, we demonstrate that induction of the IEG Egr2 in the ventrolateral striatum, as well as the cells within which it is expressed, are required for the development of cocaine seeking.Impact statementVLS ensembles are dynamically recruited by cocaine experiences to mediate cocaine reward.

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Proteomic Profiling Reveals Specific Molecular Hallmarks of the Pig Claustrum

et al. 2023

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The present study, employing a comparative proteomic approach, analyzes the protein profile of pig claustrum (CLA), putamen (PU), and insula (IN). Pig brain is an interesting model whose key translational features are its similarities with cortical and subcortical structures of human brain. A greater difference in protein spot expression was observed in CLA vs PU as compared to CLA vs IN. The deregulated proteins identified in CLA resulted to be deeply implicated in neurodegenerative (i.e., sirtuin 2, protein disulfide-isomerase 3, transketolase) and psychiatric (i.e., copine 3 and myelin basic protein) disorders in humans. Metascape analysis of differentially expressed proteins in CLA vs PU comparison suggested activation of the α-synuclein pathway and L1 recycling pathway corroborating the involvement of these anatomical structures in neurodegenerative diseases. The expression of calcium/calmodulin-dependent protein kinase and dihydropyrimidinase like 2, which are linked to these pathways, was validated using western blot analysis. Moreover, the protein data set of CLA vs PU comparison was analyzed by Ingenuity Pathways Analysis to obtain a prediction of most significant canonical pathways, upstream regulators, human diseases, and biological functions. Interestingly, inhibition of presenilin 1 (PSEN1) upstream regulator and activation of endocannabinoid neuronal synapse pathway were observed. In conclusion, this is the first study presenting an extensive proteomic analysis of pig CLA in comparison with adjacent areas, IN and PUT. These results reinforce the common origin of CLA and IN and suggest an interesting involvement of CLA in endocannabinoid circuitry, neurodegenerative, and psychiatric disorders in humans.

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Claustral Neurons Projecting to Frontal Cortex Mediate Contextual Association of Reward

Cited by 37 publications

References 71 publications

Whole-brain activation signatures of weight-lowering drugs

Whole-brain activation signatures of weight-lowering drugs

Egr2 induction in Drd1⁺ ensembles of the ventrolateral striatum supports the development of cocaine reward

Proteomic Profiling Reveals Specific Molecular Hallmarks of the Pig Claustrum

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Claustral Neurons Projecting to Frontal Cortex Mediate Contextual Association of Reward

Cited by 37 publications

References 71 publications

Whole-brain activation signatures of weight-lowering drugs

Whole-brain activation signatures of weight-lowering drugs

Egr2 induction in Drd1+ ensembles of the ventrolateral striatum supports the development of cocaine reward

Proteomic Profiling Reveals Specific Molecular Hallmarks of the Pig Claustrum

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Egr2 induction in Drd1⁺ ensembles of the ventrolateral striatum supports the development of cocaine reward