Genetic mapping identifies Homer1 as a developmental modifier of attention.
| العنوان: | Genetic mapping identifies Homer1 as a developmental modifier of attention. |
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| المؤلفون: | Gershon Z; Laboratory of Neural Dynamics & Cognition, Rockefeller University; New York, NY 10065 USA., Bonito-Oliva A; Laboratory of Neural Dynamics & Cognition, Rockefeller University; New York, NY 10065 USA., Kanke M; Department of Biomedical Sciences, Cornell University; Ithaca, NY 14853 USA., Terceros A; Laboratory of Neural Dynamics & Cognition, Rockefeller University; New York, NY 10065 USA., Rankin G; Laboratory of Neural Dynamics & Cognition, Rockefeller University; New York, NY 10065 USA., Fak J; Laboratory of Neural Dynamics & Cognition, Rockefeller University; New York, NY 10065 USA., Harada Y; Laboratory of Neural Dynamics & Cognition, Rockefeller University; New York, NY 10065 USA., Iannone AF; Feil Family Brain and Mind Research Institute, Weill Cornell; New York, NY 10021, USA., Gebremedhin M; Laboratory of Neural Dynamics & Cognition, Rockefeller University; New York, NY 10065 USA., Fabella B; Laboratory of Sensory Neuroscience, The Rockefeller University; New York, NY 10065, USA., De Marco Garcia NV; Feil Family Brain and Mind Research Institute, Weill Cornell; New York, NY 10021, USA., Sethupathy P; Department of Biomedical Sciences, Cornell University; Ithaca, NY 14853 USA., Rajasethupathy P; Laboratory of Neural Dynamics & Cognition, Rockefeller University; New York, NY 10065 USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 28. Date of Electronic Publication: 2024 Feb 28. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Attention is required for most higher-order cognitive functions. Prior studies have revealed functional roles for the prefrontal cortex and its extended circuits to enabling attention, but the underlying molecular processes and their impacts on cellular and circuit function remain poorly understood. To develop insights, we here took an unbiased forward genetics approach to identify single genes of large effect on attention. We studied 200 genetically diverse mice on measures of pre-attentive processing and through genetic mapping identified a small locus on chromosome 13 (95%CI: 92.22-94.09 Mb) driving substantial variation (19%) in this trait. Further characterization of the locus revealed a causative gene, Homer1, encoding a synaptic protein, where down-regulation of its short isoforms in prefrontal cortex (PFC) during early postnatal development led to improvements in multiple measures of attention in the adult. Subsequent mechanistic studies revealed that prefrontal Homer1 down-regulation is associated with GABAergic receptor up-regulation in those same cells. This enhanced inhibitory influence, together with dynamic neuromodulatory coupling, led to strikingly low PFC activity at baseline periods of the task but targeted elevations at cue onset, predicting short-latency correct choices. Notably high- Homer1 , low-attentional performers, exhibited uniformly elevated PFC activity throughout the task. We thus identify a single gene of large effect on attention - Homer1 - and find that it improves prefrontal inhibitory tone and signal-to-noise (SNR) to enhance attentional performance. A therapeutic strategy focused on reducing prefrontal activity and increasing SNR, rather than uniformly elevating PFC activity, may complement the use of stimulants to improve attention. Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests. |
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| معلومات مُعتمدة: | DP2 AG058487 United States AG NIA NIH HHS; R01 MH110553 United States MH NIMH NIH HHS; T32 GM007739 United States GM NIGMS NIH HHS |
| تواريخ الأحداث: | Date Created: 20230330 Latest Revision: 20240307 |
| رمز التحديث: | 20240307 |
| مُعرف محوري في PubMed: | PMC10055164 |
| DOI: | 10.1101/2023.03.17.533136 |
| PMID: | 36993710 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.03.17.533136 |
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