Adolescent isolation disrupts medial amygdala and ventral tegmental area maturation and sex-specifically dysregulates transcriptional responses to cocaine and stress.
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| Titel: | Adolescent isolation disrupts medial amygdala and ventral tegmental area maturation and sex-specifically dysregulates transcriptional responses to cocaine and stress. |
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| Autoren: | Andrus MD; Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd, Mail Code: L470, Portland, OR, 97239, USA., Vu T; Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd, Mail Code: L470, Portland, OR, 97239, USA., Juarez B; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA., Walker DM; Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd, Mail Code: L470, Portland, OR, 97239, USA. Electronic address: walkerde@ohsu.edu. |
| Quelle: | Neuropharmacology [Neuropharmacology] 2025 Nov 15; Vol. 279, pp. 110629. Date of Electronic Publication: 2025 Aug 12. |
| Publikationsart: | Journal Article |
| Sprache: | English |
| Info zur Zeitschrift: | Publisher: Pergamon Press Country of Publication: England NLM ID: 0236217 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7064 (Electronic) Linking ISSN: 00283908 NLM ISO Abbreviation: Neuropharmacology Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Pergamon Press Original Publication: Oxford, New York, Pergamon. |
| MeSH-Schlagworte: | Ventral Tegmental Area*/drug effects , Ventral Tegmental Area*/growth & development , Ventral Tegmental Area*/metabolism , Cocaine*/pharmacology , Sex Characteristics* , Stress, Psychological*/metabolism , Social Isolation*/psychology , Corticomedial Nuclear Complex*/drug effects , Corticomedial Nuclear Complex*/metabolism , Corticomedial Nuclear Complex*/growth & development , Dopamine Uptake Inhibitors*/pharmacology, Animals ; Male ; Female ; Mice, Inbred C57BL ; Mice ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics ; Receptors, Dopamine D2/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism |
| Abstract: | Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Deena Walker reports financial support was provided by National Institute on Drug Abuse, The Medical Research Foundation of Oregon, and The Center for Women's Health Circle of Giving at OHSU. Barbara Juarez reports financial support was provided by National Institute on Drug Abuse. Mason Andus reports financial support was provided by National Institute on Drug Abuse. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Adolescence is a sensitive developmental period marked by immense social and neural changes during which stressful experiences are associated with susceptibility to neuropsychiatric disorders. The medial amygdala (meA) is especially sensitive to the persistent transcriptional effects of adolescent social isolation. Although critical for social reward, the meA is generally considered to be outside the canonical reward circuitry; however, tracing studies reveal extensive connectivity of the meA with reward circuitry. Here, we show that cocaine-responsive transcriptional concordance is disrupted between the meA and ventral tegmental area (VTA) but not other regions of the mesocorticolimbic reward circuitry by adolescent isolation. This loss of concordance is driven by sex-specific differences in stimulus- and cocaine-responsive gene transcription within and between meA-VTA. We use retrograde tracing techniques to show that these effects are not due to differences in meA-VTA connectivity, nor are they due to differences in dopamine neuronal firing rate in the VTA. Finally, we find that adolescent isolation induced sex-specific disruption of maturational profiles of glutamatergic signaling genes in the meA and VTA. In the meA, isolation increased gene expression of glutamatergic markers Camk2b and Slc17a7 in females, but decreased expression of Camk2a and Camk2b in males. In the VTA, isolation increases expression of NMDA receptor subunits Grin1 and Grin2b in females, while reducing Grin1 and increasing dopamine receptor Drd2 expression in males. These findings establish an integral role of a meA-VTA circuit in the etiology and expression of features of adolescent-onset neuropsychiatric disruptions. (Copyright © 2025 Elsevier Ltd. All rights reserved.) |
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| Grant Information: | K99 DA054265 United States DA NIDA NIH HHS; T32 DA007262 United States DA NIDA NIH HHS; P01 DA047233 United States DA NIDA NIH HHS; R00 DA042100 United States DA NIDA NIH HHS; R00 DA054265 United States DA NIDA NIH HHS; R01 DA014133 United States DA NIDA NIH HHS; K99 DA042100 United States DA NIDA NIH HHS |
| Contributed Indexing: | Keywords: Adolescence; Cocaine; Dopamine; Gene transcription; RNA-Sequencing; Social isolation; Substance use disorder |
| Substance Nomenclature: | I5Y540LHVR (Cocaine) 0 (Dopamine Uptake Inhibitors) EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) 0 (Receptors, Dopamine D2) 0 (Receptors, N-Methyl-D-Aspartate) |
| Entry Date(s): | Date Created: 20250814 Date Completed: 20250905 Latest Revision: 20250926 |
| Update Code: | 20250926 |
| PubMed Central ID: | PMC12452784 |
| DOI: | 10.1016/j.neuropharm.2025.110629 |
| PMID: | 40812510 |
| Datenbank: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstract: | Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Deena Walker reports financial support was provided by National Institute on Drug Abuse, The Medical Research Foundation of Oregon, and The Center for Women's Health Circle of Giving at OHSU. Barbara Juarez reports financial support was provided by National Institute on Drug Abuse. Mason Andus reports financial support was provided by National Institute on Drug Abuse. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br />Adolescence is a sensitive developmental period marked by immense social and neural changes during which stressful experiences are associated with susceptibility to neuropsychiatric disorders. The medial amygdala (meA) is especially sensitive to the persistent transcriptional effects of adolescent social isolation. Although critical for social reward, the meA is generally considered to be outside the canonical reward circuitry; however, tracing studies reveal extensive connectivity of the meA with reward circuitry. Here, we show that cocaine-responsive transcriptional concordance is disrupted between the meA and ventral tegmental area (VTA) but not other regions of the mesocorticolimbic reward circuitry by adolescent isolation. This loss of concordance is driven by sex-specific differences in stimulus- and cocaine-responsive gene transcription within and between meA-VTA. We use retrograde tracing techniques to show that these effects are not due to differences in meA-VTA connectivity, nor are they due to differences in dopamine neuronal firing rate in the VTA. Finally, we find that adolescent isolation induced sex-specific disruption of maturational profiles of glutamatergic signaling genes in the meA and VTA. In the meA, isolation increased gene expression of glutamatergic markers Camk2b and Slc17a7 in females, but decreased expression of Camk2a and Camk2b in males. In the VTA, isolation increases expression of NMDA receptor subunits Grin1 and Grin2b in females, while reducing Grin1 and increasing dopamine receptor Drd2 expression in males. These findings establish an integral role of a meA-VTA circuit in the etiology and expression of features of adolescent-onset neuropsychiatric disruptions.<br /> (Copyright © 2025 Elsevier Ltd. All rights reserved.) |
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| ISSN: | 1873-7064 |
| DOI: | 10.1016/j.neuropharm.2025.110629 |